Patent Publication Number: US-2022211700-A1

Title: Methods for Objective Assessment of Memory, Early Detection of Risk for Alzheimer&#39;s Disease, Matching Individuals With Treatments, Monitoring Response to Treatment, and New Methods of Use for Drugs

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application claims priority to U.S. Provisional Application No. 62/852,081 filed on May 23, 2019. This application is incorporated herein by reference in its entirety for all purposes. 
    
    
     STATEMENT OF GOVERNMENT SUPPORT 
     This invention was made with government support under OD007363 awarded by the National Institutes of Health and CX000139 merit award by the Veterans Administration. The government may have rights in the invention. 
    
    
     BACKGROUND 
     Alzheimer&#39;s disease is a clear and present danger to older adults, and has a profound socio-economic impact. Existing therapies are limited in efficacy. Early identification of subjects at risk may open the door to preventive approaches. Short-term memory dysfunction is a key early feature of Alzheimer&#39;s disease. Psychiatric patients may be at higher risk for memory dysfunction and subsequent Alzheimer&#39;s disease due to the negative effects of stress and depression on the brain. 
     Existing drugs have potential utility in other diseases and disorders. Biomarkers can serve as companion diagnostics for clinical trials for the development of new medications and also for repurposing existing drugs for other diseases and disorders. 
     Accordingly, methods are needed for early identification of memory dysfunction and Alzheimer&#39;s disease. Additionally, methods are needed for identifying and repurposing existing drugs and natural compounds for use as treatments of other disorders and diseases. 
     SUMMARY 
     The present disclosure is generally directed at methods for assessing memory dysfunction and early identification/prediction of risk for future memory dysfunction, Alzheimer&#39;s disease and cognitive decline, using computer assisted methods that derive scores based on biomarker data, in some instances blood biomarker data. Further, the present disclosure relates to methods for matching individuals with drugs to reduce the risk of and mitigate memory dysfunction, Alzheimer&#39;s disease and cognitive decline, and methods for monitoring response to treatment. Finally, the invention relates to new methods of use for candidate drugs and natural compounds repurposed for treating memory dysfunction, Alzheimer&#39;s disease and cognitive decline. All the above-mentioned methods may include computer-assisted methods that generate scores based on analyses of the expression of panels of genes, clinical measures, and drug databases. A universal approach in everybody, as well as a personalized approach by gender, and by diagnosis, are disclosed. 
     In one aspect, the present disclosure is directed to a method for identifying a biomarker for Alzheimer&#39;s disease, the method comprising: obtaining a first biological sample from a subject and administering a first memory test to the subject; obtaining a second biological sample from the subject and administering a second memory test to the subject; identifying a first cohort of subjects by identifying subjects having about 20% change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test; identifying candidate biomarkers in the first cohort by identifying biomarkers having a change in expression. 
     In one aspect, the present disclosure is directed to a method to reduce the risk of and mitigate memory dysfunction, Alzheimer&#39;s disease, and cognitive decline in a subject in need thereof, the method comprising administering a therapy to the subject, the therapy being selected from the group consisting of one or more compounds from Tables 5A1-A5, and 5B1-B5, and 5C1-C2. 
     In one aspect, the present disclosure is directed to a computer-implemented method for assessing a low memory state in a subject, and for assessing risk of future Alzheimer Disease and cognitive decline in a subject, the method comprising: computing a score based on RNA level, protein level, DNA methylation, a single nucleotide polymorphism, a panel of at least one biomarker in one of Table 2, Table 4A and Table 4B, and combinations thereof in a sample obtained from a subject; computing a score based on a reference expression level of the panel of biomarkers; and identifying a difference between the score in the sample obtained from the subject and the score in the reference sample, wherein the difference in the score in the sample obtained from the subject and the score in the reference sample indicates a risk for a low memory state in the subject. In other aspects, the present disclosure is directed to a method for assessing and mitigating memory dysfunction, Alzheimer&#39;s disease, and cognitive decline in a subject in need thereof, comprising determining an expression level of a panel of biomarkers listed in Table 2, Table 4, or Table 5 in a sample, wherein the expression level of the biomarkers in the sample is different relative to a reference expression level, identifying the subject currently having or at risk of having in the future memory dysfunction, Alzheimer&#39;s disease, and cognitive decline based on a biomarker panel score relative to a biomarker panel score of a reference; and administering to the subject a therapy being selected based on the score from the group consisting of one or more compounds from Tables 5A1-A5, and 5B1-B5, and 5C1-C2. 
     In some aspects, of the disclosed methods, the therapy is lithium, an antidepressant, pioglitazone, sulfadimidine, SB-203580, mesalazine, metamizole, levonorgestrel, meglumine, lymecycline, rimexolone, ketanserin, quipazine, cisapride, proparacaine, tenoxicam, bexarotene, an omega-3 fatty acid, salsolidine, ginkgolide A, icariin, docosahexaenoic acid, or combinations thereof. 
     In some aspects, the sample comprises a peripheral tissue, blood, saliva, cerebrospinal fluid (CSF), serum, urine, or stool. 
     In other aspects, the present disclosure is directed to a composition comprising one or more compounds from Tables 5A1-A5, and 5B1-B5, and 5C1-C2 for use in a method for treating memory dysfunction, Alzheimer&#39;s disease, and cognitive decline. 
     In some aspects, the compound comprises lithium, an antidepressant, pioglitazone, sulfadimidine, SB-203580, mesalazine, metamizole, levonorgestrel, meglumine, lymecycline, rimexolone, ketanserin, quipazine, cisapride, proparacaine, tenoxicam, bexarotene, an omega-3 fatty acid, salsolidine, ginkgolide A, icariin, docosahexaenoic acid, or combinations thereof. In some aspects, the compound comprises one or more of the compounds from Tables 5A1-A5, and 5B1-B5, and 5C1-C2. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIGS. 1A-1C  are illustrations depicting the methods described in the present disclosure.  FIG. 1A  depicts the cohorts used in study, depicting flow of discovery, prioritization, and testing of biomarkers.  FIG. 1B  depicts the differential gene expression in the discovery cohort-number of genes identified with differential expression (DE) and absent-present (AP) methods with an internal score of 2 and above. In  FIG. 1C , the pyramid on the left depicts the number of discovery step probesets, identified based on their score for tracking memory, with a maximum of internal points of 6 (33% (2 pt), 50% (4 pt) and 80% (6 pt)), and the pyramid on the right depicts prioritization with CFG for prior evidence of involvement in AD. 
         FIG. 2  is a schematic illustrating the interaction networks for top candidate biomarkers (n=111 top genes, 136 probe sets). 
         FIGS. 3A and 3B  are graphs depicting the best single biomarkers for predictors of state (low memory retention state) ( FIG. 3A ) and trait (future neuropsychosis) ( FIG. 3B ). Bold—top CFG scoring biomarkers on the list (CFG≥12, n=21 probe sets). Bar graph shows best predictive biomarkers in each group. *Nominally significant p&lt;0.05. Table underneath the figures displays the actual number of biomarkers for each group whose ROC AUC p-values ( FIG. 3A ) and Cox Regression Odds Ratio p-values ( FIG. 3B ) are at least nominally significant. Some female diagnostic groups were not shown in the graph as they did not have subjects to be tested or any significant biomarkers. Cross-sectional was based on levels at one visit. Longitudinal was based on levels at multiple visits (integrates levels at most recent visit, maximum levels, slope into most recent visit, and maximum slope). Dividing lines represent the cutoffs for a test performing at chance levels (white), and at the same level as the best biomarkers for all subjects in cross-sectional (gray) and longitudinal (black) based predictions. All biomarkers performed better than chance. Biomarkers performed better when personalized by gender and diagnosis. 
         FIGS. 4A and 4B  are graphs depicting RHEB as a possible personalized biomarker predictor for risk of future AD in Males with Schizophrenia. Subject Phchp098 was a male with schizophrenia (SZ) tested in 2009. He was first diagnosed with paranoid schizophrenia in 1977. In 2016, he was also diagnosed by neuropsychological testing with ADRD and impaired decision-making capacity. At that time, he was 66 years old. Subject was the only one so far with an ADRD diagnosis in the independent replication follow-up cohort. RHEB levels were Z-scored by gender and diagnosis. Subject Phchp098 had the highest levels of RHEB in testing from all the subjects with future neuropsychological testing ( FIG. 4A ), and in fact the highest level of RHEB from all the 111 subjects in that cohort ( FIG. 4B ). 
         FIG. 5  is a schematic illustrating the pharmacogenomics of the top biomarkers modulated by existing drugs. 
         FIG. 6  is a schematic diagram depicting the matching of patients to drugs, the pharmacogenomics. 
     
    
    
     DETAILED DESCRIPTION 
     Disclosed are methods for identifying biomarkers for memory dysfunction and early identification of Alzheimer&#39;s disease. Also disclosed are methods using biomarker expression levels for identifying and treating one or more populations or subpopulations for reducing risk of and mitigating memory dysfunction, Alzheimer&#39;s disease, and cognitive decline. Further, the present disclosure relates to methods for identifying candidate drugs and natural compounds repurposed for treating memory dysfunction, Alzheimer&#39;s disease and cognitive decline. The methods are useful for early detection of Alzheimer&#39;s disease in subjects and identifying existing drugs and natural compounds that can be repurposed for treating subjects for memory dysfunction, Alzheimer&#39;s disease and cognitive decline. 
     In one aspect, the present disclosure is directed to a method for identifying a one or more biomarker(s) for Alzheimer&#39;s disease, the method comprising: obtaining a first biological sample from a subject and administering a first memory test to the subject; obtaining a second biological sample from the subject and administering a second memory test to the subject; identifying a first cohort of subjects by identifying subjects having about 20% change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test; identifying candidate biomarker(s) in the first cohort by identifying biomarkers having a change in expression. 
     The method can further include prioritizing the candidate biomarkers by identifying candidate biomarkers known to be associated with Alzheimer&#39;s disease. 
     A suitable memory test is Hopkins Verbal Learning Test-Revised (HVLT-R). Suitable subjects include those having a psychiatric disorder. Suitable subjects can be male subjects and female subjects. 
     As used herein, “sample” or “biological sample” refers to the sample from which biomarkers are measured. In some embodiments, the sample is blood. In some embodiments, the sample can be saliva, cerebrospinal fluid (CSF), serum, urine, stool, and/or another bodily fluid. In some embodiments, the sample is a peripheral tissue. 
     As used herein, “expression level of a biomarker” refers to the process by which a gene product is synthesized from a gene encoding the biomarker as known by those skilled in the art. The gene product can be, for example, RNA (ribonucleic acid) and protein. Expression level can be quantitatively measured by methods known by those skilled in the art such as, for example, northern blotting, amplification, polymerase chain reaction, microarray analysis, tag-based technologies (e.g., serial analysis of gene expression and next generation sequencing such as whole transcriptome shotgun sequencing or RNA-Seq), Western blotting, enzyme linked immunosorbent assay (ELISA), and combinations thereof. In some embodiments, the biomarker is a polymorphic biomarker profile. In some embodiments, the polymorphic biomarker profile includes one or more single nucleotide polymorphisms (SNPs), one or more restriction fragment length polymorphisms (RFLPs), one or more short tandem repeats (STRs), one or more variable number of tandem repeats (VNTRs), one or more hypervariable regions, one or more minisatellites, one or more dinucleotide repeats, one or more trinucleotide repeats, one or more tetranucleotide repeats, one or more simple sequence repeats, or one or more insertion elements. In some embodiments, the methods further include establishing a profile of biomarkers. 
     As used herein, “a reference expression level of a biomarker” refers to the expression level of a biomarker established for a subject with no known memory dysfunction, Alzheimer&#39;s disease and cognitive decline, expression level of a biomarker in a normal/healthy subject with no known memory dysfunction, Alzheimer&#39;s disease and cognitive decline as determined by one skilled in the art using established methods as described herein, and/or a known expression level of a biomarker obtained from literature. The reference expression level of the biomarker can further refer to the expression level of the biomarker established for a high risk subject for memory dysfunction, Alzheimer&#39;s disease and cognitive decline, including a population of high risk subjects. The reference expression level of the biomarker can also refer to the expression level of the biomarker established for a low risk memory dysfunction, Alzheimer&#39;s disease and cognitive decline subject, including a population of low risk subjects. The reference expression level of the biomarker can also refer to the expression level of the biomarker established for any combination of subjects such as a subject with no known memory dysfunction, Alzheimer&#39;s disease and cognitive decline, expression level of the biomarker in a normal/healthy subject with no known memory dysfunction, Alzheimer&#39;s disease and cognitive decline, expression level of the biomarker for a subject who has no memory dysfunction, Alzheimer&#39;s disease and cognitive decline at the time the sample is obtained from the subject, but who later exhibits memory dysfunction, Alzheimer&#39;s disease and cognitive decline. For example, depending on the biomarker(s) selected, the difference in the expression level of the biomarker(s) can indicate an increased (greater) risk that a subject will develop symptoms consistent with memory dysfunction, Alzheimer&#39;s disease and cognitive decline. Conversely, depending on the biomarker(s) selected, the difference in the expression level of the biomarker(s) can indicate a decreased (lower) risk that a subject will develop symptoms with or memory dysfunction, Alzheimer&#39;s disease and cognitive decline. 
     In some embodiments, the methods can further include genotyping the subject. The genotyping can be performed by methods such as sequencing, nucleic acid array and PCR. The nucleic acid can be double-stranded DNA, single-stranded DNA, single-stranded DNA hairpins, DNA/RNA hybrids, RNA, RNA hairpins and cDNA. The presence or absence of the one or more nucleic acids can be determined by sequencing, nucleic acid array and PCR. Suitable nucleic acid arrays include DNA arrays such as, for example polymorphism arrays. Suitable polymorphism arrays include SNP arrays, for example. 
     In one aspect, the present disclosure is directed to a method for identifying a subject suspected of having Alzheimer&#39;s disease, the method comprising: obtaining a first biological sample from a subject; obtaining a second biological sample from the subject; and identifying the subject by identifying a change in expression of at least one of RAB7A, NPC2, TGFB1, GAP43, ARSB, PERI, GUSB, MAPT, FCGR1A, UBE2L3, NKTR, RHEB, PTGS2, RGS10, ITPKB, KIDINS220, GSK3B, SERTAD3, APOE, UBE2I, FOXO3, THRA, IGF1, NPTX2, GSTM3, BACE1, PSEN1, GFAP, TREM2, NOCT, CEP350, PPP2R2B, NRP2, CTSS, VEGFA, and combinations thereof. 
     The method can further include administering a memory test to the subject when the first biological sample is obtained from the subject and administering the memory test to the subject when the second biological sample is obtained from the subject; and determining a change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test. Suitably, the memory test is Hopkins Verbal Learning Test-Revised (HVLT-R). The HVLT-R can be used to determine a ‘Low Memory Retention’, which as used herein, can also be called ‘Low Memory State’ or ‘Low Memory Retention state’ or ‘Memory Retention measure.’ Suitably, the subject can have about 20% change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test. 
     Suitable subjects include those having a psychiatric disorder. Suitable subjects can be male subjects and female subjects. 
     Suitable subjects include subjects over 21 years old. 
     In one aspect, the present disclosure is directed to a method of prophylactically treating a subject for Alzheimer&#39;s Disease, the method comprising: obtaining a first biological sample from a subject; obtaining a second biological sample from the subject; and identifying a change in expression of at least one of RAB7A, NPC2, TGFB1, GAP43, ARSB, PERI, GUSB, MAPT, FCGR1A, UBE2L3, NKTR, RHEB, PTGS2, RGS10, ITPKB, KIDINS220, GSK3B, SERTAD3, APOE, UBE2I, FOXO3, THRA, IGF1, NPTX2, GSTM3, BACE1, PSEN1, GFAP, TREM2, NOCT, CEP350, PPP2R2B, NRP2, CTSS, VEGFA, and combinations thereof; identifying a difference between the expression level of the at least one of RAB7A, NPC2, TGFB1, GAP43, ARSB, PERI, GUSB, MAPT, FCGR1A, UBE2L3, NKTR, RHEB, PTGS2, RGS10, ITPKB, KIDINS220, GSK3B, SERTAD3, APOE, UBE2I, FOXO3, THRA, IGF1, NPTX2, GSTM3, BACE1, PSEN1, GFAP, TREM2, NOCT, CEP350, PPP2R2B, NRP2, CTSS, VEGFA, and combinations thereof, and a reference expression level of at least one of RAB7A, NPC2, TGFB1, GAP43, ARSB, PERI, GUSB, MAPT, FCGR1A, UBE2L3, NKTR, RHEB, PTGS2, RGS10, ITPKB, KIDINS220, GSK3B, SERTAD3, APOE, UBE2I, FOXO3, THRA, IGF1, NPTX2, GSTM3, BACE1, PSEN1, GFAP, TREM2, NOCT, CEP350, PPP2R2B, NRP2, CTSS, VEGFA, and combinations thereof; and administering a therapy to the subject. 
     Suitable therapies can include a drug, a natural compound, and combinations thereof. Suitable drugs can include lithium, an antidepressant, pioglitazone, levonorgestrel, and bexarotene, for example. Suitable natural compounds can include omega-3 fatty acid (e.g., docosahexaenoic acid), salsolidine, ginkgolide A, and icariin, for example. 
     In one aspect, the present disclosure is directed to a method for identifying a biomarker (e.g., a blood biomarker) for short-term memory dysfunction, the method comprising: obtaining a first biological sample from a subject and administering a first memory test to the subject; obtaining a second biological sample from the subject and administering a second memory test to the subject; identifying a first cohort of subjects by identifying subjects having about 20% change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test; identifying candidate biomarkers in the first cohort by identifying biomarkers having a change in expression; and prioritizing the candidate biomarkers by identifying candidate biomarkers known to be associated with short-term memory. 
     The can further include prioritizing the candidate biomarkers by identifying candidate biomarkers known to be associated with short-term memory. 
     A suitable memory test is Hopkins Verbal Learning Test-Revised (HVLT-R). 
     Suitable subjects include those having a psychiatric disorder. Suitable subjects can be male subjects and female subjects. 
     In one aspect, the present disclosure is directed to a method for identifying a drug candidate for repurposing for use in treating Alzheimer&#39;s disease, the method comprising: obtaining a first biological sample from a subject and administering a first memory test to the subject; obtaining a second biological sample from the subject and administering a second memory test to the subject; identifying a first cohort of subjects by identifying subjects having about 20% change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test; identifying a candidate biomarker in the first cohort by identifying a biomarker having a change in expression; identifying a drug having an effect on the biomarker; and identifying the drug as a candidate for treating Alzheimer&#39;s disease. 
     Suitable drugs include those that reduce the activity of the biomarker. Other suitable drugs include those that increases the activity of the biomarker. 
     The biomarker is at least one of RAB7A, NPC2, TGFB1, GAP43, ARSB, PERI, GUSB, MAPT, FCGR1A, UBE2L3, NKTR, RHEB, PTGS2, RGS10, ITPKB, KIDINS220, GSK3B, SERTAD3, APOE, UBE2I, FOXO3, THRA, IGF1, NPTX2, GSTM3, BACE1, PSEN1, GFAP, TREM2, NOCT, CEP350, PPP2R2B, NRP2, CTSS, VEGFA, and combinations thereof. 
     In one aspect, the present disclosure is directed to a method for identifying a subject having or at risk for having cognitive decline, the method comprising: obtaining a first biological sample from a subject and administering a first memory test to the subject; obtaining a second biological sample from the subject and administering a second memory test to the subject; identifying a first cohort of subjects by identifying subjects having about 20% change in a memory retention characteristic as determined by a difference between the first memory test and the second memory test; identifying candidate biomarkers in the first cohort by identifying biomarkers having a change in expression; and prioritizing the candidate biomarkers by identifying candidate biomarkers known to be associated with cognitive decline. 
     The method can further include prioritizing the candidate biomarkers by identifying candidate biomarkers known to be associated with cognitive decline. 
     A suitable memory test is Hopkins Verbal Learning Test-Revised (HVLT-R). 
     In one embodiment, the subject also has a psychiatric disorder. 
     Suitable subjects are male subjects and female subjects. 
     The cognitive decline can be cognitive impairment dysfunction, mild cognitive impairment, and dementia. 
     In one aspect, the present disclosure is directed to a method of prophylactically treating a subject for cognitive decline, the method comprising: obtaining a first biological sample from a subject; obtaining a second biological sample from the subject; and identifying a change in expression of at least one of RAB7A, NPC2, TGFB1, GAP43, ARSB, PERI, GUSB, MAPT, FCGR1A, UBE2L3, NKTR, RHEB, PTGS2, RGS10, ITPKB, KIDINS220, GSK3B, SERTAD3, APOE, UBE2I, FOXO3, THRA, IGF1, NPTX2, GSTM3, BACE1, PSEN1, GFAP, TREM2, NOCT, CEP350, PPP2R2B, NRP2, CTSS, VEGFA, and combinations thereof; and administering a therapy to the subject. 
     Suitable therapies include drugs, natural compounds, and combinations thereof. In one embodiment, the subject can also have a psychiatric disorder. In s 
     Suitable subjects are male subjects and female subjects. 
     The cognitive decline is cognitive impairment dysfunction, mild cognitive impairment, and dementia. 
     The method can further include obtaining a memory impairment score from the subject by administering a memory impairment screening test to the subject. A suitable memory test is Hopkins Verbal Learning Test-Revised (HVLT-R). 
     In some embodiments, the method includes converting the Z-scored expression value of each biomarker into a numeric score of 1, 0.5 or 0, depending if the biomarker&#39;s expression is in the high-risk range, intermediate risk range, or low risk range, based on the reference expression values for the particular biomarker. In some instances, this score is multiplied by the biomarker&#39;s CFE (Convergent Functional Evidence) score, which serves as a weight, as not all biomarkers are equally important. See such CFE scores in Table 2. In some instances, the resulting value is then divided by the maximum possible CFE score for that particular biomarker, yielding a weighted score. In some instances, the weighted scores are added for all the biomarkers in the panel, and divided by the number of markers in the panel. In some instances, the panel score is multiplied by 100 to generate a value between 0 and 100, which can be compared to a reference score. 
     In some embodiments, for each biomarker in the panel, a list of existing psychiatric medications that modulate the expression of the biomarker in the direction of high memory can be identified bioinformatically. In some instances, each such medication can be given a score commensurate with the biomarker score, i.e. 1 or 0.5 or 0. In some instances, such a medication can modulate more than one biomarker. In some intances, an average score for each medication can be calculated based on its effects on the biomarkers in the panel, and multiplied that by 100, resulting in a score of 0 to 100 for each medication. In some embodiments, psychiatric medications can be matched to the expression of biomarkers in a particular patient and ranked in order of impact on the panel. 
     In some embodiments, large drug gene expression databases such as Connectivity Map and NIH LINCS can be interrogated, as related to particular biomarkers that are positive as high risk in the panel in a particular patient. In some instances, this can lead to an individualized drug repurposing, identifying and ranking for fit using a score. As such, a new method of use for non-psychiatric medications and nutraceuticals can be identified and used in a particular patient to reduce risk and mitigate memory dysfunction, Alzheimer&#39;s Disease and cognitive decline. 
     EXAMPLES 
     Materials and Methods 
     Two independent cohorts of psychiatric disorders patients, one for Discovery of candidate biomarkers, and one for Testing of top biomarkers (for predicting memory state, and predicting future positive neuropsychological testing for cognitive impairment) were used ( FIG. 1 , Table 1). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Aggregate demographics. Cohorts used in study. 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 Number 
                   
                   
                   
                   
                   
                 Age in years at 
                   
               
               
                   
                 of 
                   
                   
                   
                   
                   
                 time of lab visit 
                   
               
               
                   
                 subjects 
                   
                   
                   
                   
                   
                 Mean 
                   
               
               
                   
                 (number 
                   
                   
                   
                   
                   
                 (SD) 
                 T-test for age at 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Cohorts 
                 of visits) 
                 Gender 
                 Diagnosis 
                 Ethnicity 
                 (Range) 
                 time of lab visit 
               
               
                   
               
            
           
           
               
            
               
                 Discovery 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Discovery Cohort 
                 159 
                 Male =  
                 131 (414) 
                 BP =  
                 52 (187) 
                 EA =  
                 107 (347) 
                 50.26 
                   
               
               
                 (Within-Subject 
                 (with 
                 Female =  
                 28 (82) 
                 MDD =  
                 23 (64) 
                 AA =  
                 47 (135) 
                 (8.97) 
                   
               
               
                 Changes in  
                 496 
                   
                   
                 SZA =  
                 35 (97) 
                 Asian =  
                 1 (2) 
                 (22-66) 
                   
               
               
                 Memory 
                 visits) 
                   
                   
                 SZ =  
                 27 (82) 
                 Hispanic =  
                 3 (9) 
                   
                   
               
               
                 Retention) 
                   
                   
                   
                 PTSD =  
                 14 (43)  
                 Biracial =  
                 1 (3) 
                   
                   
               
               
                   
                   
                   
                   
                 MOOD =  
                 5 (14) 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 PSYCH =  
                 3 (9) 
                   
                   
                   
                   
               
            
           
           
               
            
               
                 Testing 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Independent 
                 127 
                 Male =  
                 97 (176) 
                 BP =  
                 37 (73) 
                 EA =  
                 86 (162) 
                 50.48 
                 Low Memory 
               
               
                 Testing Cohort 
                 (238  
                 Female =  
                 30 (62) 
                 MDD =  
                 24 (48) 
                 AA =  
                 40 (73) 
                 (8.2)  
                 Retention (n = 68) vs. 
               
               
                 For Predicting 
                 visits) 
                   
                   
                 SZA =  
                 27 (48) 
                 Asian =  
                 1 (3) 
                 (23-74) 
                 Others (n = 170) 
               
               
                 State (Low  
                   
                   
                   
                 SZ =  
                 23 (42) 
                   
                   
                 Low Memory 
                 0.703983 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Memory 
                   
                   
                   
                 PTSD =  
                 12 (20) 
                   
                   
                 Retention =  
                 50.9 (10.9) 
                   
               
               
                 Retention ≤40  
                   
                   
                   
                 MOOD =  
                 2 (5) 
                   
                   
                 Others =  
                 50.32 (6.83) 
                   
               
               
                 at Time of 
                   
                   
                   
                 PSYCH =  
                 2 (2 
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Assessment) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Independent 
                  56 
                 Male =  
                 47 (91) 
                 BP =  
                 11 (23) 
                 EA =  
                 33 (64) 
                 55.6  
                 Future Positive 
               
               
                 Testing Cohort For 
                 (111  
                 Female =  
                 9 (20) 
                 MDD =  
                 13 (26) 
                 AA =  
                 23 (47) 
                 (5.0)  
                 Neuropsych 
               
               
                 Predicting Trait  
                 visits) 
                   
                   
                 SZA =  
                 11 (20) 
                   
                   
                 (40-74) 
                 Testing (n = 11) vs.  
               
               
                 (Future Positive 
                   
                   
                   
                 SZ =  
                 15 (30) 
                   
                   
                 Neuropsych Testing  
                 Others (n = 100) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Neuropsych  
                   
                   
                   
                 PTSD =  
                 5 (10) 
                   
                   
                 Positive =  
                 54.2 (6.05) 
                 0.411644 
               
               
                 Testing for  
                   
                   
                   
                 MOOD =  
                 1 (2) 
                   
                   
                 Others =  
                 55.8 (4.89) 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Dementia in 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 All Years  
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Following 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Assessment) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BP-Bipolar; MDD-Major depressive disorder; SZA-schizoaffective disorder; SZ-schizophrenia, PTSD-post-traumatic stress disorder. 
               
            
           
         
       
     
     The psychiatric subjects were part of a larger longitudinal cohort of adults. Subjects were recruited from the patient population at the Indianapolis VA Medical Center. All subjects understood and signed informed consent forms detailing the research goals, procedure, caveats and safeguards, per IRB approved protocol. Subjects completed diagnostic assessments by an extensive structured clinical interview —Diagnostic Interview for Genetic Studies, and up to six testing visits, 3-6 months apart or whenever a new psychiatric hospitalization occurred. At each testing visit, they received a series of rating scales, including a Hopkins Verbal Learning Test (HVLT-R, see  FIG. 6 ), and blood was drawn. Whole blood (10 ml) was collected in two RNA-stabilizing PAXgene tubes, labeled with an anonymized ID number, and stored at −80° C. in a locked freezer until the time of future processing. Whole-blood RNA was extracted for microarray gene expression studies from the PAXgene tubes, as detailed below. 
     For this study, the within-subject longitudinal discovery cohort, from which the biomarker data were derived, consisted of 159 subjects (131 males, 28 females) with multiple testing visits (a total of 496), who each had at least one 20% change in the Retention measure of HVLT from one consecutive testing visit to another. 
     The independent test cohort for predicting state (Low Memory Retention) consisted of 127 subjects (97 males, 30 females), demographically matched with the discovery cohort, with one or more testing visits (for a total of 238 visits). Low Memory Retention was defined as a score of ≤40 ( FIG. 1 , Table 1). 
     The independent test cohort for predicting trait (future positive neuropsychological testing for cognitive impairment) consisted of 56 subjects (47 males, 9 females), demographically matched with the discovery cohort, with one or more testing visits in our lab (for a total of 111 visits). Positive neuropsychological testing was defines as a diagnosis of MCI, ADRD (Alzheimer Disorder Related Dementia), or other dementia upon neuropsychological testing done in a clinical setting, triggered by clinical concerns as part of regular clinical care ( FIG. 1 , Table 1). 
     Medications. The subjects in the discovery cohort were all diagnosed with various psychiatric disorders (see, Table 1), and had various medical co-morbidities. Their medications were listed in their electronic medical records, and documented at the time of each testing visit. Medications can have a strong influence on gene expression. However, the discovery of differentially expressed genes was based on within-subject analyses, which factor out not only genetic background effects but also minimizes medication effects, as the subjects rarely had major medication changes between visits. Moreover, there was no consistent pattern of any particular type of medication, as the subjects were on a wide variety of different medications, including both psychiatric and non-psychiatric. Furthermore, the independent validation and testing cohorts&#39; gene expression data was Z-scored by gender and diagnosis before being combined, to normalize for any such effects. 
     RNA extraction. Whole blood (2.5-5 ml) was collected into each PaxGene tube by routine venipuncture. PaxGene tubes contain proprietary reagents for the stabilization of RNA. RNA was extracted and processed as previously described (Niculescu et al.,  Mol. Psychiatry  2015 20(11): 1266-1285; Levey et al.,  Mol. Psychiatry  2016 21(6): 768-785; Le-Niculescu et al.,  Mol. Psychiatry  2013 18(12): 1249-1264). 
     Microarray. Microarray work was carried out as previously described (Niculescu et al.,  Mol. Psychiatry  2015 20(11): 1266-1285; Levey et al., 2016; Le-Niculescu et al., 2013. 
     For biomarker discovery, the subject&#39;s score from the HVLT-DR Retention measure was assessed at the time of blood collection ( FIG. 1 ). Using a 20% change threshold in Retention, differences in gene expression between visits were analyzed, using a powerful within-subject design, then an across-subjects summation ( FIG. 1 ). 
     Data was analyzed in two ways: an Absent-Present (AP) approach, and a differential expression (DE) approach. The AP approach may capture turning on and off of genes, and the DE approach may capture gradual changes in expression. A powerful within-subject design, then an across-subjects summation score was used for probe sets. Affymetrix microarray data was imported as CEL. files into Partek Genomic Suites 6.6 software package (Partek Incorporated, St Louis, Mich., USA). Using only the perfect match values, a robust multi-array analysis (RMA) by gender and diagnosis, background corrected with quantile normalization and a median polish probe set summarization of all chips, was performed to obtain the normalized expression levels of all probe sets for each chip. Then, to establish a list of differentially expressed probe sets a within-subject analysis was conducted using a fold change in expression of at least 1.2 between high stress and low stress visits within each subject. Probe sets that had a 1.2-fold change were then assigned either a 1 (increased in high stress) or a −1 (decreased in high stress) in each comparison. These values were then summed for each probe set across all the comparisons and subjects, yielding a range of raw scores. The probe sets above the 33.3% of scores received an internal score of 2 points, those above 50% received 4 points, and those above 80% received 6 points. R scripts were developed to automate and conduct all these large dataset analyses in bulk, and checked against human manual scoring. 
     Gene Symbol for the probe sets were identified using NetAffyx (Affymetrix) for Affymetrix HG-U133 Plus 2.0 GeneChips, followed by GeneCards to confirm the primary gene symbol. In addition, for those probe sets that were not assigned a gene symbol by NetAffyx, GeneAnnot or UCSC were used to obtain gene symbols, followed by GeneCard. Genes were then scored using the manually curated CFG databases as described below ( FIG. 1 ). 
     For prioritization using Convergent Functional Genomics (CFG) was used for prioritization. Databases of the human gene expression/protein expression studies (postmortem brain, peripheral tissue/fluids: CSF, blood and cell cultures), human genetic studies (association, copy number variations and linkage), and animal model gene expression and genetic studies, published to date on psychiatric disorders was manually curated. Only findings deemed significant in the primary publication, by the study authors, using their particular experimental design and thresholds, were included in the databases. The databases include only primary literature data and do not include review papers or other secondary data integration analyses to avoid redundancy and circularity. These large and constantly updated databases have been used in a CFG cross validation and prioritization platform ( FIG. 1 ). For this study, data from 213 papers on AD were present in the databases at the time of the CFG analyses (August 2018) (human genetic studies—62, human brain tissue studies—49, human peripheral tissue/fluids—83, non-human genetic studies—4, non-human brain tissue studies—13, non-human peripheral tissue/fluids—2). Analyses were performed as previously described (Niculescu et al.,  Mol. Psychiatry  2015; 20(11): 1266-1285; Levey et al.,  Mol. Psychiatry  2016 21(6): 768-785). 
     Biomarkers to be carried forward were selected after the prioritization step, using as threshold a CFG score ≥10 (n=138 probe sets, 112genes). Of these, the top candidate biomarkers had a CFG score ≥12 (n=23 probe sets, 18 genes). In Step 3, testing, Low Memory Retention state, and future positive neuropsychological testing for cognitive impairment were then predict in independent cohorts. 
     In Step 3, testing, the test cohort for predicting Low Memory Retention (state), and the test cohort for predicting Future Positive Neuropsychological Testing (trait), were assembled out of data that was RMA normalized by gender and diagnosis. The cohort was completely independent from the discovery and validation cohorts, there was no subject overlap with them. Phenomic (clinical) and gene expression markers used for predictions were Z scored by gender and diagnosis, to be able to combine different markers into panels and to avoid potential artefacts due to different ranges of expression in different gender and diagnoses. Markers were combined by simple summation of the increased risk markers minus the decreased risk markers. Predictions were performed using R-studio. For cross-sectional analyses, marker expression levels, z-scored by gender and diagnosis were used. For longitudinal analyses, four measures were combined: marker expression levels, slope (defined as ratio of levels at current testing visit vs. previous visit, divided by time between visits), maximum levels (at any of the current or past visits), and maximum slope (between any adjacent current or past visits). For decreased markers, the minimum rather than the maximum were used for level calculations. All four measures were Z-scored, then combined in an additive fashion into a single measure. The longitudinal analysis was carried out in a sub-cohort of the testing cohort consisting of subjects that had at least two test visits. 
     Predicting State Low Memory. Receiver-operating characteristic (ROC) analyses between marker levels and memory state were performed by assigning subjects visits with a HVLT Retention score of ≤40 into the Low Memory category (using the pROC package of R; Xavier Robin et al. BMC Bioinformatics 2011) (see,  FIG. 3 ). Additionally, a one-tailed t-test was performed between Low Memory group vs. the rest, and Pearson R (one-tail) was calculated between Memory scores and markerlevels. 
     Predicting Trait Future Positive Neuropsychological Testing for Cognitive Impairment. Analyses was conducted for predicting future positive neuropsychological testing performed as part of routine clinical care in subjects that had follow-up in the VA system using electronic medical records follow-up data of the study subjects (up to 12.81 years from initial visit). Analyses between genomic and phenomic markers measures (cross-sectional, longitudinal) at a specific testing visit and future positive neuropsychological test were performed as described below, based on assigning if subjects had a future positive neuropsychological test for cognitive impairment or not. A Cox regression was performed using the time in days from the lab testing visit date to the positive neuropsychological testing date. The hazard ratio was calculated such that a value greater than 1 always indicated increased risk for positive neuropsychological testing, regardless if the biomarker was increased or decreased in expression. A hazard ratio (also called odds ratio, O.R.) can be calculated using biomarker expression information as a means for predicting risk of future development of Alzheimer&#39;s and related disorders. Additionally, a Pearson R (one-tail) correlation was performed between positive neuropsychological testing frequency (number of positive neuropsychological tests divided by duration of follow-up) and marker levels. 
     Pharmacogenomics. Which of the top biomarkers from Table 3 (n=38 probe sets) known to be modulated by existing drugs were analyzed using the CFG databases, and using Ingenuity Drugs analyses (Tables 2 and 3). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Top Biomarkers. Convergent Functional Evidence for Relevance to Short-Term Memory Tracking and Alzheimer Disease (AD).  
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Step 1 
                   
                 Step 3 
                   
                   
                   
                   
               
               
                   
                   
                 Discovery 
                 Step 2 
                 Best significant 
                 Step 3 
                   
                   
                   
               
               
                   
                   
                 in blood 
                 External 
                 prediction of 
                 Best significant 
                 Other 
                 Pharmacogenomics 
                   
               
               
                   
                   
                 (Direction 
                 CFG 
                 state 
                 predictions of 
                 psychiatric 
                 Drugs that 
                   
               
               
                   
                   
                 of change 
                 evidence 
                 Low memory 
                 trait future 
                 and related 
                 modulate 
                   
               
               
                   
                   
                 tracking 
                 for 
                 retention 
                 positive 
                 disorders 
                 the 
                   
               
               
                   
                   
                 increased 
                 involve- 
                 ROC AUC/ 
                 neuropsych 
                 evidence 
                 biomarker 
                   
               
               
                   
                   
                 memory) 
                 ment in 
                 p-value 
                 OR/OR p-value 
                 (change in 
                 (Change in 
                   
               
               
                   
                   
                 method/ 
                 AD 
                 up to 6 pts 
                 Up to 6 pts 
                 opposite 
                 Same 
                   
               
               
                   
                   
                 score/ 
                 score 
                 ALL 
                 ALL 
                 direction to 
                 Direction to 
                 CFE 
               
               
                 Genesymbol/  
                   
                 % 
                 up to 
                 4 pts gender  
                 4 pts gender 
                 increased 
                 Increased 
                 polyevidence 
               
               
                 Gene name 
                 Probeset 
                 up to 6 pts 
                 12 pt 
                 2 pts gender/Dx 
                 2 pts gender/Dx 
                 memory) 
                 Memory) 
                 score 
               
               
                   
               
               
                 RAB7A 
                  227602_at 
                 (I) 
                  7 
                 
                   ALL 
                 
                 
                   Gender 
                 
                 BP 
                 TCA 
                 21 
               
               
                 RAB7A, 
                   
                 AP/2 
                   
                   L:  (17/111) 
                 Male 
                 Brain 
                 Valproate 
                   
               
               
                 member RAS  
                   
                 43.8% 
                   
                  0.66/1.73E−02 
                   C:  (7/91)   
                 arousal 
                   
                   
               
               
                 oncogene 
                   
                 (I) 
                   
                 
                   Gender Dx 
                 
                 2.51/3.08E−02 
                 depression 
                   
                   
               
               
                 family 
                   
                 DE/4 
                   
                 F-BP 
                   
                 MDD 
                   
                   
               
               
                   
                   
                 69.6% 
                   
                   L:  (2/9)    
                   
                 neuropathic 
                   
                   
               
               
                   
                   
                   
                   
                    1/2.02E−02 
                   
                 pain 
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-BP 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:   (1/27)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     1/4.76E − 02   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-PSYCHOSIS 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (8/27)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.76/1.68E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-SZ 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (5/14)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   0.8/3.59E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-SZA 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   C:  (12/33)  
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.67/4.98E−02 
                   
                   
                   
                   
               
               
                 NPC2 
                  200701_at 
                 (D) 
                  8 
                 
                   ALL 
                 
                   
                 Aging 
                   
                 20 
               
               
                 Niemann- 
                   
                 DE/6 
                   
                   L:  (17/111) 
                   
                 alcohol 
                   
                   
               
               
                 Pick disease, 
                   
                 80.8% 
                   
                  0.65/2.38E−02 
                   
                 SZ 
                   
                   
               
               
                 type C2 
                   
                   
                   
                 
                   Gender 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 Male 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (12/79)  
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.65/4.65E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-MDD 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (3/18)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.96/7.58E−03 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-SZA 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (3/13)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   0.9/2.13E−02 
                   
                   
                   
                   
               
               
                 TGF131 
                  203084_at 
                 (I) 
                  9 
                 
                   ALL 
                 
                   
                 Aging 
                 Omega-3 
                 19 
               
               
                 transforming  
                   
                 AP/4 
                   
                   C:  (68/238) 
                   
                 ASD 
                 fatty acids 
                   
               
               
                 growth 
                   
                 54.5% 
                   
                  0.58/2.88E−02 
                   
                 BP 
                   
                   
               
               
                 factor beta 1 
                   
                   
                   
                 
                   Gender 
                 
                   
                 Chronic 
                   
                   
               
               
                   
                   
                   
                   
                 Male 
                   
                 stress 
                   
                   
               
               
                   
                   
                   
                   
                   C:  (53/176) 
                   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                   0.6/2.29E−02 
                   
                 Longevity 
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                 Pain 
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-PTSD 
                 
                   
                 Phencyclidine 
                   
                   
               
               
                   
                   
                   
                   
                     C:     (4/10)    
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                     1/5.26E − 03   
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                 M-SZ 
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                   C:  (15/34)  
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.68/3.99E−02 
                   
                   
                   
                   
               
               
                 GAP43 
                  204471_at 
                 (I) 
                  7 
                 
                   Gender Dx 
                 
                 
                   ALL 
                 
                 BP 
                 Valproate 
                 19 
               
               
                 growth 
                   
                 DE/4 
                   
                 M-SZA 
                 
                   
                     C: 
                   
                   (11/111) 
                 
                 depression 
                 Benzodiazepines 
                   
               
               
                 associated 
                   
                 50.8% 
                   
                   L:  (3/13)   
                 
                   2.07/2.08E−02 
                 
                 SZ 
                   
                   
               
               
                 protein 43 
                   
                   
                   
                 0.867/3.15E−02 
                   L:  (3/50)   
                 stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                 6.14/1.51 − 02 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   Gender 
                 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 Male 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   C:  (7/91)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 2.94/1.17E−02  
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   L:  (3/43)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 5.54/1.47 − 02 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   Gender-Dx 
                 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 M-Psychosis 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   L:  (2/22)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                  5.4/2.96 − 02 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 M-SZ 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   L:  (2/13)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 4.08/3.83 − 02 
                   
                   
                   
               
               
                 ARSB 
                 1554030_at 
                 (I) 
                  6 
                 
                   ALL 
                 
                   
                 Alcohol 
                   
                 18 
               
               
                 arylsulfatase 
                   
                 DE/6 
                   
                   L:  (17/111) 
                   
                 Depression 
                   
                   
               
               
                 B 
                   
                 91.7% 
                   
                  0.72/2.19E−03 
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                 Gender 
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                 Male 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (12/79)  
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.74/4.92E−03 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 F-BP 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (2/9)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.93/3.95E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-PSYCHOSIS 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     L:     (8/27)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   0.88/1.04E − 03   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-SZ 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     L:     (5/14)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                    0.8/3.59E − 02   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-SZA 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (3/13)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     1/5.61E−03 
                   
                   
                   
                   
               
               
                 PER1 
                  242832_at 
                 (I) 
                  6 
                 
                   Gender 
                 
                 
                   Gender 
                 
                 Alcohol 
                 Lithium 
                 18 
               
               
                 period 
                   
                 DE/4 
                   
                 
                   Female 
                 
                 Male 
                 Anxiety 
                 Clozapine 
                   
               
               
                 circadian 
                   
                 61.3% 
                   
                     C:     (15/62)   
                   L:  (3/43)   
                 ASD 
                 Quetiapine 
                   
               
               
                 clock 1 
                   
                   
                   
                    0.7/9.17E − 03   
                  5.2/4.97E−03 
                 Autism 
                 Avibactam 
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                 BP 
                   
                   
               
               
                   
                   
                   
                   
                 F-BP 
                   
                 Circadian 
                   
                   
               
               
                   
                   
                   
                   
                   C:  (6/19)   
                   
                 abnormalities 
                   
                   
               
               
                   
                   
                   
                   
                  0.83/1.13E−02 
                   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                 M-BP 
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (1/27)   
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                     1/4.76E−02 
                   
                 Sleep 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Duration 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 GUSB 
                  202605_at 
                 (D) 
                  8 
                 
                   ALL 
                 
                   
                 Aging 
                 Clozapine 
                 18 
               
               
                 glucuronidase,  
                   
                 DE/4 
                   
                   L:  (17/111) 
                   
                 Methamphetamine 
                   
                   
               
               
                 beta 
                   
                 55.7% 
                   
                  0.65/2.16E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 Female 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (5/32)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.79/2.29E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 F-BP 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   C:  (6/19)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.81/1.76E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-MDD 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (3/18)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.89/1.91E−02 
                   
                   
                   
                   
               
               
                 MAPT 
                  203930_s_at 
                 (I) 
                 10 
                   
                 
                   ALL 
                 
                 Aging 
                 Lithium 
                 18 
               
               
                 microtubule 
                   
                 DE/2 
                   
                   
                     L:    (11/111) 
                 Alcohol 
                 Omega-3 
                   
               
               
                 associated 
                   
                 33.7% 
                   
                   
                 1.96/2.95E−02 
                 Intellect 
                 fatty acids 
                   
               
               
                 protein tau 
                   
                   
                   
                   
                 
                   Gender 
                 
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   Male 
                 
                 Methamphetamine 
                   
                   
               
               
                   
                   
                   
                   
                   
                     C:     (7/91)    
                 Phencyclidine  
                   
                   
               
               
                   
                   
                   
                   
                   
                   3.54/4.62E − 02   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                 M-PSYCHOSIS 
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                   
                   C:  (5/47)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 2.84/3.34E−02  
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   M-SZ 
                 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                     C:     (4/27)    
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   4.65/4.06E − 02   
                   
                   
                   
               
               
                 FCGR1A 
                  216951_at 
                 (I) 
                  7 
                   
                 
                   ALL 
                 
                   
                   
                 17 
               
               
                 Fc fragment 
                   
                 DE/4 
                   
                   
                     L:     (3/49)    
                   
                   
                   
               
               
                 of IgG, high  
                   
                 64.6% 
                   
                   
                    20/3.50−02   
                   
                   
                   
               
               
                 affinity Ia, 
                   
                   
                   
                   
                 
                   Gender 
                 
                   
                   
                   
               
               
                 receptor 
                   
                   
                   
                   
                 Male 
                   
                   
                   
               
               
                 (CD64) 
                   
                   
                   
                   
                     L:     (3/40)    
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   15.4/4.37E − 02   
                   
                   
                   
               
               
                 UBE2L3 
                  200682_s_at 
                 (D)  
                  4 
                 
                   ALL 
                 
                   
                 Aging 
                 Clozapine 
                 16 
               
               
                 ubiquitin 
                   
                 DE/6 
                   
                   L:  (17/111) 
                   
                 Alcohol 
                   
                   
               
               
                 conjugating 
                   
                 91% 
                   
                  0.63/4.13E−02 
                   
                 ASD 
                   
                   
               
               
                 enzyme 
                   
                   
                   
                 
                   Gender 
                 
                   
                 Depression 
                   
                   
               
               
                 E2L3 
                   
                   
                   
                 Male 
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (12/79)  
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                  0.65/4.92E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-BP 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     C:     (10/54)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                    0.7/2.25E − 02   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-SZA 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (3/13)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   0.9/2.13E−02 
                   
                   
                   
                   
               
               
                 NKTR 
                 1570342_at 
                 (D) 
                  4 
                 
                   ALL 
                 
                   
                 Alcohol 
                   
                 16 
               
               
                 natural killer 
                   
                 AP/6 
                   
                 
                   
                     C: 
                   
                   (68/238) 
                 
                   
                 BP 
                   
                   
               
               
                 cell 
                   
                 85% 
                   
                   0.59/1.40E − 02   
                   
                 Depression 
                   
                   
               
               
                 triggering 
                   
                   
                   
                 
                   Gender 
                 
                   
                 MDD 
                   
                   
               
               
                 receptor 
                   
                   
                   
                 Male 
                   
                 Social 
                   
                   
               
               
                   
                   
                   
                   
                 
                   
                     C: 
                   
                   (53/176) 
                 
                   
                 Isolation 
                   
                   
               
               
                   
                   
                   
                   
                   0.62/5.55E − 03   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                 M-BP 
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                   C:  (10/54)  
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.68/3.56E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-PSYCHOSIS 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     C:     (27/67)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.63/3.19E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-PSYCHOSIS 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (8/27)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.72/3.55E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-SZ 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     C:     (15/34)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   0.72/1.38E − 02   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   M-SZ 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     L:     (5/14)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                      1/1.35E − 03   
                   
                   
                   
                   
               
               
                 RHEB 
                  243008_at 
                 (D) 
                  4 
                   
                 
                   ALL 
                 
                 Suicide 
                 Antidepressants 
                 16 
               
               
                 Ras homolog 
                   
                 AP/6 
                   
                   
                   C:  (11/111) 
                 Pain 
                   
                   
               
               
                 enriched in 
                   
                 84.4% 
                   
                   
                 1.51/3.05E−02 
                 SZ 
                   
                   
               
               
                 brain 
                   
                 (D) 
                   
                   
                 
                   Gender 
                 
                   
                   
                   
               
               
                   
                   
                 DE/4 
                   
                   
                 Male 
                   
                   
                   
               
               
                   
                   
                 64.1% 
                   
                   
                   C:  (7/91)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 1.63/2.46E−02 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 M -PSYCHOSIS 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   C:  (5/47)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 2.12/5.45E−03 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   L:  (2/22)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 9.69/1.68E−02 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 M-SZ 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   C:  (4/27)   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 1.82/1.78E−02 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                     L:     (2/13)    
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   6.22/3.32E − 02   
                   
                   
                   
               
               
                 
                   PTGS2 
                 
                 1554997_a_at 
                 (D) 
                 10 
                 
                   Gender Dx 
                 
                   
                 Aggression 
                 Antipsychotics 
                 16 
               
               
                 
                   prostaglandin- 
                 
                   
                 DE/4 
                   
                 M-PTSD 
                   
                 Alcohol 
                 Lithium 
                   
               
               
                 
                   endoperoxide 
                 
                   
                 76% 
                   
                   C:  (4/10) 
                   
                 ASD 
                 Vorinostat 
                   
               
               
                 
                   synthase 2 
                 
                   
                   
                   
                  0.88/2.75E−02 
                   
                 BP 
                   
                   
               
               
                 
                   (prostaglandin 
                 
                   
                   
                   
                   
                   
                 Chronic 
                   
                   
               
               
                 
                   G/H 
                 
                   
                   
                   
                   
                   
                 Fatigue 
                   
                   
               
               
                 
                   synthase and 
                 
                   
                   
                   
                   
                   
                 Syndrome 
                   
                   
               
               
                 cyclooxygenase) 
                   
                   
                   
                   
                   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Depression- 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Related 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Neurological 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Pain 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Phencyclidine 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Social 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Isolation 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Substances/ 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Addictions 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                 RGS10 
                  214000_s_at 
                 (I) 
                  6 
                 
                   ALL 
                 
                   
                 Aging 
                   
                 16 
               
               
                 regulator of  
                   
                 DE/4 
                   
                   L:  (17/111) 
                   
                 BP 
                   
                   
               
               
                 G-protein 
                   
                 63.5% 
                   
                   0.7/3.89E−03 
                   
                 Female 
                   
                   
               
               
                 signaling 10 
                   
                   
                   
                 
                   Gender 
                 
                   
                 specific 
                   
                   
               
               
                   
                   
                   
                   
                 
                   Male 
                 
                   
                 interpersonal- 
                   
                   
               
               
                   
                   
                   
                   
                     L:     (12/79)   
                   
                 traumas 
                   
                   
               
               
                   
                   
                   
                   
                   0.74/4.73E − 03   
                   
                 Methamphetamine 
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                 Post- 
                   
                   
               
               
                   
                   
                   
                   
                 F-BP 
                   
                 Deployment 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (2/9)    
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                  0.93/3.95E−02 
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                 M-BP 
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (1/27)   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                     1/4.76E−02 
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                 M-MDD 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (3/18)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.87/2.53E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-SZ 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   C:  (15/34)  
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.68/3.70E−02 
                   
                   
                   
                   
               
               
                 
                   MAPT 
                 
                  203928_x_at 
                 (I) 
                 10 
                 
                   Gender Dx 
                 
                   
                 Aging 
                 Lithium 
                 16 
               
               
                 
                   microtubule 
                 
                   
                 DE/4 
                   
                 F-BP 
                   
                 Alcohol 
                 Omega-3 
                   
               
               
                 
                   associated 
                 
                   
                 57.5% 
                   
                   C:  (6/19)   
                   
                 Intellect 
                 fatty acids 
                   
               
               
                 
                   protein tau 
                 
                   
                   
                   
                  0.81/1.76E−02 
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Methamphetamine 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Phencyclidine 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 ITPKB 
                  232526_at 
                 (I) 
                  6 
                 
                   ALL 
                 
                   
                 Aging 
                   
                 16 
               
               
                 inositol- 
                   
                 DE/4 
                   
                 
                   
                     L: 
                   
                   (17/111) 
                 
                   
                 Alcohol 
                   
                   
               
               
                 trisphosphate 
                   
                 51.9% 
                   
                   0.73/1.60E − 03   
                   
                 MDD 
                   
                   
               
               
                 3-kinase B 
                   
                   
                   
                 
                   Gender 
                 
                   
                 Phencyclidine 
                   
                   
               
               
                   
                   
                   
                   
                 Male 
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (12/79)  
                   
                 Suicide, SZ 
                   
                   
               
               
                   
                   
                   
                   
                   0.7/1.44E−02 
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                 
                   Female 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     L:  (5/32)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   0.79/2.29E − 02   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 M-BP 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   L:  (1/27)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     1/4.76E−02 
                   
                   
                   
                   
               
               
                 KIDINS220 
                  214932_at 
                 (I) 
                  6 
                 
                   Gender Dx 
                 
                 
                   Gender 
                 
                 Alcohol 
                 Clozapine 
                 16 
               
               
                 kinase D- 
                   
                 DE/4 
                   
                 F-BP 
                 Male 
                 MDD 
                   
                   
               
               
                 interacting 
                   
                 51.9% 
                   
                   L:  (2/9)    
                   C:  (7/91)   
                 Psychosis 
                   
                   
               
               
                 substrate  
                   
                   
                   
                  0.93/3.95E−02 
                 2.49/3.78E−02  
                 Pain 
                   
                   
               
               
                 220 kDa 
                   
                   
                   
                   
                 
                   Gender-Dx 
                 
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   M-BP 
                 
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                     C:     (2/16)    
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                 
                   6.06/4.18 − 02 
                 
                   
                   
                   
               
               
                 
                   GSK3B 
                 
                  209945_s_at 
                 (D) 
                 10 
                 
                   Gender Dx 
                 
                   
                 Aging 
                 Astaxanthin- 
                 16 
               
               
                 
                   glycogen 
                 
                   
                 DE/4 
                   
                 M-SZA 
                   
                 Alcohol 
                 DHA 
                   
               
               
                 
                   synthase 
                 
                   
                 50.3% 
                   
                   L:  (3/13)   
                   
                 ASD 
                 Antipsychotics 
                   
               
               
                 
                   kinase 3 beta 
                 
                   
                   
                   
                  0.93/1.40E−02 
                   
                 BP 
                 Lithium 
                   
               
               
                   
                   
                   
                   
                   
                   
                 BP, SZ 
                 Omega-3 
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                 fatty acids 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                 Ketamine 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                 lipoteichoic 
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                 acid 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 Valproate 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 enzastaurin, 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 glycogen 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 synthase 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 kinase-3beta 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 inhibitor 
                   
               
               
                 SERTAD3 
                  219382_at 
                 (D) 
                  5 
                 
                   Gender 
                 
                   
                 Alcohol 
                   
                 15 
               
               
                 SERTA 
                   
                 DE/6 
                   
                 Female 
                   
                 ASD 
                   
                   
               
               
                 domain 
                   
                 81.4% 
                   
                   L:  (5/32)   
                   
                 Aging 
                   
                   
               
               
                 containing 3 
                   
                   
                   
                  0.79/2.29E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 F-BP 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   C:  (6/19)   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                  0.81/1.76E−02 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   F-PSYCHOSIS 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     L:     (2/13)    
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                      1/1.50E − 02   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 
                   F-SZA 
                 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                     L:     (2/8)     
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                      1/2.28E − 02   
                   
                   
                   
                   
               
               
                 
                   APOE 
                 
                  212884_x_at 
                 (D) 
                 11 
                 
                   Gender Dx 
                 
                   
                 Aggression 
                 Omega-3 
                 15 
               
               
                 
                   apolipoprotein 
                 
                   
                 AP/2 
                   
                 M-PTSD 
                   
                 Aging 
                 fatty acids 
                   
               
               
                 
                   E 
                 
                   
                 34.1% 
                   
                   C:  (4/10)   
                   
                 Alcohol 
                   
                   
               
               
                   
                   
                   
                   
                  0.88/2.75E−02 
                   
                 Anxiet 
                   
                   
               
               
                   
                   
                   
                   
                 
                   Gender Dx 
                 
                   
                 ASD 
                   
                   
               
               
                   
                   
                   
                   
                 M-SZ 
                   
                 BP 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (5/14)   
                   
                 Brain 
                   
                   
               
               
                   
                   
                   
                   
                  0.89/9.82E−03 
                   
                 arousal 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 TBI 
                   
                   
               
               
                 
                   UBE2I 
                 
                  233360_at 
                 (D) 
                  6 
                 
                   Gender Dx 
                 
                   
                 Aging 
                 Clozapine 
                 14 
               
               
                 
                   ubiquitin 
                 
                   
                 DE/6 
                   
                 F-PSYCHOSIS 
                   
                 Alcohol 
                   
                   
               
               
                 
                   conjugating 
                 
                   
                 86.8% 
                   
                   L:  (2/13)   
                   
                 ASD 
                   
                   
               
               
                 
                   enzyme E21 
                 
                   
                   
                   
                  0.91/3.78E−02 
                   
                 Hallucinations 
                   
                   
               
               
                   
                   
                   
                   
                 F-SZA 
                   
                 Mood State 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (2/8)    
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                  0.92/4.78E−02 
                   
                   
                   
                   
               
               
                 FOXO3 
                  231548_at 
                 (I) 
                  4 
                 
                   Gender Dx 
                 
                 
                   Gender Dx 
                 
                 BP 
                 Clozapine 
                 14 
               
               
                 forkhead box  
                   
                 AP/2 
                   
                 
                   F-SZA 
                 
                 
                   M-PSYCHOSIS 
                 
                 Cocaine 
                   
                   
               
               
                 O3 
                   
                 38.9% 
                   
                     C:     (5/15)    
                     C:     (5/47)    
                 Longevity 
                   
                   
               
               
                   
                   
                 (I) 
                   
                   0.78/4.32E − 02   
                   4.14/4.58E − 02   
                 PTSD 
                   
                   
               
               
                   
                   
                 DE/6 
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                 82.3% 
                   
                   
                   
                 Suicide 
                   
                   
               
               
                 
                   THRA 
                 
                  214883_at 
                 (I) 
                  8 
                 
                   Gender Dx 
                 
                   
                 Alcohol 
                 3,5- 
                 14 
               
               
                 
                   thyroid 
                 
                   
                 DE/4 
                   
                 F-BP 
                   
                 PTSD 
                 diiodothyropropionic 
                   
               
               
                 
                   hormone 
                 
                   
                 61.3% 
                   
                   C:  (6/19)   
                   
                 Stress 
                 acid,denosum 
                   
               
               
                 
                   receptor, 
                 
                   
                   
                   
                  0.79/2.18E−02 
                   
                 Suicide 
                 ab/levothyrox 
                   
               
               
                 
                   alpha 
                 
                   
                   
                   
                 M-BP 
                   
                 SZ 
                 ine,amiodaro 
                   
               
               
                   
                   
                   
                   
                   L:  (1/27)   
                   
                   
                 ne,levothyrox 
                   
               
               
                   
                   
                   
                   
                     1/4.76E−02 
                   
                   
                 ine,dextrothy 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 roxine,L- 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 triiodothyronine 
                   
               
               
                 ITPKB 
                 1554306_at 
                 (D) 
                  6 
                 
                   Gender 
                 
                   
                 Acute 
                 Omega-3 
                 14 
               
               
                 inositol- 
                   
                 AP/4 
                   
                 Female 
                   
                 Stress 
                 fatty acids 
                   
               
               
                 trisphosphate 
                   
                 61.1% 
                   
                   L:  (5/32)   
                   
                 Aging 
                   
                   
               
               
                 3-kinase B 
                   
                 (D) 
                   
                  0.81/1.37E−02 
                   
                 Alcohol 
                   
                   
               
               
                   
                   
                 DE/4 
                   
                 
                   Gender Dx 
                 
                   
                 ASD 
                   
                   
               
               
                   
                   
                 55.7% 
                   
                 F-BP 
                   
                 BP 
                   
                   
               
               
                   
                   
                   
                   
                   C:  (6/19)   
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                  0.91/2.50E−03 
                   
                 Neurological 
                   
                   
               
               
                   
                   
                   
                   
                 F-BP 
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   L:  (2/9)    
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                     1/2.02E−02 
                   
                   
                   
                   
               
               
                 
                   IGF1 
                 
                  209542_x_at 
                 (I) 
                  8 
                 
                   Gender Dx 
                 
                   
                 Aggression 
                 Lithium 
                 14 
               
               
                 
                   insulin-like 
                 
                   
                 DE/4 
                   
                 F-BP 
                   
                 Aging 
                 Clozapine 
                   
               
               
                 
                   growth 
                 
                   
                 54.1% 
                   
                   C:  (6/19)   
                   
                 Alcoho 
                 Fluoxetine 
                   
               
               
                 
                   factor 1 
                 
                   
                   
                   
                  0.79/2.18E−02 
                   
                 Anxiety 
                 (SSRI), 
                   
               
               
                 
                   (somatomedin  
                 
                   
                   
                   
                   
                   
                 BP 
                 Venlafaxine 
                   
               
               
                 
                   C) 
                 
                   
                   
                   
                   
                   
                 Depression 
                 (SNRI) 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Longevity 
                 MEDI-573, 
                   
               
               
                   
                   
                   
                   
                   
                   
                 PTSD 
                 BI836845 
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 
                   NPTX2 
                 
                  213479_at 
                 (I) 
                  8 
                 
                   Gender Dx 
                 
                   
                 Alcohol 
                 Clozapine 
                 14 
               
               
                 
                   neuronal 
                 
                   
                 DE/4 
                   
                 F-BP 
                   
                 Brain 
                 Fluoxetine 
                   
               
               
                 
                   pentraxin II 
                 
                   
                 52.5% 
                   
                   L:  (2/9)    
                   
                 arousal 
                   
                   
               
               
                   
                   
                   
                   
                  0.93/3.95E−02 
                   
                 Cocaine 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD, SZ 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Mood 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Disorders 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 NOS 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                 
                   GSTM3 
                 
                  235867_at 
                 (D) 
                  8 
                 
                   Gender Dx 
                 
                   
                 BP 
                   
                 14 
               
               
                 
                   glutathione 
                 
                   
                 DE/4 
                   
                 F-SZA 
                   
                 MDD 
                   
                   
               
               
                 
                   S- 
                 
                   
                 52.1% 
                   
                   C:  (5/15)   
                   
                 SZ 
                   
                   
               
               
                 
                   transferase 
                 
                   
                   
                   
                  0.78/4.32E−02 
                   
                   
                   
                   
               
               
                 
                   mu 3 (brain) 
                 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 
                   BACE1 
                 
                  222463_s_at 
                 (I) 
                  8 
                   
                 
                   Gender 
                 
                 MDD 
                   
                 14 
               
               
                 
                   Beta- 
                 
                   
                 DE/2 
                   
                   
                 Male 
                 Stress 
                   
                   
               
               
                 
                   Secretase 1 
                 
                   
                 44.8% 
                   
                   
                   C:  (7/91)   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                 1.97/3.78E−02 
                   
                   
                   
               
               
                 
                   PSEN1 
                 
                  203460_s_at 
                 (D) 
                  9 
                   
                   
                 Aging 
                 Omega-3 
                 13 
               
               
                 
                   presenilin 1  
                 
                   
                 DE/4 
                   
                   
                   
                 Alcohol 
                 fatty acids 
                   
               
               
                   
                   
                 54.5% 
                   
                   
                   
                 Autism 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Emotional 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stability 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Neuroticism 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 GFAP 
                  203540_at 
                 (I) 
                  9 
                 
                   Gender Dx 
                 
                   
                 Addictions 
                 Omega-3 
                 13 
               
               
                 glial 
                   
                 DE/2 
                   
                 F-BP 
                   
                 Alcohol 
                 fatty acids 
                   
               
               
                 fibrillary 
                   
                 34.3% 
                   
                   C:  (6/19)   
                   
                 BP 
                 Clozapine 
                   
               
               
                 acidic protein 
                   
                   
                   
                  0.77/3.28E−02 
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Yohimbine 
                   
                   
               
               
                 
                   TREM2 
                 
                  219725_at 
                 (I) 
                 11 
                   
                   
                 BP 
                   
                 13 
               
               
                 
                   triggering 
                 
                   
                 DE/2 
                   
                   
                   
                 SZ 
                   
                   
               
               
                 
                   receptor 
                 
                   
                 37.6% 
                   
                   
                   
                   
                   
                   
               
               
                 
                   expressed on 
                 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 
                   myeloid cells 
                 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 
                   2 
                 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 NOCT 
                  220671_at 
                 (D) 
                  6 
                 
                   Gender Dx 
                 
                   
                 PTSD 
                   
                 12 
               
               
                 nocturnin 
                   
                 AP/4 
                   
                 
                   F-PTSD 
                 
                   
                 Post- 
                   
                   
               
               
                   
                   
                 69.5% 
                   
                     C:     (3/9)     
                   
                 Deployment 
                   
                   
               
               
                   
                   
                   
                   
                      1/1.01E − 02   
                   
                 PTSD 
                   
                   
               
               
                 CEP350 
                  204373_s_at 
                 (D) 
                  6 
                   
                 
                   Gender Dx 
                 
                 Autism 
                 Antidepressants, 
                 12 
               
               
                 centrosomal 
                   
                 DE/4 
                   
                   
                 
                   M-PSYCHOSIS 
                 
                 BP 
                 Fluoxetine 
                   
               
               
                 protein 
                   
                 67.1% 
                   
                   
                     L:     (2/22)    
                 Cocaine 
                   
                   
               
               
                 350 kDa 
                   
                   
                   
                   
                   54.6/3.77E − 02   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 PPP2R2B 
                  205643_s_at 
                 (I) 
                  6 
                 
                   Gender Dx 
                 
                   
                 ADHD 
                   
                 12 
               
               
                 protein 
                   
                 DE/4 
                   
                 
                   F-BP 
                 
                   
                 Aging 
                   
                   
               
               
                 phosphatase 
                   
                 63.5% 
                   
                     L:     (2/9)     
                   
                 Alcohol 
                   
                   
               
               
                 2, regulatory 
                   
                   
                   
                      1/2.02E − 02   
                   
                 ASD 
                   
                   
               
               
                 subunit B, 
                   
                   
                   
                   
                   
                 Circadian 
                   
                   
               
               
                 beta 
                   
                   
                   
                   
                   
                 abnormalities 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Longevity 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 PTSD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 NRP2 
                  222877_at 
                 (I) 
                  6 
                 
                   Gender Dx 
                 
                   
                 Longevity 
                 Clozapine 
                 12 
               
               
                 neuropilin 2 
                   
                 DE/4 
                   
                 M-MDD 
                   
                 MDD 
                   
                   
               
               
                   
                   
                 61.3% 
                   
                   L: (3/18)    
                   
                 Phencyclidine 
                   
                   
               
               
                   
                   
                   
                   
                   0.98/5.43E − 03   
                   
                 Stress 
                   
                   
               
               
                 
                   CTSS 
                 
                  232617_at 
                 (D) 
                  8 
                   
                   
                 Aging 
                 Omega-3 
                 12 
               
               
                 
                   cathepsin S 
                 
                   
                 DE/4 
                   
                   
                   
                 Alcohol 
                 fatty acids 
                   
               
               
                   
                   
                 56.9% 
                   
                   
                   
                 ASD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 BP 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Brain 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 arousal 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Pain 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                 VEGFA 
                  211527_x_at 
                 (I) 
                  8 
                 
                   Gender Dx 
                 
                   
                 Alcohol 
                 Antipsychotics 
                 12 
               
               
                 vascular 
                   
                 DE/2 
                   
                 
                   M-MDD 
                 
                   
                 Anxiety 
                 Fluoxetine 
                   
               
               
                 endothelial 
                   
                 45.3% 
                   
                     C:     (11/38)   
                   
                 BP 
                 Steroids 
                   
               
               
                 growth factor 
                   
                   
                   
                    0.7/2.57E − 02   
                   
                 Chronic 
                   
                   
               
               
                 A 
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Depression 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Hallucinations 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Intellect 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                 . 
                   
                 Pain MSK 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 
                   MAPT 
                 
                  233117_at 
                 (I) 
                 10 
                   
                   
                 Aging 
                 Lithium 
                 12 
               
               
                 
                   microtubule 
                 
                   
                 DE/2 
                   
                   
                   
                 Alcohol 
                 Omega-3 
                   
               
               
                 
                   associated 
                 
                   
                 44.2% 
                   
                   
                   
                 Intellect 
                 fatty acids 
                   
               
               
                 
                   protein tau 
                 
                   
                   
                   
                   
                   
                 MDD 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Methamphetamine 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Phencyclidine 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                   
                   
               
               
                 
                   GSK3B 
                 
                  240562_at 
                 (I) 
                 10 
                   
                   
                 Aging 
                 Antipsychotics 
                 12 
               
               
                 
                   glycogen 
                 
                   
                 DE/2 
                   
                   
                   
                 Alcohol 
                 Antipsychotics 
                   
               
               
                 
                   synthase 
                 
                   
                 39.2% 
                   
                   
                   
                 ASD 
                 Pregnenolone 
                   
               
               
                 
                   kinase 3 beta 
                 
                   
                   
                   
                   
                   
                 BP 
                 sulfate 
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                 Fluoxetine 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Methamphetamine 
                 (SSRI) 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Psychological Stress 
                 Lithium 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                 mood 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                 stabilizing 
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                 drugs 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Yohimbine 
                 Valproate 
                   
               
               
                 
                   GS1C3B 
                 
                  242336_at 
                 (D) 
                 10 
                   
                   
                 Aging 
                 Astaxanthin- 
                 12 
               
               
                 
                   glycogen 
                 
                   
                 AP/2 
                   
                   
                   
                 Alcohol 
                 DHA 
                   
               
               
                 
                   synthase 
                 
                   
                 34.1% 
                   
                   
                   
                 ASD 
                 Antipsychotics 
                   
               
               
                 
                   kinase 3 beta 
                 
                   
                   
                   
                   
                   
                 BP 
                 Lithium 
                   
               
               
                   
                   
                   
                   
                   
                   
                 BP,SZ 
                 Omega-3 
                   
               
               
                   
                   
                   
                   
                   
                   
                 MDD 
                 fatty acids 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Stress 
                 Ketamine 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Suicide 
                 lipoteichoic 
                   
               
               
                   
                   
                   
                   
                   
                   
                 SZ 
                 acid 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 Valproate 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 enzastaurin, 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 glycogen 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 synthase 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 kinase-3beta 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 inhibitor 
                   
               
               
                 
                   BACE1 
                 
                  224335_s_at 
                 (I) 
                  8 
                   
                   
                 MDD 
                   
                 10 
               
               
                 
                   Beta- 
                 
                   
                 DE/2 
                   
                   
                   
                 Stress 
                   
                   
               
               
                 
                   Secretase 1 
                 
                   
                 43.1% 
                   
                   
                   
                 Suicide 
               
               
                   
               
               
                 Bold-top biomarkers after discovery and prioritization (n = 23, CFG ≥ 12)). Underlined-best predictor in a category after testing of the longer list candidate biomarkers after discovery and prioritization (n = 138, CFG ≥ 10), as depicted in Figure 3. We tabulated into a convergent functional evidence (CFE) score all the evidence from discovery (up to 6 points), prioritization (up to 12 points), testing (State Memory Retention State and Trait Future Positive Neuropsychological Testing (up to 6 points each if significantly predicts in all subjects, 4 points if predicts by gender, 2 points if predicts in gender/diagnosis subgroups). The goal is to highlight, based on the totality of our data and of the evidence in the field to date, biomarkers that have all around evidence: track memory, are implicated in AD, and predict memory state and future dementia. Such biomarkers merit priority evaluation in future clinical trials. As depicted in Figure 1B, the top row of values-increased in expression (I) in high memory, bottom row of values-decreased in expression (D) in high memory. DE-differential expression, AP-Absent/Present. “C”-Cross-sectional analyses; “L”-Longitudinal analyses, using levels and slopes from multiple visits. In All, by Gender, and personalized by Gender and Diagnosis (Gender/Dx). “DE”-differential expression, “AP”-Absent/Present. For Step 3 Predictions, C-cross-sectional (using levels from one visit), L-longitudinal. “M”-males, “F”-Females. “MDD”-depression, “BP”-bipolar, “SZ”-schizophrenia, “SZA”-schizoaffective, PSYCHOSIS-schizophrenia and schizoaffective combined, “PTSD”-post-traumatic stress disorder. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Matching with drugs. Evidence for modulation by drugs in same direction as increased memory retention (see also, FIG. 5). 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Step 1 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Discovery  
                   
                   
                   
                   
                   
               
               
                   
                   
                 in Blood  
                 Step 2 
                   
                   
                   
                   
               
               
                   
                   
                 (Direction 
                 External  
                   
                   
                   
                   
               
               
                   
                   
                 of Change  
                 CFG 
                   
                   
                   
                   
               
               
                   
                   
                 tracking  
                 Evidence  
                   
                   
                   
                   
               
               
                   
                   
                 Memory 
                 For 
                   
                   
                   
                   
               
               
                   
                   
                 Increase 
                 Involvement 
                   
                   
                   
                   
               
               
                   
                   
                 Method/ 
                 in AD 
                   
                   
                   
                   
               
               
                 Genesymbol/ 
                   
                 Score/% 
                 Score 
                   
                   
                 Anti- 
                   
               
               
                 Gene name 
                 Probesets 
                 Up to 6 pts 
                 Up to 12 pts 
                 Lithium 
                 Omega-3 
                 depressants 
                 Other drugs 
               
               
                   
               
               
                 APOE 
                  212884_x_at 
                 (D) 
                 11 
                   
                 (D) 
                   
                   
               
               
                 apolipoprotein 
                   
                 AP/2 
                   
                   
                 Lymphocytes 
                   
                   
               
               
                 E 
                   
                 34.1% 
                   
                   
                 (males) 
                   
                   
               
               
                   
                   
                   
                   
                   
                 Omega-3  
                   
                   
               
               
                   
                   
                   
                   
                   
                 fatty acids 318   
                   
                   
               
               
                 GSK3B 
                  242336_at 
                 (D) 
                 10 
                 (D) 
                 (D) 
                   
                 (D)  
               
               
                 glycogen 
                  209945_s_at 
                 AP/2 
                   
                 olfactory 
                 PFC 
                   
                 HIP 
               
               
                 synthase  
                   
                 34.1% 
                   
                 neurons 
                 (females) 
                   
                 Ketamine 320   
               
               
                 kinase 
                   
                 (D) 
                   
                 Lithium 298   
                 Omega-3 
                   
                 (D)  
               
               
                 3 beta 
                   
                 DE/4 
                   
                 Lithium 319   
                 fatty acids 318   
                   
                 HIP 
               
               
                   
                   
                 50.3% 
                   
                   
                 (D) 
                   
                 lipoteichoic acid 301   
               
               
                   
                   
                   
                   
                   
                 HIP 
                   
                 (D)  
               
               
                   
                   
                   
                   
                   
                 Alzheimer&#39;s Disease 
                   
                 Caudate putamen 
               
               
                   
                   
                   
                   
                   
                 Astaxanthin-DHA 43   
                   
                 Valproate 222   
               
               
                   
                   
                   
                   
                   
                   
                   
                 (D)  
               
               
                   
                   
                   
                   
                   
                   
                   
                 Frontal Cortex 
               
               
                   
                   
                   
                   
                   
                   
                   
                 Antipsychotics 321   
               
               
                   
                   
                   
                   
                   
                   
                   
                 Enzastaurin 
               
               
                 MAPT 
                  203930_s_at 
                 (I)  
                 10 
                 (I) 
                 (I)  
                   
                   
               
               
                 microtubule  
                  233117_at 
                 DE/2 
                   
                 Schneider 
                 HIP  
                   
                   
               
               
                 associated 
                  203928_at 
                 33.7% 
                   
                 2 (S2) cells 
                 (males) 
                   
                   
               
               
                 protein tau 
                   
                 (I)  
                   
                 Lithium 322   
                 Omega-3 
                   
                   
               
               
                   
                   
                 DE/2 
                   
                   
                 fatty acids 318   
                   
                   
               
               
                   
                   
                 44.2% 
                   
                   
                   
                   
                   
               
               
                   
                   
                 (I)  
                   
                   
                   
                   
                   
               
               
                   
                   
                 DE/4 
                   
                   
                   
                   
                   
               
               
                   
                   
                 57.5% 
                   
                   
                   
                   
                   
               
               
                 PTGS2 
                 1554997_a_at 
                 (D)  
                 10 
                 (D)  
                   
                   
                 (D)  
               
               
                 prostaglan 
                   
                 DE/4 
                   
                 PBMC 
                   
                   
                 Serum, HIP 
               
               
                 dinendoperoxide 
                   
                 76% 
                   
                 Lithium 165   
                   
                   
                 Vorinostat 323   
               
               
                 synthase 2 
                   
                   
                   
                   
                   
                   
                 (D)  
               
               
                 (prostaglandin 
                   
                   
                   
                   
                   
                   
                 PBMC 
               
               
                 G/H synthase  
                   
                   
                   
                   
                   
                   
                 Antipsychotics 165   
               
               
                 and 
                   
                   
                   
                   
                   
                   
                 Acetaminophen 
               
               
                 cyclooxygenase) 
                   
                   
                   
                   
                   
                   
                 NSAIds 
               
               
                 GFAP 
                  203540_at 
                 (I)  
                  9 
                   
                 (I)  
                   
                 (I)  
               
               
                 glial fibrillary 
                   
                 DE/2  
                   
                   
                 Brain 
                   
                 AMY, HIP, PFC 
               
               
                 acidic protein 
                   
                 34.3% 
                   
                   
                 Omega-3  
                   
                 Clozapine 171   
               
               
                   
                   
                   
                   
                   
                 fatty acids 324   
                   
                   
               
               
                 PSEN1 
                  203460_s_at 
                 (D)  
                  9 
                   
                 (D)  
                   
                 tarenflurbil 
               
               
                 presenilin 1 
                   
                 DE/4 
                   
                   
                 Lymphocytes 
                   
                   
               
               
                   
                   
                 54.5% 
                   
                   
                 (females) 
                   
                   
               
               
                   
                   
                   
                   
                   
                 Omega-3  
                   
                   
               
               
                   
                   
                   
                   
                   
                 fatty acids 318   
                   
                   
               
               
                 TGFB1 
                  203084_at 
                 (D)  
                  9 
                   
                 (D)  
                   
                 dalantercept, 
               
               
                 transforming 
                   
                 AP/4 
                   
                   
                 Lymphocytes 
                   
                 fresolimumab, 
               
               
                 growth factor 
                   
                 54.5% 
                   
                   
                 (females) 
                   
                 LY3200882, 
               
               
                 beta 1 
                   
                   
                   
                   
                 Omega-3  
                   
                 MSB0011359C 
               
               
                   
                   
                   
                   
                   
                 fatty acids 318   
                   
                   
               
               
                 BACE1 
                  222463_s_at 
                 (I)  
                  8 
                   
                   
                   
                   
               
               
                 Beta-Secretase 1 
                  224335_s_at 
                 DE/6  
                   
                   
                   
                   
                   
               
               
                   
                   
                 44.8% 
                   
                   
                   
                   
                   
               
               
                   
                   
                 (I)  
                   
                   
                   
                   
                   
               
               
                   
                   
                 DE/6  
                   
                   
                   
                   
                   
               
               
                   
                   
                 43.1% 
                   
                   
                   
                   
                   
               
               
                 CTSS 
                  232617_at 
                 (D)  
                  8 
                   
                 (D)  
                   
                   
               
               
                 cathepsin S 
                   
                 DE/4 
                   
                   
                 Lymphocytes 
                   
                   
               
               
                   
                   
                 56.9% 
                   
                   
                 (females) 
                   
                   
               
               
                   
                   
                   
                   
                   
                 Omega-3  
                   
                   
               
               
                   
                   
                   
                   
                   
                 fatty acids 318   
                   
                   
               
               
                 GUSB 
                  202605_at 
                 (D)  
                  8 
                   
                   
                   
                 (D)  
               
               
                 glucuronidase,  
                   
                 DE/4 
                   
                   
                   
                   
                 VT 
               
               
                 beta 
                   
                 55.7% 
                   
                   
                   
                   
                 Clozapine 171   
               
               
                 IGF1 
                  209542_x_at 
                 (I)  
                  8 
                 (I) 
                   
                 (I)  
                 (I)  
               
               
                 insulin-like 
                   
                 DE/4 
                   
                 lymphoblastoid 
                   
                 HIP 
                 VT 
               
               
                 growth factor 1 
                   
                 54.1% 
                   
                 cell lines 
                   
                 Fluoxetine 
                 Clozapine 171   
               
               
                 (somatomedin C) 
                   
                   
                   
                 Lithium 325   
                   
                 (SSRI), 
                   
               
               
                   
                   
                   
                   
                   
                   
                 Venlafaxine 
                   
               
               
                   
                   
                   
                   
                   
                   
                 (SNRI) 326   
                   
               
               
                 NPTX2 
                  213479_at 
                 (I)  
                  8 
                   
                   
                 (I)  
                 (I)  
               
               
                 neuronal 
                   
                 DE/4 
                   
                   
                   
                 HIP 
                 VT 
               
               
                 pentraxin II 
                   
                 52.5% 
                   
                   
                   
                 Fluoxetine 327   
                 Clozapine 171   
               
               
                 THRA 
                  214883_at 
                 (I)  
                  8 
                   
                   
                   
                 thyroxine 
               
               
                 thyroid hormone 
                   
                 DE/4 
                   
                   
                   
                   
                   
               
               
                 receptor, alpha 
                   
                 61.3% 
                   
                   
                   
                   
                   
               
               
                 VEGFA 
                  211527_x_at 
                 (I)  
                  8 
                   
                   
                 (I)  
                 (I)  
               
               
                 vascular 
                   
                 DE/2 
                   
                   
                   
                 Cortex 
                 Plasma 
               
               
                 endothelial  
                   
                 45.3% 
                   
                   
                   
                 Fluoxetine 328   
                 Antipsychotics 204   
               
               
                 growth factor A 
                   
                   
                   
                   
                   
                   
                 (I)  
               
               
                   
                   
                   
                   
                   
                   
                   
                 Blood Steroid 329   
               
               
                 GAP43 
                  204471_at 
                 (I)  
                  7 
                   
                   
                   
                 (I)  
               
               
                 growth associated 
                   
                 DE/4 
                   
                   
                   
                   
                 Human 
               
               
                 protein 43 
                   
                 50.8% 
                   
                   
                   
                   
                 astrocyte-derived 
               
               
                   
                   
                   
                   
                   
                   
                   
                 cells (U-87 MG) 
               
               
                   
                   
                   
                   
                   
                   
                   
                 Valproate 330   
               
               
                   
                   
                   
                   
                   
                   
                   
                 (I)  
               
               
                   
                   
                   
                   
                   
                   
                   
                 HIP 
               
               
                   
                   
                   
                   
                   
                   
                   
                 Benzodiazepines 331   
               
               
                 RAB7A 
                  227602_at 
                 (I)  
                  7 
                   
                   
                 (I) 
                 (I)  
               
               
                 RAB7A, member 
                   
                 AP/2 
                   
                   
                   
                 basal forebrain 
                 Caudate putamen 
               
               
                 RAS oncogene 
                   
                 43.8% 
                   
                   
                   
                 TCA 332   
                 Valproate 222   
               
               
                 family 
                   
                 (I)  
                   
                   
                   
                   
                   
               
               
                   
                   
                 DE/4 
                   
                   
                   
                   
                   
               
               
                   
                   
                 69.6% 
                   
                   
                   
                   
                   
               
               
                 KIDINS220 
                  214932_at 
                 (I)  
                  6 
                   
                   
                   
                 (I)  
               
               
                 kinase 
                   
                 DE/4 
                   
                   
                   
                   
                 VT 
               
               
                 D-interacting 
                   
                 51.9% 
                   
                   
                   
                   
                 Clozapine 171   
               
               
                 substrate 
                   
                   
                   
                   
                   
                   
                   
               
               
                 220 kDa 
                   
                   
                   
                   
                   
                   
                   
               
               
                 CD36 
                  242197_x_at 
                 (D)  
                  6 
                   
                   
                   
                 (D)  
               
               
                 CD36 molecule 
                   
                 DE/4 
                   
                   
                   
                   
                 Lymphocytes 
               
               
                 (thrombospondin 
                   
                 67.1% 
                   
                   
                   
                   
                 Benzodiazepines 331   
               
               
                 receptor) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 CEP350 
                  204373_s_at 
                 (D)  
                  6 
                   
                   
                 (D)  
                   
               
               
                 centrosomal 
                   
                 DE/4 
                   
                   
                   
                 AMY 
                   
               
               
                 protein 
                   
                 67.1% 
                   
                   
                   
                 Antidepressants, 
                   
               
               
                 350 kDa 
                   
                   
                   
                   
                   
                 Fluoxetine 225   
                   
               
               
                 ITPKB 
                 1554306_at 
                 (D)  
                  6 
                   
                 (D)  
                   
                   
               
               
                 inositol- 
                   
                 AP/4 
                   
                   
                 lymphocytes  
                   
                   
               
               
                 triphosphate 
                   
                 61.1% 
                   
                   
                 (males) 
                   
                   
               
               
                 3-kinase B 
                   
                 (D)  
                   
                   
                 Omega-3  
                   
                   
               
               
                   
                   
                 DE/4 
                   
                   
                 fatty acids 318   
                   
                   
               
               
                   
                   
                 55.7% 
                   
                   
                   
                   
                   
               
               
                 NRP2 
                  222877_at 
                 (I)  
                  6 
                   
                   
                   
                 (I)  
               
               
                 neuropilin 2 
                   
                 DE/4 
                   
                   
                   
                   
                 CP 
               
               
                   
                   
                 61.3% 
                   
                   
                   
                   
                 Clozapine 171   
               
               
                 PER1 
                  242832_at 
                 (I)  
                  6 
                 (I)  
                   
                   
                 (I)  
               
               
                 period circadian 
                   
                 DE/4 
                   
                 Cerebral 
                   
                   
                 VT 
               
               
                 clock 1 
                   
                 61.3% 
                   
                 cortex (right) 
                   
                   
                 Clozapine 171   
               
               
                   
                   
                   
                   
                 Lithium 333   
                   
                   
                 (I)  
               
               
                   
                   
                   
                   
                 (I)  
                   
                   
                 AMY 
               
               
                   
                   
                   
                   
                 lymphoblastoid 
                   
                   
                 Quetiapine 335   
               
               
                   
                   
                   
                   
                 cell lines (LCLs) 
                   
                   
                   
               
               
                   
                   
                   
                   
                 derived 
                   
                   
                   
               
               
                   
                   
                   
                   
                 Lithium 334   
                   
                   
                   
               
               
                 UBE21 
                  233360_at 
                 (D)  
                  6 
                   
                   
                   
                 (D)  
               
               
                 ubequitin  
                   
                 DE/6 
                   
                   
                   
                   
                 VT 
               
               
                 conjugating 
                   
                 86.8% 
                   
                   
                   
                   
                 Clozapine 171   
               
               
                 enzyme E2I 
                   
                   
                   
                   
                   
                   
                   
               
               
                 FOXO3 
                  231548_at 
                 (I)  
                  4 
                   
                   
                   
                 (I)  
               
               
                 forkhead 
                   
                 AP/2 
                   
                   
                   
                   
                 Lymphocytes,  
               
               
                 box O3 
                   
                 38.9% 
                   
                   
                   
                   
                 VT Clozapin 171   
               
               
                   
                   
                 (I)  
                   
                   
                   
                   
                   
               
               
                   
                   
                 DE/6 
                   
                   
                   
                   
                   
               
               
                   
                   
                 82.3% 
                   
                   
                   
                   
                   
               
               
                 RHEB 
                  243008_at 
                 (D)  
                  4 
                   
                   
                   
                 (D)  
               
               
                 Ras homolog 
                   
                 AP/6 
                   
                   
                   
                   
                 NR1 336   
               
               
                 enriched in brain 
                   
                 84.4% 
                   
                   
                   
                   
                   
               
               
                   
                   
                 (D)  
                   
                   
                   
                   
                   
               
               
                   
                   
                 DE/4 
                   
                   
                   
                   
                   
               
               
                   
                   
                 64.1% 
                   
                   
                   
                   
                   
               
               
                 UBE2L3 
                  200682_s_at 
                 (D)  
                  4 
                   
                   
                   
                 (D)  
               
               
                 ubiquitin 
                   
                 DE/6 
                   
                   
                   
                   
                 VT 
               
               
                 conjugating 
                   
                 91% 
                   
                   
                   
                   
                 Clozapine 171   
               
               
                 enzyme E2L 3 
               
               
                   
               
            
           
         
       
     
     Tables 4A &amp; 4B. Methods for Personalized Assessment of Memory State (Table 4A) and Prediction of Future Risk for Alzheimer and Related Disorders (Table 4B). Personalized by Gender and Psychiatric Diagnosis. 
     M—males; F—females; BP—bipolar; MDD—Major Depressive Disorder; PTSD—Post-Traumatic Stress Disorder; PSYCHOSIS—schizophrenia or schizoaffective disorder; SZ—schizophrenia; SZA—schizoaffective disorder; I—increased; D—decreased. 
     N— 
       
     
       
         
           
               
             
               
                 TABLE 4A 
               
             
            
               
                   
               
               
                 Assessment for Memory State 
               
            
           
           
               
               
               
            
               
                   
                   
                 Direction of 
               
               
                   
                   
                 Change in Low 
               
               
                 Diagnosis 
                 Best Individual Biomarker 
                 Memory 
               
               
                   
               
            
           
           
               
               
               
            
               
                 M-BP 
                 NAV2 
                 D 
               
               
                 M-BP 
                 UBE2L3 
                 I 
               
               
                 M-MDD 
                 CD40 
                 I 
               
               
                 M-MDD 
                 LOC101928123 
                 D 
               
               
                 M-PSYCHOSIS 
                 ARSB 
                 D 
               
               
                 M-PTSD 
                 TGFB1 
                 I 
               
               
                 M-SZ 
                 NKTR 
                 I 
               
               
                 M-SZA 
                 ARSB 
                 D 
               
               
                 M-SZA 
                 CD36 
                 I 
               
               
                 F-BP 
                 CACNA1S 
                 D 
               
               
                 F-BP 
                 ITPKB 
                 I 
               
               
                 F-PSYCHOSIS 
                 SERTAD3 
                 I 
               
               
                 F-PSYCHOSIS 
                 LINC01398 
                 D 
               
               
                 F-PTSD 
                 NOCT 
                 I 
               
               
                 F-SZA 
                 SERTAD3 
                 I 
               
               
                 F-SZA 
                 LINC01398 
                 D 
               
               
                   
               
            
           
         
       
     
                     TABLE 4B                  Prediction of Future Risk for Alzheimer&#39;s and Related       Disorders                                 Direction of               Change in Low       Diagnosis   Best Individual Biomarker   Memory                                 M-BP   KIDINS220   D       M-PSYCHOSIS   CEP350   I       M-PSYCHOSIS   CALHM1   D       M-SZ   RHEB   I       M-SZ   MAPT   D                    
Tables 5A-5C. New Therapeutics. Discovery of new method of use for drugs/repurposing. Table 5A. Connectivity Map (CMAP) analysis. Query for signature is done using exact Affymetrix probe sets and direction of change. Drugs that have same gene expression profile effects to our high memory retention biomarkers signatures. A score of 1 indicates the perfect match, i.e. the best potential therapeutic for increasing memory retention. Table 5B. NIH LINCS analysis using the L1000CDS2 (LINCS L1000 Characteristic Direction Signature Search Engine) tool. Query for signature is done using gene symbols and direction of change. Shown are compounds mimicking direction of change in high memory. A higher score indicates a better match. Table 5C. CRowd Extracted Expression of Differential Signatures (CREEDS) analysis. Query for signature is done using gene symbols and direction of change. Shown are compounds mimicking direction of change in high memory. A higher score indicates a better match.
 
Table 5A. Drug repurposing using Connectivity Map (CMAP from Broad Institute/MIT)
 
     
       
         
           
               
             
               
                 TABLE 5A1 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Top Biomarkers CFG ≥ 12 
               
               
                 (n = 23 probe sets; 7 increased and 6 decreased were present in HG-U133A  
               
               
                 array used by CMAP). 
               
               
                 Panel of genes increased in expression: MAPT (2 probe sets), TREM2, GFAP,  
               
               
                 THRA, IGF1, NPTX2 
               
               
                 Panel of genes decreased in  
               
               
                 expression: NPC2, GSK3B, GUSB, TGFB1, APOE, PSEN1 
               
            
           
           
               
               
               
               
            
               
                 rank 
                 CMAP name 
                 score 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 verteporfin 
                 1 
                 A benzoporphyrin derivative, it is a medication used as 
               
               
                   
                   
                   
                 a photosensitizer for photodynamic therapy to eliminate 
               
               
                   
                   
                   
                 the abnormal blood vessels in the eye associated with 
               
               
                   
                   
                   
                 conditions such as the wet form of macular 
               
               
                   
                   
                   
                 degeneration. 
               
               
                 2 
                 pioglitazone 
                 0.987 
                 A drug of the thiazolidinedione (TZD) class with 
               
               
                   
                   
                   
                 hypoglycemic (antihyperglycemic, antidiabetic) action, 
               
               
                   
                   
                   
                 used to treat diabetes. PPAR gamma agonist. There is 
               
               
                   
                   
                   
                 evidence to suggest piolitazone is associated with a 
               
               
                   
                   
                   
                 lower risk of dementia in type 2 diabetics. Phase 3 
               
               
                   
                   
                   
                 clinical trials failed to meet endpoints using 
               
               
                   
                   
                   
                 pioglitazone as a therapeutic for MCI/AD. 
               
               
                 3 
                 salsolidine 
                 0.972 
                 A tetrahydroisoquinoline isolated from plants of the 
               
               
                   
                   
                   
                 genus  Salsola . Tetrahydroisoquinolines are 
               
               
                   
                   
                   
                 steroselective competitive inhibitors of the enzyme 
               
               
                   
                   
                   
                 MAO. They are also a competitive inhibitors of 
               
               
                   
                   
                   
                 COMT. 
               
               
                 4 
                 sulfadimidine 
                 0.97 
                 A sulfonamide antibacterial. 
               
               
                 5 
                 SB-203580 
                 0.968 
                 Specific inhibitor of p38MAPK. 
               
               
                 6 
                 ronidazole 
                 0.966 
                 An antiprotozoal agent used in veterinary medicine. 
               
               
                 7 
                 mesalazine 
                 0.961 
                 Anti-inflammatory salycilate derivative used to treat 
               
               
                   
                   
                   
                 ulcerative colitis. 
               
               
                 8 
                 dioxybenzone 
                 0.946 
                 An organic compound used in sunscreen to block UVB 
               
               
                   
                   
                   
                 and short-wave UVA rays. It is a derivative of 
               
               
                   
                   
                   
                 benzophenone. 
               
               
                 9 
                 metamizole 
                 0.942 
                 A non-steroidal anti-inflammatory drug. 
               
               
                 10 
                 8-azaguanine 
                 0.936 
                 A purine analog with antineoplastic activity. 
               
               
                 11 
                 sulfaphenazole 
                 0.935 
                 A long-acting sulfonamide antibiotic used in the 
               
               
                   
                   
                   
                 treatment of leprosy. 
               
               
                 12 
                 dicoumarol 
                 0.933 
                 A naturally occurring anticoagulant drug that depletes 
               
               
                   
                   
                   
                 stores of vitamin K. In general, vitamin K antagonists 
               
               
                   
                   
                   
                 may have a negative influence on visual memory, 
               
               
                   
                   
                   
                 verbal fluency, and brain volume. 
               
               
                 13 
                 tolazamide 
                 0.915 
                 An intermediate-acting, first-generation sulfonylurea 
               
               
                   
                   
                   
                 with hypoglycemic activity. 
               
               
                 14 
                 pipemidic acid 
                 0.911 
                 A member of the pyridopyrimidine class of 
               
               
                   
                   
                   
                 antibacterials. 
               
               
                 15 
                 NS-398 
                 0.911 
                 A COX-2 inhibitor. May acutely prevent the 
               
               
                   
                   
                   
                 suppression of hippocampal long-term plasticity by 
               
               
                   
                   
                   
                 amyloid beta. 
               
               
                 16 
                 morantel 
                 0.901 
                 An anthelmintic drug used for the removal of parasitic 
               
               
                   
                   
                   
                 worms in livestock. An inhibitor of 
               
               
                   
                   
                   
                 acetylcholinesterase. 
               
               
                 17 
                 indapamide 
                 0.901 
                 A thiazide-like diuretic drug generally used in the 
               
               
                   
                   
                   
                 treatment of hypertension, as well as decompensated 
               
               
                   
                   
                   
                 heart failure. Indapamide has been shown to suppress 
               
               
                   
                   
                   
                 the production of amyloid beta and improve clearance. 
               
               
                 18 
                 promazine 
                 0.893 
                 Blocks postsynaptic dopamine receptors D1 and D2 in 
               
               
                   
                   
                   
                 the mesolimbic and medullary chemoreceptor trigger 
               
               
                   
                   
                   
                 zone. Has significant interaction with multiple 
               
               
                   
                   
                   
                 Alzheimer target proteins. 
               
               
                 19 
                 tinidazole 
                 0.893 
                 A nitroimidazole antitrichomonal agent effective 
               
               
                   
                   
                   
                 against  Trichomonas vaginalis , Entamoeba histolytica, 
               
               
                   
                   
                   
                 and Giardia lamblia infections. 
               
               
                 20 
                 estradiol 
                 0.892 
                 An estrogen steroid hormone. There is evidence that 
               
               
                   
                   
                   
                 suggests lifetime exposure to estrogen seems to lower 
               
               
                   
                   
                   
                 risk of AD. Women who began estradiol treatment 
               
               
                   
                   
                   
                 within one year of menopause had preserved metabolic 
               
               
                   
                   
                   
                 activity in regions in and around the hippocampus. It is 
               
               
                   
                   
                   
                 unclear whether above the age of 50 years, if 
               
               
                   
                   
                   
                 estrogen/estradiol is protective against AD. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5A2 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Top  
               
               
                 Biomarkers CFG ≥ 10 (n = 138 probe sets; 45 increased  
               
               
                 and 38 decreased were present in HG-U133A array used by 
               
               
                 CMAP). 
               
               
                 Panel of genes increased in expression: BCAM, HFE, SLC1A7, FTL,  
               
               
                 MAPT, GFAP, LDLR, SNCA, THRA, C4A, TREM2, CSF1, SNCA,  
               
               
                 VEGFA, IL1A, SNCA, CSF1, NRP2, GAP43, CHAT, KIDINS220, 
               
               
                 NPTX2, ANK1, IGF1, IGHG1, MAPT, FXYD1, LMNA, ANK1, IGHG1,  
               
               
                 AXL, THRA, PPP2R2B, ANK1, RGS10, FCGR1A, LMNA, ITGB5,  
               
               
                 APOA1, ZBTB16, OPHN1, ARG2, TSPAN5, AIMP2, RPL38.  
               
               
                 Panel of genes decreased in expression: APOE, VEGFA, HSPA5,  
               
               
                 ZFP36L1, TGFB1, NDUFA5, DKK1, NOCT, WDR45, IGF1,  
               
               
                 CSF1R, ICAM1, VEGFA, ABCA7, GSK3B, GAPDH (2), SREBF1,  
               
               
                 DUSP6, UQCRC1, TPK1, MICA, PSEN1, PSMA4, GUSB, NDUFS3,  
               
               
                 BST2, TYROBP, CEP350, FDPS, MTF2, NPC2, SERTAD3, HSBP1,  
               
               
                 SEC24A, SNRK, TRIM38, UBE2L3.  
               
            
           
           
               
               
               
               
            
               
                 rank 
                 CMAP name 
                 score 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 levonorgestrel 
                 1 
                 Progesterone derivative used as contraceptive. 
               
               
                   
                   
                   
                 Progesterone and its derivatives have some evidence for 
               
               
                   
                   
                   
                 promoting brain cell growth, at least in adult rats, and some 
               
               
                   
                   
                   
                 studies have shown that it can improve cognitive 
               
               
                   
                   
                   
                 performance in the aging mouse. 
               
               
                 2 
                 aminohippuric 
                 0.955 
                 Non-toxic diagnostic tool to measure effective renal plasma 
               
               
                   
                 acid 
                   
                 flow. 
               
               
                 3 
                 meglumine 
                 0.933 
                 Meglumine, also known as megluminum or 
               
               
                   
                   
                   
                 methylglucamine, belongs to the class of organic 
               
               
                   
                   
                   
                 compounds known as hexoses. Often used as an excipient 
               
               
                   
                   
                   
                 in pharmaceuticals. Methylglucamine orotate is a memory- 
               
               
                   
                   
                   
                 improving drug, although the ortoate component was 
               
               
                   
                   
                   
                 thought to be the active compound. 
               
               
                 4 
                 mesalazine 
                 0.932 
                 Non-steroidal anti-inflammatory drug used to 
               
               
                   
                   
                   
                 treat inflammatory bowel diseases. 
               
               
                 5 
                 lymecycline 
                 0.92 
                 Tetracycline antibiotic; tetracyclines have been shown to 
               
               
                   
                   
                   
                 have beneficial effects in neurodegenerative diseases. 
               
               
                 6 
                 torasemide 
                 0.918 
                 Diuretic. 
               
               
                 7 
                 dioxybenzone 
                 0.916 
                 Sunscreen compound. 
               
               
                 8 
                 ginkgolide A 
                 0.915 
                 A natural compound with neuroprotective and possible AD 
               
               
                   
                   
                   
                 preventing effects. 
               
               
                 9 
                 rimexolone 
                 0.907 
                 Rimexolone is a derivative of prednisolone, a synthetic 
               
               
                   
                   
                   
                 glucocorticoid with anti-inflammatory and 
               
               
                   
                   
                   
                 immunosuppressive property. 
               
               
                 10 
                 ketanserin 
                 0.905 
                 Ketanserin is a selective serotonin receptor antagonist with 
               
               
                   
                   
                   
                 weak adrenergic receptor blocking properties. Effective in 
               
               
                   
                   
                   
                 lowering blood pressure in essential hypertension. Also 
               
               
                   
                   
                   
                 inhibits platelet aggregation. Well tolerated in older 
               
               
                   
                   
                   
                 patients. 
               
               
                 11  
                 dicloxacillin 
                 0.903 
                 A Penicillin-class antibacterial. 
               
               
                 12  
                 talampicillin 
                 0.898 
                 A beta lactam antibiotic from the penicillin family. 
               
               
                 13 
                 sulfadimidine 
                 0.897 
                 A sulfonamide antibacterial. 
               
               
                 14 
                 naringin 
                 0.892 
                 Naturally occurring flavinoid in citrus fruits, especially 
               
               
                   
                   
                   
                 grapefruit. There is evidence in studies with rats that 
               
               
                   
                   
                   
                 narigin acts through inhibition of oxidative cellular stress 
               
               
                   
                   
                   
                 which attenuates autophagic stress especially in the 
               
               
                   
                   
                   
                 hippocampus. Furthermore, there is evidence that ICV-STZ 
               
               
                   
                   
                   
                 rats chronically treated with naringin dose dependently 
               
               
                   
                   
                   
                 restored cognitive deficits. 
               
               
                 15 
                 naproxen 
                 0.891 
                 Nonsteroidal anti-inflammatory drug. Several large scale 
               
               
                   
                   
                   
                 studies have demonstrated that long term treatment with 
               
               
                   
                   
                   
                 naproxen confers no protection against cognitive decline. 
               
               
                 16 
                 flunixin 
                 0.888 
                 A nonsteroidal anti-inflammatory drug, analgesic, and 
               
               
                   
                   
                   
                 antipyretic used in horses, cattle and pigs. 
               
               
                 17 
                 tubocurarine 
                 0.887 
                 A neuromuscular blocker and active ingredient in curare; 
               
               
                   
                 chloride 
                   
                 plant based alkaloid of Menispermaceae. There is evidence 
               
               
                   
                   
                   
                 that anticholinergics in general are associated with future 
               
               
                   
                   
                   
                 incidence of dementia. 
               
               
                 18 
                 cyanocobalamin 
                 0.885 
                 Vitamin B12. There is evidence that increased plasma 
               
               
                   
                   
                   
                 levels of homocysteine (which can be caused by low levels 
               
               
                   
                   
                   
                 of vitamin B12) is a strong and independent risk factor for 
               
               
                   
                   
                   
                 the development of dementia and AD. 
               
               
                 19 
                 dequalinium 
                 0.883 
                 A topical bacteriostat. There is evidence that dequalinium 
               
               
                   
                 chloride 
                   
                 induces protofibril formation of alpha-synuclein. 
               
               
                 20 
                 meticrane 
                 0.882 
                 A sulphonamide-derivative with thiazide-like diuretic 
               
               
                   
                   
                   
                 activity. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5A3 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Predictive 
               
               
                 Biomarkers in All (n = 16 probe sets/genes; 5 increased and 11  
               
               
                 decreased were present in HG-U133A array used by CMAP).  
               
               
                 Panel of genes increased in expression: FCGR1A, GAP43, MAPT, HFE, RGS10,  
               
               
                 Panel of genes decreased in expression: NDUFA5, SEC24A, PSMA4,  
               
               
                 UBE2L3, NPC2, GUSB, TGFB1, TRIM38, CD40, ZNF345, IGF1. 
               
            
           
           
               
               
               
               
            
               
                 rank 
                 CMAP name 
                 score 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 mesalazine 
                 1 
                 Non-steroidal anti-inflammatory drug used to 
               
               
                   
                   
                   
                 treat inflammatory bowel diseases. 
               
               
                 2 
                 mepenzolate 
                 0.985 
                 An oral, quaternary anticholinergic gastrointestinal agent 
               
               
                   
                 bromide 
                   
                 used for adjunctive treatment of peptic ulcer disease. 
               
               
                 3 
                 ozagrel 
                 0.974 
                 Antiplatelet agent working as a thromboxane A2 synthesis 
               
               
                   
                   
                   
                 inhibitor. Commonly used in the treatment of stroke. 
               
               
                 4 
                 protriptyline 
                 0.954 
                 A tricyclic antidepressant that increases the synaptic 
               
               
                   
                   
                   
                 concentration of serotonin and/or norepinephrine. In vitro, 
               
               
                   
                   
                   
                 protriptyline has been shown to inhibit 
               
               
                   
                   
                   
                 acetylcholinesterase, β-secretase, amyloid β aggregation, 
               
               
                   
                   
                   
                 and glycation induced amyloid aggregation-all causal 
               
               
                   
                   
                   
                 factors in AD progression (Bansode et al. 2014) 
               
               
                 5 
                 guanfacine 
                 0.945 
                 A selective alpha 2A -adrenoreceptor agonist that is used as 
               
               
                   
                   
                   
                 an antihypertensive. It also preferentially binds 
               
               
                   
                   
                   
                 postsynaptic alpha 2A -adrenoreceptors in the prefrontal 
               
               
                   
                   
                   
                 cortex which allows its use in improving symptoms 
               
               
                   
                   
                   
                 associated with ADHD. It is not a CNS stimulant. 
               
               
                 6 
                 saquinavir 
                 0.94 
                 An anti-retroviral protease inhibitor commonly used in the 
               
               
                   
                   
                   
                 treatment of HIV. 
               
               
                 7 
                 tomatidine 
                 0.938 
                 A steroidal alkaloid that has been found in the skins and 
               
               
                   
                   
                   
                 leaves of tomatoes. It suppresses NF-κB signaling in LPS- 
               
               
                   
                   
                   
                 stimulated macrophages, blocking induced expression of 
               
               
                   
                   
                   
                 inducible nitric oxide synthase and COX-2. 
               
               
                 8 
                 eldeline 
                 0.936 
                   
               
               
                 9 
                 zuclopenthixol 
                 0.931 
                 An antipsychotic agent working as an antagonist at D1 and 
               
               
                   
                   
                   
                 D2 dopamine receptors. 
               
               
                 10 
                 fenoterol 
                 0.929 
                 A synthetic adrenergic β 2 -agonist that is used as a 
               
               
                   
                   
                   
                 bronchodilator and tocolytic. 
               
               
                 11 
                 vincamine 
                 0.929 
                 A monoterpenoid indole alkaloid obtained from the leaves 
               
               
                   
                   
                   
                 of  Vinca minor  with a vasodilatory property. 
               
               
                 12 
                 imipenem 
                 0.926 
                 A carbapenem antibacterial. 
               
               
                 13 
                 isradipine 
                 0.924 
                 A second generation calcium channel blocker that is used 
               
               
                   
                   
                   
                 to treat hypertension. 
               
               
                 14 
                 3-hydroxy-DL- 
                 0.919 
                 A metabolite of tryptophan, which filters UV light in the 
               
               
                   
                 kynurenine 
                   
                 human lens. 
               
               
                 15 
                 amiodarone 
                 0.912 
                 A class III antiarrhythmic agent, amiodarone blocks the 
               
               
                   
                   
                   
                 myocardial calcium, potassium and sodium channels in 
               
               
                   
                   
                   
                 cardiac tissue, resulting in prolongation of the cardiac 
               
               
                   
                   
                   
                 action potential and refractory period. In addition, this 
               
               
                   
                   
                   
                 agent inhibits alpha- and beta-adrenergic receptors, 
               
               
                   
                   
                   
                 resulting in a reduction in sympathetic stimulation of the 
               
               
                   
                   
                   
                 heart, a negative chronotropic effect, and a decrease in 
               
               
                   
                   
                   
                 myocardial oxygen demands. 
               
               
                 16 
                 lansoprazole 
                 0.911 
                 A proton pump inhibitor (PPI) and a potent inhibitor of 
               
               
                   
                   
                   
                 gastric acidity. 
               
               
                 17 
                 nialamide 
                 0.911 
                 A non-selective, irreversible monoamine oxidase inhibitor 
               
               
                   
                   
                   
                 of the hydrazine class that was used as an antidepressant. It 
               
               
                   
                   
                   
                 was withdrawn by Pfizer several decades ago due to the 
               
               
                   
                   
                   
                 risk of hepatotoxicity. 
               
               
                 18 
                 hydralazine 
                 0.909 
                 An antihypertensive with vasodilatory effects. 
               
               
                 19 
                 S-propranolol 
                 0.906 
                 The active enantiomer of propranolol, a β-adrenergic 
               
               
                   
                   
                   
                 receptor antagonist. 
               
               
                 20 
                 nomifensine 
                 0.906 
                 A norepinephrine-dopamine reuptake inhibitor. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5A4 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Predictive  
               
               
                 Biomarkers in Males (n = 17 probe sets/genes; 6 increased and 11  
               
               
                 decreased were present in HG-U133A array used by CMAP). 
               
               
                 Panel of genes increased in expression: FCGR1A, GAP43, MAPT,  
               
               
                 KIDINS220, AIMP2, RGS10 
               
               
                 Panel of genes decreased in expression: NDUFA5, SEC24A, PSMA4, UBE2L3, 
               
               
                 NPC2, BST2, TGFB1, TRIM38, ZNF345, IGF1, VEGFA 
               
            
           
           
               
               
               
               
            
               
                 rank 
                 CMAP name 
                 score 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 natamycin 
                 1 
                 Ophthalmic antifungal suspension. 
               
               
                 2 
                 mepenzolate 
                 0.9 
                 An oral, quaternary anticholinergic gastrointestinal agent 
               
               
                   
                 bromide 
                   
                 used for adjunctive treatment of peptic ulcer disease. 
               
               
                 3 
                 valinomycin 
                 0.896 
                 A natural antibiotic derived from  Streptomyces . It also 
               
               
                   
                   
                   
                 binds potassium ions and facilitates their transfer across 
               
               
                   
                   
                   
                 lipid bilayers. 
               
               
                 4 
                 aminohippuric 
                 0.881 
                 Non-toxic diagnostic tool to measure effective renal 
               
               
                   
                 acid 
                   
                 plasma flow. 
               
               
                 5 
                 dexpropranolol 
                 0.859 
                 A non-selective β-adrenergic blocker. Studies have shown 
               
               
                   
                   
                   
                 propranolol reduces cognitive deficits and amyloid/tau 
               
               
                   
                   
                   
                 pathology in AD simulated mice. 
               
               
                 6 
                 valproic acid 
                 0.851 
                 A histone deacetylase inhibitor commonly used as an 
               
               
                   
                   
                   
                 anticonvulsant and antimanic agent. Studies show valproic 
               
               
                   
                   
                   
                 acid enhances memory and cognition in mice models. 
               
               
                 7 
                 dicloxacillin 
                 0.85 
                 A penicillin antibiotic. 
               
               
                 8 
                 pronetalol 
                 0.837 
                 An early non-selective β-blocker candidate that was not 
               
               
                   
                   
                   
                 used clinically as it formed a carcinogenic metabolite in 
               
               
                   
                   
                   
                 mice. 
               
               
                 9 
                 iobenguane 
                 0.837 
                 A guanidine analog with specific affinity for tissues of the 
               
               
                   
                   
                   
                 sympathetic nervous system. The radiolabeled forms are 
               
               
                   
                   
                   
                 used as antineoplastic or radioactive imaging agents. May 
               
               
                   
                   
                   
                 be useful for diagnosing AD or dementia with Lewey 
               
               
                   
                   
                   
                 bodies. 
               
               
                 10 
                 todralazine 
                 0.829 
                 An antihypertensive agent with central and peripheral 
               
               
                   
                   
                   
                 action. It has some CNS depressant effects as well. 
               
               
                 11 
                 torasemide 
                 0.827 
                 An anilinopyridine sulfonylurea belonging to the class of 
               
               
                   
                   
                   
                 loop diuretics. 
               
               
                 12 
                 gallamine 
                 0.824 
                 A non-depolarising muscle relaxant. It acts by combining 
               
               
                   
                 triethiodide 
                   
                 with the cholinergic receptor sites in muscle and 
               
               
                   
                   
                   
                 competitively blocking the transmitter action of 
               
               
                   
                   
                   
                 acetylcholine. 
               
               
                 13 
                 sulconazole 
                 0.822 
                 An antifungal medication of the imidazole class. 
               
               
                 14 
                 chlormezanone 
                 0.82 
                 A non-benzodiazepine muscle relaxant. It was 
               
               
                   
                   
                   
                 discontinued worldwide in 1996 due to rare but serious 
               
               
                   
                   
                   
                 cases of toxic epidermal necrolysis. 
               
               
                 15 
                 amantadine 
                 0.818 
                 A primary amine that has both antiviral and dopaminergic 
               
               
                   
                   
                   
                 activity and is used in the therapy of influenza A and 
               
               
                   
                   
                   
                 management of Parkinson disease. 
               
               
                 16 
                 tubocurarine 
                 0.818 
                 A neuromuscular blocker and active ingredient in curare; 
               
               
                   
                 chloride 
                   
                 plant based alkaloid of Menispermaceae. 
               
               
                 17 
                 protriptyline 
                 0.805 
                 A tricyclic antidepressant. 
               
               
                 18 
                 indometacin 
                 0.8 
                 A nonsteroidal anti-inflammatory drug (NSAID). 
               
               
                 19 
                 thioguanosine 
                 0.799 
                 A thio analogue of the naturally occurring purine base 
               
               
                   
                   
                   
                 guanine used to treat acute myeloid leukemia, acute 
               
               
                   
                   
                   
                 lymphocytic leukemia, and chronic myeloid leukemia. 
               
               
                 20 
                 adenosine 
                 0.797 
                 A nucleotide that is found in RNA. 
               
               
                   
                 phosphate 
                   
                   
               
               
                   
               
            
           
         
       
     
                     TABLE 5A5                  Drugs Identified Using Gene Expression Panels of Predictive Biomarkers       in Females (n = 13 probe sets/genes; 1 increased and 4 decreased were present       in HG-U133A array used by CMAP).        Panel of genes increased in expression: CHAT        Panel of genes decreased in expression: GUSB, CD40, SERTAD3, TBRG4                             rank   CMAP name   score   Description                                     1   benserazide   1   Peripherally acting aromatic L-amino acid decarboxylase                   or DOPA decarboxylase inhibitor, which is unable to                   cross the blood-brain barrier. Recent studies by Jonkers                   et al. and Shen et al. revealed that benserazide can enter                   the brain and affect levodopa metabolism.       2   TTNPB   0.99   Selective and highly potent retinoic acid analog with                   affinity for retinoic acid receptors (RAR) α, β, and γ,                   which are nuclear transcription factors. Activation of                   RAR and RXR is known to impede the pathogenesis of                   AD in mice by inhibiting accumulation of amyloids.       3   suxibuzone   0.979   Analgesic used for joint and muscular pain.       4   15-delta   0.962   Prostaglandin J derivative. It has a role as a metabolite,           prostaglandin J2       an electrophilic reagent and an insulin-sensitizing drug.                   Koma et al. found 15d-PGJ2-impaired memory retrieval                   significantly. Pereira et al. concluded therapeutic                   potential of targeting the J2 prostaglandin pathway to                   prevent/delay neurodegeneration associated with                   neuroinflammation       5   hydroquinine   0.961   Anti-arrhythmia agent and parasympatholytic.       6   rosiglitazone   0.954   An antidiabetic drug in the thiazolidinedione class. It                   works as an insulin sensitizer, by binding to the PPAR in                   fat cells and making the cells more responsive to insulin.                   Rosiglitazone reverses memory decline and hippocampal                   glucocorticoid receptor down-regulation in an                   Alzheimer&#39;s disease mouse model (Escribano 2009). In                   Phase 2 clinical trials for determining role in learning and                   memory in patients diagnosed with MCI.       7   colchicine   0.942   An anti-inflammatory which acts by inhibition of                   microtubule polymerization. Impairs memory function in                   a dose-dependent manner and is used as a model to                   induce Alzheimer&#39;s disease in rats.       8   2,6-   0.942   —           dimethylpiperidine               9   primaquine   0.939   An antimalarial agent that acts by interfering with the                   mitochondria of parasites.       10   15-delta   0.931   Prostaglandin J derivative. It has a role as a metabolite,           prostaglandin J2       an electrophilic reagent and an insulin-sensitizing drug.                   Koma et al. found 15d-PGJ2-impaired memory retrieval                   significantly. Pereira et al. concluded therapeutic                   potential of targeting the J2 prostaglandin pathway to                   prevent/delay neurodegeneration associated with                   neuroinflammation       11   meropenem   0.925   Carbapenem antibiotic.       12   anabasine   0.924   A nicotine analog that is an alkaloid. Has demonstrated                   improvement in memory and attention in rats.       13   cyclizine   0.919   A piperazine-derivative antihistamine used as an                   antivertigo/antiemetic agent.       14   norcyclobenzaprine   0.919   A metabolite of cyclobenzaprine (a muscle relaxant).       15   naftopidil   0.918   An α1-adrenergic receptor antagonist.       16   BAS-012416453   0.914   —       17   AG-012559   0.912   —       18   terbutaline   0.91   A β2 adrenergic receptor agonist.       19   clomipramine   0.908   A tricyclic antidepressant used in the therapy of                   obsessive-compulsive disorder. Associated with                   diminished metamemory and impaired priming and                   working memory.       20   methyldopa   0.904   An antihypertensive that is a competitive inhibitor of the                   enzyme DOPA decarboxylase which converts L-DOPA                   into dopamine. Has been associated with verbal memory                   impairment.                    
Table 5B. Drug repurposing using L1000 Characteristic Direction Signature Search Engine.
 
     
       
         
           
               
             
               
                 TABLE 5B1 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Top Biomarkers CFG ≥ 
               
               
                 12 (n = 18 unique genes; 8 increased and 10 decreased). 
               
               
                 Panel of genes increased in expression: MAPT, GFAP, TREM2, ARSB, 
               
               
                 IGF1, THRA, NPTX2 
               
               
                 BACE1 
               
               
                 Panel of genes decreased in expression: GSK3B, NPC2, PTGS2, PSEN1,  
               
               
                 CTSS, GSTM3, UBE2I, GUSB, APOE, TGFB1 
               
            
           
           
               
               
               
               
            
               
                 Rank 
                 Score 
                 Drug 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 0.2778 
                 BRD-K03371390 
                   
               
               
                 2 
                 0.2778 
                 NCGC00185923-01 
                   
               
               
                 3 
                 0.2222 
                 BENZANTHRONE 
                 Dye that binds to amyloid fibrils. 
               
               
                 4 
                 0.2222 
                 SQ 22536 
                 Adenylyl cyclase inhibitor. 
               
               
                 5 
                 0.2222  
                 ICARIIN 
                 Prenylated flavanol glycoside from Epimedium 
               
               
                   
                   
                   
                 sagittatum. Jin et al. 2014 has found that Icariin 
               
               
                   
                   
                   
                 significantly improved learning and memory of 
               
               
                   
                   
                   
                 transgenic mice models of AD via stimulation of 
               
               
                   
                   
                   
                 the NO/cGMP pathway. Sheng et al. 2017 
               
               
                   
                   
                   
                 concluded that Icariin improves synaptic 
               
               
                   
                   
                   
                 plasticity, and therefore learning and memory, in 
               
               
                   
                   
                   
                 rat models of AD via the BDNF/TrkB/Akt 
               
               
                   
                   
                   
                 pathway. 
               
               
                 6 
                 0.2222 
                 YM 90709 
                 IL-5 receptor antagonist. 
               
               
                 7 
                 0.2222 
                 QUIPAZINE 
                 Binds to serotonin receptors, particularly to 
               
               
                   
                   
                 MALEATE 
                 5HT2A and 5HT3. 
               
               
                 8 
                 0.2222 
                 Cisapride 
                 Serotonin 5-HT 4  receptor agonist. Galeotti et al. 
               
               
                   
                   
                   
                 1997 revealed that cisapride prevented 
               
               
                   
                   
                   
                 dicylomine-induced amnesia in mice suggesting 
               
               
                   
                   
                   
                 it plays an important role in modulation of 
               
               
                   
                   
                   
                 memory processes. No further studies have been 
               
               
                   
                   
                   
                 published. 
               
               
                 9 
                 0.2222 
                 LEUCINE 
                 Enkephalin. Meilandt et al. 2008 found that 
               
               
                   
                   
                 ENKEPHALIN 
                 enkephalin elevations may contribute to 
               
               
                   
                   
                   
                 cognitive impairments in mice models of AD. 
               
               
                 10 
                 0.2222 
                 MLN4924 
                 An ubiquitin-like protein with roles relevant to 
               
               
                   
                   
                   
                 cellular processes important for cancer cell 
               
               
                   
                   
                   
                 survival. 
               
               
                 11 
                 0.2222 
                 2-(trifluoromethyl)- 
                   
               
               
                   
                   
                 10H-phenothiazine 
                   
               
               
                 12 
                 0.2222 
                 brucine 
                 An alkaloid antagonist at glycine receptors and 
               
               
                   
                   
                   
                 paralyzes inhibitory neurons. It is a low potency 
               
               
                   
                   
                   
                 M 1  positive allosteric modulator. 
               
               
                   
                   
                   
                 There is high expression of M 1  in areas of the 
               
               
                   
                   
                   
                 brain responsible for learning, cognition, and 
               
               
                   
                   
                   
                 memory. 
               
               
                 13 
                 0.2222 
                 Clodronate 
                 A bisphosphonate that affects calcium 
               
               
                   
                   
                   
                 metabolism and inhibits bone resorption. Park 
               
               
                   
                   
                   
                 et al. 2017 concluded that in mice studies 
               
               
                   
                   
                   
                 clodronate diminishes brain perivascular 
               
               
                   
                   
                   
                 macrophages which prohibits amyloid-beta 
               
               
                   
                   
                   
                 from damaging brain blood vessels. 
               
               
                   
                   
                   
                 However, this effect is limited to a few weeks. 
               
               
                 14 
                 0.1667 
                 Vincristine sulfate 
                 An alkaloid that irreversibly binds to 
               
               
                   
                   
                   
                 microtubules and spindle proteins. It is an 
               
               
                   
                   
                   
                 antineoplastic agent used to treat a variety of 
               
               
                   
                   
                   
                 cancers. 
               
               
                 15 
                 0.1667 
                 AZ 10417808 
                 A selective caspase-3 inhibitor. 
               
               
                 16 
                 0.1667 
                 CCCP 
                 A proton ionophore. 
               
               
                 17 
                 0.1667 
                 Flurofamide 
                 A potent inhibitor of bacterial urease. 
               
               
                 18 
                 0.1667 
                 Chelidonine (+) 
                 An inhibitor of tubulin polymerization inducing a 
               
               
                   
                   
                   
                 G2/M mitotic arrest. Dickey et al. 2006 reported 
               
               
                   
                   
                   
                 that chelidonine reduced tau levels in vitro. 
               
               
                 19 
                 0.1667 
                   
                 Commonly known as turmeric. It is a scavenger 
               
               
                   
                   
                   
                 of oxygen species and inhibits lipid peroxidation 
               
               
                   
                   
                   
                 as well as peroxide-induced DNA damage. Small 
               
               
                   
                   
                   
                 et al. 2018 found that daily oral curcumin may 
               
               
                   
                   
                   
                 lead to improved memory and attention in non- 
               
               
                   
                   
                   
                 demented adults. Zhang et al. 2006 concluded 
               
               
                   
                   
                   
                 that curcumin may enhance amyloid-beta uptake 
               
               
                   
                   
                   
                 by macrophages in AD patients. 
               
               
                   
                   
                   
                 Lin et al. 2008 reported that curcumin 
               
               
                   
                   
                   
                 significantly blocks the formative effect of iron 
               
               
                   
                   
                   
                 on neurofibrillary tangles in vitro. 
               
               
                   
                   
                   
                 Several studies have revealed anti-Alzheimer&#39;s 
               
               
                   
                   
                   
                 effects in mice and rat models (Lim et al. 2001, 
               
               
                   
                   
                   
                 Garcia-Alloza et al. 2007, Ahmed et al. 2011). 
               
               
                 20 
                 0.1667 
                 rizatriptan 
                 A selective agonist of serotonin type 1B and 
               
               
                   
                   
                   
                 1D receptors. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B2 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Top Biomarkers  
               
               
                 CFG ≥ 10 (n = 112 unique genes; 53 increased and 59 decreased). 
               
               
                 Panel of genes increased in expression: LMNA, FOXO3, CCND2, PMP22, BCAM,  
               
               
                 ELOVL6, HFE, NAV2, SLC1A7, FTL, MAPT, GFAP, LDLR, C4A, SNCA, THRA,  
               
               
                 TREM2, CSF1, IL1A, NRP2, GAP43, RCOR1, KIDINS220, CHAT,  
               
               
                 NPTX2, PON2, ANK1, IGF1, IGHG1, KLF3, FXYD1, COX6A1  
               
               
                 AXL, PER1, SH3RF2, PPP2R2B, CLDN10, RGS10, FCGR1A, ITGB5,  
               
               
                 APOA1, WASF2, ZBTB16, OPHN1, ARG2, SHC3, TSPAN5, NLGN3,  
               
               
                 ARSB, AIMP2, CSNK1A1, RPL38, BACE1  
               
               
                 Panel of genes decreased in expression: GSK3B, APOE, HELZ, VEGFA,  
               
               
                 HSPA5, ZFP36L1 
               
               
                 TGFB1, NDUFA5, ITPKB, DKK1, NOCT, SLC44A1, RHEB, NKTR, PGK1,  
               
               
                 SALL3, WDR45, CSF1R  
               
               
                 ICAM1, ABCA7, INPP5D, GAPDH, DUSP6, SREBF1, UQCRC1, TPK1,  
               
               
                 GSTM3, MICA, DLD, PSMA4  
               
               
                 PSEN1, GUSB, BST2, CD36, NDUFS3, CTSS, MPEG1, TYROBP, B2M,  
               
               
                 RNASET2, FNBP1, USPL1  
               
               
                 CEP350, FDPS, MTF2, RAB7A, PTGS2, NPC2, LYST, SERTAD3, SEC24A,  
               
               
                 HSBP1, SNRK, TRIM38  
               
               
                 NUP214, UBE2I, ASPHD2, UBE2L3, ZC3HAV1.  
               
            
           
           
               
               
               
               
            
               
                 Rank 
                 Score 
                 Drug 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 0.1038 
                 Proparacaine hydrochloride 
                 Local anesthetic 
               
               
                 2 
                 0.0943 
                 BRD-K00944562 
                   
               
               
                 3 
                 0.0943 
                 BRD-A80151636 
                   
               
               
                 4 
                 0.0943 
                 BRD-K05361803 
                   
               
               
                 5 
                 0.0943 
                 BRD-K82137294 
                   
               
               
                 6 
                 0.0943 
                 BRD-K34206396 
                   
               
               
                 7 
                 0.0943 
                 Pioglitazone 
                 A drug of the thiazolidinedione 
               
               
                   
                   
                   
                 (TZD) class with hypoglycemic 
               
               
                   
                   
                   
                 (antihyperglycemic, antidiabetic) 
               
               
                   
                   
                   
                 action, used to treat diabetes 
               
               
                 8  
                 0.0849 
                 TENOXICAM 
                 NSAID 
               
               
                 9  
                 0.0849 
                 AC-1133 
                   
               
               
                 10  
                 0.0849 
                 Vincamine 
                 An antihypertensive with 
               
               
                   
                   
                   
                 vasodilatory effects. 
               
               
                 11 
                 0.0755 
                 5-nonyloxytryptamine 
                 An 5-HT1B selective agonist. 
               
               
                 12 
                 0.0755 
                 CINANSERIN 
                 A serotonin antagonist. 
               
               
                 13 
                 0.0755 
                 Phenoxazine 
                 A dye which consists of an 
               
               
                   
                   
                   
                 oxazine fused to two benzene 
               
               
                   
                   
                   
                 rings. 
               
               
                 14 
                 0.0755 
                 elesclomol 
                 An inducer of heat shock protein 
               
               
                   
                   
                   
                 70 that activates natural killer cell- 
               
               
                   
                   
                   
                 mediated tumor killing. 
               
               
                 15 
                 0.0755 
                 curcumin 
                 A scavenger of oxygen species 
               
               
                   
                   
                   
                 and inhibits lipid peroxidation as 
               
               
                   
                   
                   
                 well as peroxide-induced DNA 
               
               
                   
                   
                   
                 damage. 
               
               
                 16 
                 0.0755 
                 TOLAZAMIDE 
                 A sulfonylurea with hypoglycemic 
               
               
                   
                   
                   
                 activity. 
               
               
                 17 
                 0.0755 
                 Gly-Gly-delta-N-(phosphonacetyl)-L- 
                   
               
               
                   
                   
                 ornithine 
                   
               
               
                 18 
                 0.0755 
                 bestatin 
                 A metalloprotease inhibitor 
               
               
                   
                   
                   
                 selective for aminopeptidase. 
               
               
                 19 
                 0.0755 
                 levofloxacin 
                 A fluoroquinolone antibiotic. 
               
               
                 20 
                 0.0755 
                 valaciclovir 
                 A DNA polymerase inhibitor. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B3 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Predictive Biomarkers in 
               
               
                 All (n = 31 genes; 14 increased and 17 decreased). 
               
               
                 Panel of genes increased in expression: FCGR1A, GAP43, MAPT, HFE, RGS10,  
               
               
                 CALHM1 ARSB, LOC101928760, LOC101928123, RAB7A, TYMSOS,  
               
               
                 LOC100499194, ITPKB, LOC105371414 
               
               
                 Panel of genes decreased in expression: NDUFA5, SEC24A, PSMA4, UBE2L3,  
               
               
                 NPC2, GUSB, TGFB1, TRIM38, CD40, ZNF345, IGF1, LOC101927027,  
               
               
                 MIS18BP1, RHEB, CARD11, NKTR, MS4A14 
               
            
           
           
               
               
               
               
            
               
                 Rank 
                 Score 
                 Drug 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 0.1818 
                 CUNEATIN METHYL ETHER 
                   
               
               
                 2 
                 0.1818 
                 GR 159897 
                 A potent and selective NK 2   
               
               
                   
                   
                   
                 receptor antagonist. 
               
               
                 3 
                 0.1818 
                 Compound 58 
                   
               
               
                 4 
                 0.1818 
                 ROLIPRAM 
                 A selective phosphodiesterase-4 
               
               
                   
                   
                   
                 inhibitor. 
               
               
                 5 
                 0.1818 
                 BRD-K01089529 
                   
               
               
                 6 
                 0.1818 
                 BRD-K15888437 
                   
               
               
                 7 
                 0.1818 
                 BRD-K17025677 
                   
               
               
                 8 
                 0.1818 
                 7618107 
                   
               
               
                 9 
                 0.1818 
                 BL-074 
                   
               
               
                 10 
                 0.1818 
                 BRD-A79981887 
                   
               
               
                 11 
                 0.1818 
                 BRD-A32164164 
                   
               
               
                 12 
                 0.1818 
                 BRD-K02562327 
                   
               
               
                 13 
                 0.1818 
                 BRD-K74767048 
                   
               
               
                 14 
                 0.1364 
                 vorinostat 
                 A histone deacetylase inhibitor. 
               
               
                 15 
                 0.1364 
                 curcumin 
                 A scavenger of oxygen species and 
               
               
                   
                   
                   
                 inhibits lipid peroxidation as well 
               
               
                   
                   
                   
                 as peroxide-induced DNA damage. 
               
               
                 16 
                 0.1364 
                 trichostatin A 
                 A histone deacetylase inhibitor. 
               
               
                 17 
                 0.1364 
                 JW-7-24-1 
                   
               
               
                 18 
                 0.1364 
                 geldanamycin 
                 A benzoquinone antineoplastic 
               
               
                   
                   
                   
                 antibiotic isolated from the 
               
               
                   
                   
                   
                 bacterium  Streptomyces   
               
               
                   
                   
                   
                   hygroscopicus . 
               
               
                 19 
                 0.1364 
                 MAPP, L-erythro 
                   
               
               
                 20 
                 0.1364 
                 Piperacetazine 
                 An antipsychotic prodrug. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B4 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Panels of Predictive  
               
               
                 Biomarkers in Males (n = 34 genes; 15 increased and 19 decreased). 
               
               
                 Panel of genes increased in expression: FCGR1A, GAP43, MAPT,  
               
               
                 KIDINS220, AIMP2, RGS10, PER1, RAB7A, KLF3, CALHM1, BACE1,  
               
               
                 ARSB, LOC101928123, LOC100499194, ITPKB 
               
               
                 Panel of genes decreased in expression: NDUFA5, SEC24A, PSMA4,  
               
               
                 UBE2L3, NPC2, BST2, TGFB1, TRIM38, ZNF345, IGF1, VEGFA,  
               
               
                 LOC101927027, MIS18BP1, RHEB CARD11, NKTR, MS4A14,  
               
               
                 B2M, EPB42 
               
            
           
           
               
               
               
               
            
               
                 Rank 
                 Score 
                 Drug 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 0.1786 
                 Triamcinolone 
                 A synthetic glucocorticorsteroid. 
               
               
                 2 
                 0.1786 
                 N20C hydrochloride 
                 Non-competitive NMDA receptor 
               
               
                   
                   
                   
                 open-channel blocker. 
               
               
                 3 
                 0.1786 
                 manumycin A 
                 An antibiotic that acts as a potent 
               
               
                   
                   
                   
                 and selective farnesyltransferase 
               
               
                   
                   
                   
                 inhibitor. 
               
               
                 4 
                 0.1786 
                 NCGC00183397-01 
                   
               
               
                 5 
                 0.1786 
                 BRD-K71917235 
                   
               
               
                 6 
                 0.1786 
                 BRD-A32164164 
                   
               
               
                 7 
                 0.1429 
                 L-690,330 
                   
               
               
                 8 
                 0.1429 
                 PERHEXILINE  
                 A carnitine CPT1 and CPT2 
               
               
                   
                   
                 MALEATE 
                 inhibitor. 
               
               
                 9 
                 0.1429 
                 Clobetasol propionate 
                 A corticosteroid. 
               
               
                 10 
                 0.1429 
                 GR 159897 
                 A NK2 receptor antagonist. 
               
               
                 11 
                 0.1429 
                 NOBILETIN 
                 An O-methylated flavone that has 
               
               
                   
                   
                   
                 the activity to rescue bulbectomy- 
               
               
                   
                   
                   
                 induced memory impairment. 
               
               
                 12 
                 0.1429 
                 ENDECAPHYLLIN  
                 A glucose tetra-(3-  
               
               
                   
                   
                 X 
                 nitropropanoate) ester. 
               
               
                 13 
                 0.1429 
                 Flurandrenolide 
                 A corticosteroid. 
               
               
                 14 
                 0.1429 
                 SDZ WAG 994 
                 A potent and selective A1 
               
               
                   
                   
                   
                 adenosine receptor agonist. 
               
               
                 15 
                 0.1429 
                 Timolol maleate salt 
                 A non-selective beta-adrenergic 
               
               
                   
                   
                   
                 antagonist. 
               
               
                 16 
                 0.1429 
                 RHAPONTIN 
                 A crystalline glucoside found in 
               
               
                   
                   
                   
                 rhubarb. 
               
               
                 17 
                 0.1429 
                 16759925 
                   
               
               
                 18 
                 0.1429 
                 simvastatin 
                 A HMG-CoA reductase inhibitor. 
               
               
                 19 
                 0.1429 
                 2541665-P2 
                   
               
               
                 20 
                 0.1429 
                 Compound 58 
               
               
                   
               
            
           
         
       
     
                     TABLE 5B5                  Drugs Identified Using Gene Expression Panels of Predictive Biomarkers        in Females (n = 12 genes; 6 increased and 6 decreased).       Panel of genes increased in expression: DEFB104B, LINC01398,        CHAT, RTCB, LOC105371414, PER1       Panel of genes decreased in expression: ITPKB, GUSB, CD40,        SERTAD3, TBRG4, MS4A14                             Rank   Score   Drug   Description                                     1   0.2857   Fluticasone propionate   A synthetic trifluorinated                   glucocorticoid receptor agonist.       2   0.2857   Anisomycin   An antibiotic isolated from                   various  Streptomyces  species.       3   0.2857   DIGOXIN   A cardiotonic glycoside                    obtained mainly from                      Digitalis lanata .       4   0.2857   NICARDIPINE   A calcium channel blockader               HYDROCHLORIDE   with vasodilatory properties.       5   0.2857   BRD-K06593056           6   0.2857   Inhibitor BEC    A competitive inhibitor of               hydrochloride   arginases I and II that causes                   NO-dependent smooth muscle                   relaxation.       7   0.2857   Emetine    A protein synthesis inhibitor               Dihydrochloride    derived from ipecac root.               Hydrate (74)           8   0.2857   Importazole   A nuclear transport receptor                   importin-beta inhibitor.       9   0.2857   Salermide   An inhibitor of SIRT1 and                   SIRT2 causing tumor-specific                   apoptotic cell death.       10   0.2857   BRD-K72264770           11   0.2857   dibenzyline   An alpha-adrenergic antagonist.       12   0.2857   CGP-60474   A cyclin-dependent kinase                   inhibitor.       13   0.2857   HG-5-88-01           14   0.2857   Scopolamin-N-oxide    An antagonist of the                hydrobromide   muscarinic acetylcholine                    receptor.       15   0.2857   REV-5901   An antagonist of cysteinyl-                   leukotriene receptors.       16   0.2857   TRANS-7-HYDROXY-   A dopamine D3 receptor                PIPAT   ligand.       17   0.2857   Biotin   Vitamin B7.       18   0.2857   NNC 711   An anticonvulsant that works                    as a selective inhibitor of                    GABA uptake by GAT-1.       19   0.2857   L-693,403 maleate   σ ligand selectivity over the                   dopamine D2 receptor.       20   0.2857   W-7 hydrochloride   Calmodulin antagonist.                    
Table 5C. Drug Repurposing using Crowd Extracted Expression of Differential Signatures (CREED)
 
     
       
         
           
               
             
               
                 TABLE 5C1 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Signature of Top Biomarkers  
               
               
                 CFG ≥ 12 (n = 18 unique genes; 8 increased and 10 decreased). 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Signed 
                   
               
               
                 Rank 
                 Name 
                 Jaccard Index 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 Lorazepam 
                 0.00727 
                 A benzodiazepine. 
               
               
                 2 
                 Finasteride 
                 0.00656 
                 A 5-alpha reductase inhibitor. 
               
               
                 3 
                 Bromhexine 
                 0.00649 
                 An expectorant/mucolytic 
               
               
                   
                   
                   
                 agent. 
               
               
                 4 
                 Ethinylestradiol 
                 0.00641 
                 A semisynthetic estrogen. 
               
               
                 5 
                 Dicumarol 
                 0.00639 
                 Isolated from molding sweet- 
               
               
                   
                   
                   
                 clover hay, with anticoagulant 
               
               
                   
                   
                   
                 and vitamin K depletion 
               
               
                   
                   
                   
                 activities. 
               
               
                 6 
                 Letrozole 
                 0.00613 
                 A nonsteroidal inhibitor of 
               
               
                   
                   
                   
                 aromatase. 
               
               
                 7 
                 Promazine 
                 0.0061 
                 A phenothiazine derivative with 
               
               
                   
                   
                   
                 antipsychotic and antiemetic 
               
               
                   
                   
                   
                 properties. 
               
               
                 8 
                 Diisopropyl  
                 0.00598 
                 An irreversible cholinesterase 
               
               
                   
                 Fluorophosphate 
                   
                 inhibitor. 
               
               
                 9 
                 Rapamycin 
                 0.00568 
                 A mTOR Inhibitor. 
               
               
                 10 
                 Doxorubicin 
                 0.00549 
                 A topoisomerase inhibitor. 
               
               
                 11 
                 Artemisinin 
                 0.00542 
                 A sesquiterpene lactone 
               
               
                   
                   
                   
                 obtained from  Artemisia annua , 
               
               
                   
                   
                   
                 which has been recently found 
               
               
                   
                   
                   
                 to have potent activity against 
               
               
                   
                   
                   
                 many forms of malarial 
               
               
                   
                   
                   
                 organisms. 
               
               
                 12 
                 Colchicine 
                 0.0054 
                 Microtubule inhibitor. 
               
               
                 13 
                 Mifepristone 
                 0.00526 
                 Progestin antagonist. 
               
               
                 14 
                 Zopiclone 
                 0.00526 
                 A central nervous system 
               
               
                   
                   
                   
                 depressant and a sedative. 
               
               
                 15 
                 Amlodipine 
                 0.00526 
                 Calcium channel blocker. 
               
               
                 16 
                 Busulfan 
                 0.00524 
                 An alkylating agent used in the 
               
               
                   
                   
                   
                 treatment of CML. 
               
               
                 17 
                 Rosiglitazone 
                 0.00524 
                 A selective agonist for PPAR 
               
               
                   
                   
                   
                 GAMMA. 
               
               
                 18 
                 Norethindrone 
                 0.00523 
                 A synthetic progestin. 
               
               
                 19 
                 Letrozole 
                 0.00521 
                 A nonsteroidal inhibitor of 
               
               
                   
                   
                   
                 aromatase. 
               
               
                 20 
                 Omeprazole 
                 0.00517 
                 Proton pump inhibitor. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5C2 
               
             
            
               
                   
               
               
                 Drugs Identified Using Gene Expression Signature of Top  
               
               
                 Biomarkers CFG ≥ 10 (n = 112 unique genes; 68 increased and 64 decreased). 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Signed 
                   
               
               
                   
                   
                 Jaccard 
                   
               
               
                 Rank 
                 Drug 
                 Index 
                 Description 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 Hydralazine 
                 0.01735 
                 An antihypertensive. 
               
               
                 2 
                 Rofecoxib 
                 0.0135 
                 NSAID. 
               
               
                 3 
                 Ethylene Glycol 
                 0.0134 
                 Dihydroxy alcohol. 
               
               
                 4 
                 Doxycycline 
                 0.01339 
                 A tetracycline antibiotic. 
               
               
                 5 
                 Levamisole 
                 0.0131 
                 An anthelmintic drug that has been tried 
               
               
                   
                   
                   
                 as an adjuvant to chemotherapy. 
               
               
                 6 
                 Suxamethonium Chloride 
                 0.01301 
                 A depolarizing skeletal muscle relaxant. 
               
               
                 7 
                 Tiapride 
                 0.013 
                 A D2 and D3 dopamine receptor 
               
               
                   
                   
                   
                 antagonist. 
               
               
                 8 
                 Bupropion 
                 0.01295 
                 An antidepressant of the aminoketone 
               
               
                   
                   
                   
                 class and a non-nicotine aid to smoking 
               
               
                   
                   
                   
                 cessation. 
               
               
                 9 
                 Promethazine 
                 0.01295 
                 A first generation antihistamine that is 
               
               
                   
                   
                   
                 used an antiemetic. 
               
               
                 10 
                 Pyrazinamide 
                 0.01278 
                 A synthetic pyrazinoic acid amide 
               
               
                   
                   
                   
                 derivative with bactericidal properties 
               
               
                   
                   
                   
                 against  Mycobacterium tuberculosis . 
               
               
                 11 
                 Antimycin A 
                 0.01277 
                 An antibacterial that blocks electron 
               
               
                   
                   
                   
                 transport between coenzyme Q and 
               
               
                   
                   
                   
                 cytochrome c. 
               
               
                 12 
                 Metoprolol 
                 0.01273 
                 Competitive beta-1 adrenergic receptor 
               
               
                   
                   
                   
                 antagonist. 
               
               
                 13 
                 Catechol 
                 0.01271 
                 It has a role as a genotoxin, an 
               
               
                   
                   
                   
                 allelochemical and a plant metabolite. 
               
               
                 14 
                 Azathioprine 
                 0.01264 
                 A purine analogue that is used as an 
               
               
                   
                   
                   
                 immunosuppressive agent. 
               
               
                 15 
                 Gadopentetate 
                 0.01262 
                 A gadolinium-based paramagnetic 
               
               
                   
                 Dimeglumine 
                   
                 contrast agent. 
               
               
                 16 
                 Epirubicin 
                 0.01247 
                 An anthracycline topoisomerase 
               
               
                   
                   
                   
                 inhibitor. 
               
               
                 17 
                 Propylene Glycol 
                 0.01246 
                 Used as an organic solvent. 
               
               
                 18 
                 Thiabendazole 
                 0.01239 
                 A broad spectrum antihelmintic agent. 
               
               
                 19 
                 Leflunomide 
                 0.01231 
                 An immunomodulatory agent. 
               
               
                 20 
                 Imatinib 
                 0.01231 
                 Tyrosine kinase receptor inhibitor. 
               
               
                   
               
            
           
         
       
     
     For the top biomarkers (see, Table 5), all the evidence from discovery (up to 6 points), prioritization (up to 12 points), testing (state, trait—up to 6 points each if significantly predicts in all subjects, 4 points if predicts by gender, 2 points if predicts in gender/diagnosis) were tabulated into a convergent functional evidence (CFE) score. The total score could be up to 30 points: 18 from the experimental data and 12 from literature data. The experimental data was weighed more than the literature data. 
     Example 1 
     In this example, biomarkers for short-term memory were determined. 
     Longitudinal studies were conducted in psychiatric disorder subjects, a population enriched in memory retention abnormalities. The subjects had blood gene expression data at multiple testing visits, and were phenotyped at each visit, including with Hopkins Verbal Learning Test (HVLT). Subject&#39;s electronic medical records were also available for long term follow-up of outcomes. 
     In Step 1 Discovery, blood gene expression biomarkers were identified that track memory using a powerful within-subject design in a cohort of subjects who displayed at least a 20% change in the retention measure between different visits (n=159 subjects, with 496 visits), normalized (Z-scored) across genders and various psychiatric diagnoses. In Step 2 Prioritization, a Convergent Functional Genomics approach was used to prioritize the candidate biomarkers in Step 1, using published literature evidence (genetic, gene expression and proteomic), from human and animal model studies, for involvement in AD. In Step 3 Testing, an independent cohort (n=127) from the one used for discovery was examined for whether the top biomarkers prioritized in Step 2 were predictive of memory retention measure (state), and of future positive neuropsychological testing for MCI, AD or other dementia (trait), using electronic medical records follow-up data of the study subjects (up to 12.81 years from initial visit). 
     The top biological pathways where the candidate biomarkers map were related to LXR/RXR activation, neuroinflammation signaling atherosclerosis signaling, and amyloid processing (Table 2). Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for observed brain pathological changes. The STRING gene interaction analysis ( FIG. 2 ) revealed at least 3 networks. Network 1 (red) includes TREM2, along with GUSB and RHEB; it may be involved in reactivity and inflammatory responses. Network 2 (green) includes MAPT (tau), along with PSEN1 and SNCA; it may be involved in activity and cellular trophicity. Network 3 (blue) includes APOE, along with TGFB1 and FOXO3; it may be involved in connectivity and synaptic integrity. GSK3B is at the overlap of Networks 2 and 3. 
     The top candidate biomarkers were prioritized for convergent evidence for involvement in AD (Table 5). They also had prior evidence of involvement in other psychiatric and related disorders, providing a molecular underpinning for the possible precursor effects of these disorders in AD. 
     Gene expression biomarkers that were predictive in independent cohorts of memory state and of future neuropsychological testing positive for cognitive decline were successfully identified. Top predictive biomarkers for state were NKTR, ITPK, RGS10, PERI, and ARSB ( FIG. 3A ). The AUC ROCs ranged from over 0.7 for all subjects tested to over 0.8 personalized by gender, and over 0.9 personalized by gender and diagnosis. Top predictive biomarkers for trait were KLF3, CEP350, FOXO3, MAPT, and RHEB ( FIG. 3B ). The Cox Regression Odds Ratios ranged from over 2-fold for all subjects tested to over 4-fold personalized by gender and diagnosis. 
     RHEB, which represents the best biomarker for male schizophrenia, was identified as a future Alzheimer Disorder Related Dementia predictor in males with schizophrenia ( FIG. 4 ). Subject Phchp098 was a male with schizophrenia (SZ) initially tested in 2009. The subject was first diagnosed with paranoid schizophrenia in 1977. In 2016, he was also diagnosed by neuropsychological testing with ADRD and impaired decision-making capacity. At that time, he was 66 years old. Subject was the only subject so far withan ADRD diagnosis in the independent replication follow-up cohort. We tested RHEB, the best predictive biomarker for males with SZ ( FIG. 2B ). RHEB levels were Z-scored by gender and diagnosis. Subject Phchp098 had the highest levels of RHEB in the lab testing visit compared to all the subjects with future neuropsychological testing ( FIG. 4A ) and the highest level of RHEB from all the 111 subjects in that cohort ( FIG. 4B ). 
     Based on the studies and analyses, the biomarkers with the top overall convergent functional evidence (CFE) for relevance to memory and AD were NPC2, TGFB1, ARSB, GUSB, and KLF3, and then GSK3B, MAPT (tau), APOE, PSEN1, and TREM2. The fact that key genes for AD brain pathology came out of the unbiased whole-genome discovery was reassuring and served as de facto positive controls for the approach. 
     Some of the biomarkers are targets of existing drugs, such as lithium, antidepressants, and omega-3 fatty acids ( FIG. 5 ; Table 3), of potential utility in patient stratification and pharmacogenomics approaches. Moreover, the top biomarkers gene expression signature, upon bioinformatics drug repurposing analyses, yielded new drug candidates (such as pioglitazone and levonorgestrel), and natural compounds (such as salsolidine, ginkgolide A and icariin). Thus, the signature can be used for targeted enrollment of patients in clinical trials for these compounds, which would increase the odds of success, and for objectively measuring response to treatment. 
     The methods described herein provide a novel approach for discovering biomarkers of relevance to Alzheimer&#39;s disease, as well as testing the biomarkers in independent cohorts. The results provide evidence for precision medicine, diagnostics and therapeutics. The methods can provide improved early diagnosis of risk and preventive treatment for memory disorders in general, and Alzheimer&#39;s disease in particular, that result in decreased quality and quantity of life, at a massive cost to individuals, families and society. 
     In view of the above, it will be seen that the several advantages of the disclosure are achieved and other advantageous results attained. As various changes could be made in the above methods without departing from the scope of the disclosure, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense. 
     When introducing elements of the present disclosure or the various versions, embodiment(s) or aspects thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.