bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sovateltide promotes regeneration and reduces β‐amyloid burden in a transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Roy Kathryn , Gulati Anil 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a devastating condition with no known effective treatment. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat AD. However, the mechanism of action of sovateltide remains elusive. Therefore, we investigated its mechanism of action in neuronal regeneration in APP/PS1 transgenic mouse model.MethodAPP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 µg/kg) was intravenously injected, three times at 2‐hour intervals on days 1, 3 and 6 of every month until study end points (3‐, 6‐ and 12‐months age). Control mice received an equal volume of saline. Separate sets of mice were sacrificed at the end of 3, 6 and 12 months and beta amyloid plague formation, mitochondrial dysfunction, neuro‐ and synapto‐genesis were assessed in the brain.ResultAPP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated levels of Aβ plaque along with decreased levels of neuro and synaptogenic markers, which reflected the adverse effect of disease progression. Treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 months and 12 months aged transgenic mice. Moreover, sovateltide attenuated neuronal loss in the hippocampus and enhanced neurogenesis in APP/PS1 mice as evident by increased expression of NeuroD1 (p<0.0001), DoubleCortin (p<0.0001) and NeuN (p<0.0001) along with an upregulation of synaptic proteins (synapsin‐1, synaptophysin, and postsynaptic density‐95) compared to vehicle at 6 and 12 months. Sovateltide treatment also decreased mitochondrial fission (Drp1; p<0.001), increased mitochondrial fusion (Mfn2; p<0.001) and mitochondrial cross‐sectional area (p<0.01). Additionally, caspase‐3 level was significantly (p<0.001) higher in vehicle group than that in the sham group, and treatment with sovateltide significantly (p<0.01) reduced caspase‐3 level. There were no changes in the expression of any of these markers at three months.ConclusionThese findings suggest that sovateltide treatment promotes regeneration while simultaneously decreasing the pathology associated with Alzheimer’s disease.
Non‐APOE Polygenic risk score derived from European ancestry data are more predictive of dementia among Hispanics who are APOE ε4 carriers
Authors: Xu Yuexuan , Reyes‐Dumeyer Dolly , Gunasekaran Tamil Iniyan , Qiao Min N , Piriz Angel , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Vardarajan Badri N. , Mayeux Richard 
Published: January 2025

AbstractBackgroundDespite concerns about the transferability of polygenic risk scores (PRS) derived from European ancestry data to Hispanics, recent research suggests that many genetic loci identified through European ancestry genome‐wide association studies (GWAS) for complex traits are also relevant in Hispanics. Furthermore, studies on dementia have shown improved PRS performance in this group, even with PRS developed from European GWAS. Recent research also indicates that APOE ε4‐independent PRS associations vary depending on APOE ε4 status. This study evaluates the relationship between multiple recent European GWAS‐derived APOE‐independent PRS in Hispanics and the interaction between APOE ε4 and PRS in relation to Alzheimer’s Disease (AD).MethodsWe constructed a range of PRS based on three recently published GWAS (Kunkle et al., 2019, Bellenguez et al., 2022, FinnGen) of European ancestry among 1,429 Hispanics from the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP) using clumping and thresholding methods. For each GWAS, we first evaluated the associations of several P‐value thresholds with AD to determine the threshold for further analysis. Empirical P‐values were used to avoid overfitting for the optimized PRS. We then tested whether and how APOE ε4 can modify the association between PRS and AD. All associations were fitted by logistic regression with sex, age, education, and the first 5 principal components as covariates.ResultsAcross all European GWAS, the optimal P‐threshold for the most predictive PRS is at a conservative P‐threshold (Kunkle: 2.87e‐6, Bellenguez: 1.11e‐6, FinnGen: 1.80e‐5). PRS constructed based on the Bellenguez GWAS are most strongly associated with AD (OR = 1.29, 95% CI: 1.17‐1.42), and the FinnGen‐derived PRS show the least association (OR = 1.06, 95% CI: 0.98‐1.14). The association of all three PRSs is stronger among APOΕ ε4 carriers (ORKunkle: 1.51, 95% CI: 1.26‐1.81; ORBellenguez: 1.60, 95% CI: 1.35‐1.91; ORFinnGen: 1.12, 95% CI: 0.97‐1.26) compared to non‐carriers (ORKunkle: 1.09, 95% CI: 0.96‐1.23; ORBellenguez: 1.16, 95% CI: 1.03‐1.31; ORFinnGen: 1.03, 95% CI: 0.93‐1.14). Similar findings were observed concerning cognition and progression to dementia.ConclusionPRS derived from a European GWAS identified individuals at high risk for AD dementia among Hispanics, and the association is strongest among APOE ε4 carriers.
Neuroticism and poor cardiovascular health may signal early cognitive dysfunction related to Alzheimer’s risk in older African Americans
Authors: Powell Ashley , Fausto Bernadette A. , Gluck Mark A. 
Published: January 2025

AbstractBackgroundAfrican Americans bear a disproportionate burden of both cardiovascular diseases and Alzheimer’s disease (AD). Assessment of the Five‐Factor personality dimensions–Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness, particularly, higher levels of neuroticism–is linked to greater adverse cardiovascular and cognitive outcomes, including AD. Generalization–the ability to apply prior learning to new circumstances–is presented as a putative cognitive marker for the earliest stages of preclinical AD. However, the relationship between personality, cardiovascular health, and cognition is understudied in older African Americans. This study explored the relationship between personality, cardiovascular health, and cognitive function in a cohort of older African Americans.Method83 cognitively healthy older African American participants from the Pathways to Healthy Aging in African Americans cohort study (Mage = 68.34 years, SD = 6.99; Meducation = 13.93 years, SD = 2.36; MMMSE = 27.65, SD = 1.95) provided a blood sample for blood sugar levels (HbA1c); participated in anthropometric/physiological measurements (e.g., body mass index and resting heart rate); completed an aerobic fitness assessment (six‐minute walk test for VO2max estimate); completed a cognitive battery including a generalization task (Concurrent Discrimination and Transfer Task) and neuropsychological tests; and responded to mood and demographic questionnaires. We binarized each personality dimension at the median creating a lower and higher group. Independent sample t‐tests and correlations were performed to assess the relationship between each of the personality dimensions, cardiovascular health, and cognitive variables.ResultIndividuals in the higher neuroticism group had higher resting heart rate (d = ‐0.45), HbA1c levels (d = ‐0.58), and depressive symptomology (d = ‐0.80) while also demonstrating poorer aerobic fitness (d = 0.58) than their lower neuroticism counterparts. Subsequently, higher HbA1c was associated with poorer performance on the generalization task: Concurrent Discrimination and Transfer Task training phase (r = ‐.343, p = .002) and probe phase performance, (r = ‐.292, p = .008).ConclusionWe identified that cognitive function, specifically the ability to generalize prior learning is indirectly related to poor cardiovascular health in individuals that have a higher level of neuroticism. Our findings suggest that in older African American populations, the propensity to experience negative emotions (e.g., worry or any of the other neurotic traits) may negatively impact cardiovascular health, which may indirectly lead to poor cognitive outcomes such as dysfunction and AD.
Leukocyte Surface Biomarkers for Clinical Diagnosis of Sporadic Alzheimer’s Disease
Authors: Durrant Abe , Gu Ben J , Dickson Samuel P. , Nicodemus‐Johnson Jessie , Duncan Garrett B , Hendrix Suzanne B. 
Published: January 2025

AbstractBackgroundMounting evidence indicates that the accumulation of amyloid in AD starts 20 to 30 years before clinically detectable cognitive impairment is observed, suggesting the presence of a long period of asymptomatic AD. Although the specific onset of this preclinical period is difficult to target, it is potentially significant to identify subjects in this asymptomatic preclinical stage of the disease. This is because newly developed disease modifying treatments may have increased effectiveness if begun during this asymptomatic period. Currently, the preclinical phase of AD is identified in asymptomatic individuals as abnormal amyloid levels detected via neuroimaging or fluid biomarkers. However, this approach is not feasible as a routine screening tool in a clinical environment, therefore there is a critical need to develop blood‐based, cost‐effective screening tools to detect AD in asymptomatic patients. Because of this, the search for preclinical blood‐based biomarkers has become a major focus.Method200 Participants were randomly selected from the Australian Imaging, Biomarkers, and Lifestyle study (AIBL). A total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Leukocyte markers were used in addition to age, ApoE4 status, years of education, and sex to predict the PET Aβ status. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.ResultWe identified 12 specific leukocyte markers that were differentially expressed in cognitively normal (CN) patients designated as amyloid negative compared with CN individuals who are amyloid positive (Amyloid PET Centiloid >25). Combinations of these 12 markers produced AUC values as high as 0.94 in‐sample, and 0.90 out‐of‐sample. Specifically, markers CD11c, CD59, CD91, and CD163 had high performance when predicting amyloid positivity. These markers also showed strong predictive performance at other levels of Centiloid, maintaining AUCs greater than 0.85.ConclusionResults suggest that leukocyte surface biomarkers involved in Aβ transportation, innate phagocytosis and completement mediated clearance pathways are the first blood‐based biomarkers that can accurately predict amyloid load and detect amyloid at 25 centiloids. These biomarkers could have a major impact on clinical practice by allowing primary care physicians to identify individuals at high risk of having amyloid burden in their brains with a simple blood test.
Association of Social Determinants of Health with Acute TBI Care Among U.S. Older Adults
Authors: Sumida Catherine , Diaz‐Ramirez L. Grisell , Yaffe Kristine , Boscardin W John , Gardner Raquel C. , Kornblith Erica S 
Published: January 2025

AbstractBackgroundOlder adults have the highest incidence of traumatic brain injury (I‐TBI), which is associated with increased Alzheimer’s disease and related dementia (ADRD) risk. Timely medical assessment, including computed tomography (CT) or magnetic resonance imaging (MRI), is vital for optimal I‐TBI care and recovery. The current study builds on our recent work by examining social determinants of comprehensiveness of I‐TBI care amongst older adults.MethodEnrollees 65+ years in the nationally representative Health and Retirement Study (HRS), whose HRS survey and Medicare claims data were linked and first TBI diagnosis code occurred between 2000‐2018, were studied. I‐TBI was defined by International Classification of Disease (ICD9&10) inpatient and outpatient codes in Medicare claims (2000‐2018). HRS participants’ acute TBI level of care (TBI‐LC) was ranked from least to most comprehensive: a)neither ER nor imaging codes, b)ER code only, or c)ER and imaging (MRI/CT) codes within ±1day of I‐TBI code. Cognitive status was defined at baseline using Langa‐Weir Dementia Probability, an HRS‐derived predictive model.ResultOf those respondents with I‐TBI (N = 1148), 15.5% had neither ER nor imaging codes, 14.7% had ER code only, and 69.8% had an ER and imaging code within ±1 day of TBI code. TBI‐LC was associated with rural status (Rao‐Scottc2(2) = 11.97, p = .003): Rural elders received ER services (20.3% no ER code; 64.9% ER and imaging codes) less frequently compared to non‐rural elders (13.2% no ER code; 72.1% ER and imaging codes). Frequency of ER presentation without imaging were similar amongst rural (14.8%) and non‐rural elders (14.6%). TBI‐LC was not associated with marriage status, income, or cognitive status.ConclusionConsistent with prior findings amongst rural adults of all ages, rurality is associated with disparity in acute TBI care comprehensiveness amongst older adults specifically. Interestingly, monthly income, thought to account in part for differences between rural and non‐rural populations, was not associated with TBI care comprehensiveness. These findings suggest further research is needed to examine unique factors contributing to rurality as a barrier to care in elders with TBI (e.g. lack of transportation) and resulting downstream health outcomes (e.g., risk of cognitive decline, ADRD).
Assessment of the Empact of IGC‐AD1 on Hepatic Biomarkers in Alzheimer’s Disease: Insights from a Phase 1 Trial
Authors: Rodriguez‐Soacha Diego , Cañon Andres , Sánchez Laura Tatiana , Rao Jagadeesh S , Delgado‐Murillo Laura , Venegas Margarita , Tangarife Maria Alejandra , Arbelaez Maria Juanita , Gutiérrez Evelyn , Shahnawaz Saadia , Ghazaryan Varduhi , De Jesus William Julio , Grimaldi Claudia , Hong Elliot , Mukunda Ram 
Published: January 2025

AbstractBackgroundIGC‐AD1 comprises of Tetrahydrocannabinol (“THC”) and melatonin. The two active pharmaceuticals are known for their neuroprotective properties. In this analysis we studied multiple dosing of IGC‐AD1 in Alzheimer’s (“AD”) populations vulnerable to hepatic complications. We present the impact of three different doses on hepatic functions, offering insights into dosage‐dependent safety and potential therapeutic implications.MethodThirteen Puerto Rican AD patients (mean age: 80.18±6.22 years, 70% women) participated in this three‐cohort trial to assess the effects of IGC‐AD1. Cohorts 1, 2 and 3 received 1 mL once, twice, or thrice daily, respectively, for 14 days (“EOT”) with ∼4‐day washout period between cohorts. Key hepatic and renal biomarkers measured at baseline and EOT included AST, ALT, ALP, total and direct bilirubin.ResultFindings showed a larger increase in the mean difference of ALTI in the placebo group compared to active in cohorts 2 and 3 (Cohort‐1, Active; = ‐2.11 ± 6.01, Placebo = ‐0.5 ± 0.71; Cohort‐2, Active = ‐2.25 ± 4,79, Placebo = ‐8.0; Cohort‐3, Active; = ‐3.5 ± 9.73, Placebo = ‐7.0 ± 8.49). ALP levels decreased for both treatments in cohort 1 but increased for cohorts 2 and 3 (ALP Cohort‐1, Active; = 2.89 ± 4.34, Placebo = 3.5 ± 7.78; Cohort‐2, Active = ‐0.6± 18.15, Placebo = ‐5.0; Cohort‐3, Active; = ‐2.8 ±5.57, Placebo = ‐3.0 ± 7.07). Indirect bilirubin levels increased in the active groups for cohort 3, no tendency was observed for placebos (Indirect bilirubin Cohort‐1, Active; = 0.02 ± 0.05, Placebo = 0.05 ± 0.03; Cohort‐2, Active = 0.07 ± 0.07, Placebo = ‐0.03; Cohort‐3, Active; = ‐0.04 ± 0.14, Placebo = 0.07). All other biomarkers were within expected ranges, supporting the treatment’s safety profile.ConclusionBased on this safety trial, the findings suggest that the treatment with THC and melatonin does not exert adverse effects on liver function in patients with AD. Overall, the treatment demonstrated good tolerability, with no significant differences in hepatic biomarkers compared to placebo, supporting its potential safety in elderly patients with AD. Future research should continue to monitor these biomarkers in larger, more diverse populations to confirm these findings and assess long‐term safety and efficacy.
Tracking the timeline: from initial documentation of cognitive decline to dementia diagnosis in the electronic health records
Authors: Wang Liqin , Yang Richard , Bates David W , Zhou Li , Marshall Gad A 
Published: January 2025

AbstractBackgroundRecent breakthroughs in the treatment of Alzheimer’s Disease underscore the critical needs for early detection. In clinical settings, the diagnosis of Alzheimer’s disease and related dementias (ADRD) is often delayed or overlooked, potentially missing critical opportunities for timely care and treatment. Cognitive symptoms can appear many years before the stage of dementia, potentially serving as a trigger for thorough cognitive assessments, which could prompt an early diagnosis of cognitive decline. However, it remains unclear how this information is presented to clinicians and documented in patient charts, and how early these symptoms appear before an ADRD diagnosis.MethodThis retrospective cohort study utilized electronic health records (EHRs) from Mass General Brigham (MGB) to examine primary care patients aged 55 and older who received an initial ADRD diagnosis at MGB between 2018 and 2019. We analyzed EHR data to identify evidence of cognitive decline preceding the ADRD diagnosis. This analysis involved searching for cognition‐related keywords and diagnostic codes, and screening clinical notes using a validated deep learning model for cognitive symptoms. We assessed the duration from initial cognitive symptoms to ADRD diagnosis and examined demographic and socio‐economic factors for their correlation with documentation of cognitive decline.ResultThe study included 10,119 ADRD patients (median age of 80, 42.5% male). Of these, 2,890 (28.6%) had no prior documented cognitive decline. Patients without prior documentation were slightly older at diagnosis (median age: 81 years), more likely to have unspecified education background (39.2% vs. 20.3%), and came from more deprived areas. Among patients with prior cognitive decline documented, the average time to ADRD diagnosis was 3.7 years. Patients with initial cognitive evidence from clinical notes (78.7%, n = 5,692) experienced earlier documentation of cognitive symptoms compared to those identified through other sources. In contrast, those without documented marital status, with Medicaid insurance, and residing in highly deprived neighborhoods experienced delayed documentation of cognitive symptoms prior to ADRD diagnosis.ConclusionOur analysis reveals significant disparity in documenting cognitive decline among socio‐economically disadvantaged groups. This underscores the need for targeted outreach and intervention, and reinforces the role of comprehensive documentation in improving patient outcomes by facilitating earlier diagnosis and treatment.
Pathway Enrichment of Longitudinal AD Endophenotypes Identifies Potential Therapeutic Targets for Modifying Disease Trajectory
Authors: Rosewood Thea Jacobson , Nho Kwangsik , Risacher Shannon L. , Liu Shiwei , Gao Sujuan , Saykin Andrew J. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by longitudinal changes of biomarker endophenotypes over the course of the disease prodrome, onset, and progression. The genetic pathways that influence these heterogenous changes in longitudinal endophenotype trajectories may provide insight into disease mechanisms and represent potential therapeutic targets.MethodsLongitudinal endophenotypes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected: amyloid‐β (Amyloid PET and CSF), total tau and phosphorylated tau (CSF), glucose metabolism (FDG PET), neurodegeneration (atrophy on MRI), and cognition (composite scores for memory and executive functioning). Genome‐wide association analysis for the selected longitudinal endophenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), with (Time x Subject) as a random effect and age as the time variable. Gene‐based association analysis was performed using MAGMA on SNP P values from the LMM. The SNP to gene assignment was performed in two steps to select SNPs with a functional relation to each target gene: SNPs within gene transcription start and end positions, and SNPs that have significant eQTLs in brain tissue from the MetaBrain eQTL project. Gene‐based analysis results were then processed for gene‐set enrichment with MAGMA and the C2 curated gene set collection from the Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB).ResultsPathway enrichment analysis identified 19 pathways (Figure 1) as significantly associated with longitudinal trajectories of AD endophenotypes. These pathways fall into six groups, with each pathway group having stronger association with different types of endophenotypes. Immune and cytoskeletal pathways largely associated with changes in amyloid trajectory. Metabolic pathways associated strongly with changes in amyloid and tau trajectories. Glycosylation pathways were associated with changes in brain atrophy. Pathways related to cell and neuronal signaling associated with changes in cognition, tau, and amyloid trajectories. Cell growth and survival was associated with changes in neurodegeneration trajectory (structural atrophy and hypometabolism).ConclusionsPathway enrichment analysis of genetic variation associated with longitudinal changes of AD endophenotypes identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition. These pathways may provide insight into AD pathological mechanisms and constitute new potential therapeutic targets to modify disease trajectory.