bluuebunny/crossref_metadata_2025_split huggingface dataset:
Orexin/hypocretin modulation of neuroinflammation in a rodent model: implications for age‐related cognitive decline
Authors: Frick Marla A , Somera Brandy Lynn , Woodruff Jennifer L. , Reagan Lawrence P. , Fadel Jim R. 
Published: January 2025

AbstractBackgroundThe orexin/hypocretin neuropeptide system, primarily found in the lateral hypothalamus and perifornical region, modulates sleep, wakefulness, appetite, and cognitive function. One region with dense orexinergic projections is the basal forebrain (BF), which is the major source of acetylcholine in the neocortex and limbic structures such as the hippocampus. The basal forebrain cholinergic system mediates cognition and dysfunction is one of the key hallmarks of Alzheimer’s disease. We have previously shown significant reductions in orexin signaling and orexinergic innervation of cholinergic cells within the BF of aged rodents. Loss of orexin impairs cholinergic neurotransmission and cognitive function, but the mechanisms responsible for such deficits remain poorly understood. Recent evidence suggests neuroinflammation as a contributing factor to the pathogenesis of Alzheimer’s disease. It has been suggested that orexin may be neuroprotective, and we hypothesize that the age‐related loss of orexin neurons diminishes the brain’s anti‐inflammatory response, leading to basal forebrain cholinergic dysfunction.MethodLentivirus mediated expression of Preproorexin antisense or sense was administered into the lateral hypothalamus of young adult (3 months; antisense) and aged (22‐26 months; sense), male and female Fisher 344/Brown Norway F1 hybrid rats. Three weeks later, a neuroinflammatory response was induced with an acute lipopolysaccharide (1 mg, intraperitoneal) challenge. 6 hours later, brains were removed and bilaterally dissected with one hemisphere post‐fixed in 4% paraformaldehyde for immunohistochemical analysis and one hemisphere frozen for cytokine analysis.ResultLentivirus efficacy was verified using immunohistochemistry for GFP expression and changes in orexin expression within the lateral hypothalamus and terminal regions. There was no significant difference in total Iba‐1 in the basal forebrain, but there was a shift in activation state towards an activated, pro‐inflammatory, “M1” phenotype in the orexin antisense treated rats. In addition, there was an increase in IL‐6 and TNF‐alpha in the prefrontal cortex of orexin antisense treated male rats.ConclusionLoss of orexin expression in aging may facilitate neuroinflammatory processes in key regions, such as the basal forebrain and prefrontal cortex, and thereby contribute to neurodegeneration and cognitive decline.Acknowledgements: Supported by NIH R01 AG050518 and 2RF1 AG050518. Karly Pikel provided technical assistance.
Standardizing Care for Agitation in Alzheimer’ Dementia: Results from a Randomized Controlled Trial of an Integrated Care Pathway versus Usual Care ‐The StaN trial
Authors: Kumar Sanjeev , Burhan Amer M. , Chu Li , Colman Sarah , Davies Simon , Derkach Peter , Elmi Sarah , Gerretsen Philip , Graff‐Guerrero Ariel , Hussain Maria , Ismail Zahinoor , Kim Donna , Krisman Linda , Ma Clement , Moghabghab Rola , Mulsant Benoit H. , Nair Vasavan , Pollock Bruce G. , Rej Soham , Rostas Aviva , Streiner David , Van Bussel Lisa , Rajji Tarek K. ,   StaN Study Group
Published: January 2025

AbstractBackgroundAdherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed an Integrated Care Pathway (ICP) that standardized behavioral and pharmacological interventions for agitation in dementia, and evaluated it against treatment‐as‐usual (TAU). The two primary hypotheses were that, compared to TAU, the ICP would result in (1) lower agitation and (2) lower rates of polypharmacy at study end.MethodThe Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) trial (ClinicalTrials.gov # NCT03672201) was conducted at five academically affiliated inpatient units (Inpatient) and seven long‐term‐care homes (LTCHs). Participants with agitation related to Alzheimer’s dementia were randomized 1:1 to receive the ICP or TAU for 12 weeks. Primary outcomes were: (1) Cohen Mansfield Agitation Inventory (CMAI) completed at weeks 3, 8, and 12 (primary), and (2) polypharmacy defined as using more than one psychotropic medication assessed at weeks 1, 3, 4, 6, 8, 10, and 12 (primary) post‐randomization. Linear mixed effect models and generalized estimating equations were used to test our hypotheses controlling for age, gender, and stage of dementia. The study was powered for Inpatient and LTCH settings separately.Result185 participants were randomized: 93 in Inpatient (46 ICP: 47 TAU; females = 32 (34.4%); mean (standard deviation [SD]) age = 75.0 (8.4) years), and 92 in LTCH (46 ICP: 46 TAU; women = 63 (68.5%); mean (SD) age = 85.9 (7.6) years). There were no significant time*group interactions for the CMAI scores for Inpatient (F4, 297.9 = 0.8, p = 0.53) or LTCH (F4, 297.3 = 1.1, p = 0.36) and no significant differences at week‐12 (Inpatient: ICP‐TAU adjusted difference = 0.025; 95% Confidence Interval (CI): ‐0.410, 0.460; LTCH: ICP‐TAU adjusted difference = ‐0.214; 95%CI: ‐0.699, 0.270). However, there were significant time*group interactions for polypharmacy for both Inpatient (χ27 = 18.6, p = 0.01) and LTCH (Χ27 = 22.9, p = 0.002). Differences were not significant at week‐12 (Inpatient: ICP‐TAU adjusted difference = 0.15; 95%CI: ‐0.11, 0.40; LTCH: ICP‐TAU adjusted difference = 0.33; 95%CI: ‐0.06, 0.72), the ICP group had lower rates of polypharmacy than TAU group at weeks 3, 4, and 6 on Inpatient, and week 3 in LTCH.ConclusionStandardizing care for agitation in dementia may result in less polypharmacy without affecting efficacy. Future studies should assess the ICP in broader community and outpatient settings.
Brain and Blood Transcriptome‐Wide Association Studies Identify Three Novel Genes Associated with Cognitive Resilience
Authors: Mews Makaela , Naj Adam C. , Below Jennifer Elizabeth , Dumitrescu Logan C. , Hohman Timothy J. , Griswold Anthony J. , Bush William S. 
Published: January 2025

AbstractBackgroundWhile there are numerous genome‐wide association studies (GWAS) assessing the genetic basis of Alzheimer’s disease (AD), there are far fewer studies examining genetic factors for cognitive and global resilience to AD neuropathology. By focusing on a gene‐level rather than a single‐variant basis, transcriptome‐wide association studies (TWAS) have increased statistical power relative to GWAS and can assess the role of genetically regulated gene expression in AD resilience. We leveraged the largest available cis‐eQTL meta‐analysis summary statistics from brain tissue (MetaBrain Brain‐Cortex; N = 2,547) and whole blood (eQTLGen; N = 31,684) and applied them to the largest cognitive and global resilience to AD neuropathology summary statistics from Dumitrescu et al. 2020 (N = 5,108; Cognitively Unimpaired(CU) = 3,820) to identify novel resilience genes using the OTTERS TWAS pipeline.MethodWe modified the OTTERS approach (Dai et al. 2023) to only include genes with concordant effect size directions across the five TWAS methods it implements. We used the 1000 Genomes high‐coverage dataset as a LD reference, and characterized genes as novel by excluding regions that overlapped a 1MB window around the previously identified GWAS hits from the GWAS catalog. We also validated our hits using one‐tailed T‐tests applied to RNA‐seq expression data from an independent NHW whole‐blood dataset (MAGENTA: AD = 119; Controls = 117) and a partially independent brain RNA microarray dataset called KRONOSII that was curated for high AD pathology and low secondary pathology (AD = 168; Controls = 177).ResultWithin blood, we identified and validated one gene (LCLAT1, p = 1.97e‐10) where the expression was positively associated with cognitive resilience in a CU subset and we confirmed AD cases had significantly lower expression relative to controls. Within brain, we identified and validated two genes that were negatively associated with all resilience phenotypes (SNX7, p = 8.05e‐08) or resilience using CU subsets (FAM117B, p = 2.34e‐13) and we validated AD cases had significantly higher expression relative to controls. Notably, SNX7 is a member of the sorting nexin protein family which have been implicated in APP trafficking and degradation.ConclusionBy combining multiple large scale eQTL summary statistics with resiliency GWAS results, we have identified multiple new gene associations to cognitive and global resilience to AD.
FKBP51: A Promising Therapeutic Target for Tauopathies
Authors: Gebru Niat T , Guergues Jennifer , Stevens Stanley M. , Gulick Danielle , Blair Laura J. 
Published: January 2025

AbstractBackgroundTau accumulation, a hallmark of Alzheimer’s disease, fuels cognitive decline and neuronal death. Our team identified FKBP51, a stabilizer of neurotoxic tau oligomers. Notably, FKBP51 levels increase with age and further in AD brains, where it is found associated with pathological tau. FKBP51 has also been linked to vulnerability in excitatory neurons in the AD brain and poorer cognitive stability. In mice, the absence of FKBP51 has been shown to be protective from stress‐induced deficits. Recognizing this critical role, we are now developing methods to lower FKBP51 and understand the detailed molecular effects of its removal.MethodWe designed and synthesized locked‐nucleic acid (LNA) GapmeR ASOs targeting conserved regions in FKBP5, the gene that encodes FKBP51. The ASOs were tested in cultured cells and the brains of wild‐type mice. We also performed proteomic profiling of aged FKBP51 KO mice compared to young and aged wild‐type controls using a trapped ion mobility spectrometry (TIMS)‐QTOF instrument (timsTOF Pro, Bruker).ResultLNA GapmeR ASOs significantly lowered FKBP51 levels using less than10 nM doses with no signs of toxicity. In vivo, greater than 25% reductions of FKBP51 were found in the initial studies. Proteomic profiling revealed preservation of specific proteins and pathways in a young‐like state in mice lacking FKBP51.ConclusionASOs targeting FKBP51 show promise as a potential therapeutic avenue for reducing tau. The silencing of FKBP51 long‐term may directly reduce tau phosphorylation and aggregation, and indirectly protect neurons from tau‐mediated damage. Further optimization in vivo will commence shortly, followed by assessments in tau transgenic mice.
Identification of genetically driven Therapeutic Targets for Alzheimer’s disease
Authors: Goate Alison M. , Marcora Edoardo , Cruchaga Carlos 
Published: January 2025

AbstractTherapeutics against targets supported by human genetics are more than twice as likely to make it to the clinic as an FDA approved drug. In 2012 the National Institute on Aging in response to the U.S. congressional initiative established the Alzheimer’s Disease Sequencing Project (ADSP), a large‐scale genetics effort to further our fundamental understanding of Alzheimer disease and related disorders (ADRD) with the goal to accelerate the development of effective treatments for ADRD. The ADSP has used genome‐wide association studies (GWAS) of SNP array data and whole genome sequencing to identify more than one hundred loci associated with Alzheimer’s disease (AD) risk. Post GWAS analyses has identified candidate causal genes for a good proportion of these loci. We integrated human genetics and functional genomics to identify the cell types, genes and pathways that may modulate AD risk. Induced pluripotent stem cells and multi‐OMICs were used to validate the impact of risk alleles and genes on AD relevant phenotypes in vitro and in vivo. Functional genomics has implicated myeloid cells including microglia and other macrophages in AD risk. Pathway‐based analyses demonstrate that efferocytosis is a disease risk hub and that TREM2 signaling is implicated by multiple risk genes. Immunotherapies targeting TREM2, MS4A4A, MS4A6A are under development. Progress toward developing therapies to these and other targets will be reviewed. Immunotherapies, gene‐based and small molecule approaches are being developed to target TREM2 signaling, APOE biology and other aspects of macrophage/microglial function such as efferocytosis.
Exploring the Impact of Race, African Ancestry, and APOE4 on Sex Differences in Amyloid Pathology and Cognitive Outcomes in an Admixed Population‐Based Neuropathological Sample
Authors: Raya Maison Abu , Paes Vitor Ribeiro , Leite Renata Elaine Paraizo , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Suemoto Claudia Kimie , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundPrior research investigating sex and racial differences in amyloid pathology burden has yielded inconsistent findings. We examined the impact of sex and other confounding factors on neuritic plaque burden and cognitive outcomes.MethodThis study included 1,857 individuals, with post‐mortem brain tissues, from the Biobank for Aging Studies of the University of São Paulo Medical School, collected from 2004‐2023. In a subset of subjects, global ancestry was analyzed dichotomously, using a 2% cutoff for African Ancestry (AFR), first quartile of the AFR distribution. We employed multinomial logistic regression and general linear models to explore the associations of sex, reported race (White versus Black and Brown groups combined), AFR, and APOE4 genotype on CERAD scores and cognitive outcomes measured by Clinical Dementia Rating Scale Sum of Boxes(CDR‐SOB) while adjusting for age at death and education.ResultWomen (48% of the sample) were older than men (76.8±12.3 yo versus 71.4±12.3 yo, p<0.001). Men had higher educational attainment with a mean(SD) of 5.5(4.2) years and 3.9(3.9) years in women, (p<0.001). Dementia prevalence was higher in women (31% vs.18.5%, p<0.001). The sample was predominantly white (64.7%), followed by black (23.1%), and Asian (2.2%). 76.7% of men and 76.5% of women had AFR+ (p = 0.96). Women had higher odds of ‘Frequent’ CERAD scores with OR(95%CI) = 2.3(1.42‐3.72), p<0.001) Table 1 (Frequent‐Sparse or None) model 2. Black race was associated with lower odds of ‘Moderate’ CERAD scores compared to whites. A significant three‐way interaction among sex, APOE4, and race showed that Black men without APOE4 had lower odds of ‘Moderate’ and ‘Frequent’ CERAD scores (Table 1). Similar trends were found with Sex*APOE4*AFR. Testing the association of CERAD scores with cognitive outcomes, higher CERAD scores were associated with lower CDR‐SOB (P<0.001), and sex moderated this effect showing that women with ‘Moderate’ CERAD scores had worse cognitive outcomes than men (Figure 1). Notably, black race (Figure 2), but not AFR (Figure 3), modified the interaction between sex and CERAD on cognitive outcomes.ConclusionWomen exhibited increased susceptibility to amyloid pathology, resulting in more pronounced cognitive impairment, suggesting that sex‐specific genetic, biological, and sociocultural factors may play a role in women’s higher AD vulnerability.
Storyteller: Normative data for the brief, remote, unsupervised automated speech‐based AD/MCI clinical trial screening measure
Authors: Skirrow Caroline , Meepegama Udeepa , Ropacki Michael T. , Weston Jack , Fristed Emil 
Published: January 2025

AbstractBackgroundStoryteller, a brief self‐administered test that uses speech analysis to measure cognitive functioning, has demonstrated ability to predict Mild Cognitive Impairment (MCI) and mild Alzheimer’s disease (AD). The test is being implemented globally in Sponsor clinical trials, ADNI, and Sites for pre‐screening and will be used across heterogeneous populations. Normative data for Storyteller exists and is important for contextualising test performance, but has not been previously published.MethodUS residents aged 50+ were recruited into the AMYWEB study (NCT05298501). Participants completed a remote assessment via web application on their own personal devices, including screening and demographic questionnaires, the Patient Health Questionnaire‐8 (PHQ8), and Storyteller. Participants’ spoken responses were recorded, automatically transcribed and analysed to obtain a measure of proportional recall, “G‐match”, that leveraged two immediate and one delayed story recall conditions. Linear regression examined the influence of age, education, and sex on G‐match. Z‐scores were calculated to determine normative task performance ranges.Result679 participants (381 females, 298 males; age range 50‐84, mean 59.52) were recruited after excluding individuals with incomplete submissions, history of mild cognitive impairment (MCI), dementia or stroke and PHQ‐8≥10. The sample was demographically diverse, with residents across 49 US states and representation from minoritized groups (n = 115 overall: Black or African American n = 66; Hispanic or Latino/a n = 28; Asian n = 22; Native American or Alaska Native n = 18; Pacific Islander n = 4)). Assessments were completed across a range of common devices and browsers. Z‐scores identified score bands across different performance ranges (Fig 1). Regression analyses showed no significant age‐related change (β = ‐0.07, p = 0.21), but revealed higher scores for more educated participants (β = 0.80, p<0.001) and lower scores in males (β = ‐3.00, p<0.001).ConclusionStoryteller’s remote, unsupervised completion across a diverse U.S. sample generated valuable normative data, allowing contextualization of how impaired recruited samples are within AD/MCI clinical trials and in the broader population. Although G‐match showed no meaningful decline with age, the current findings replicate research showing a protective effect of education on cognitive function, and modestly better performance by women for story recall tasks.
Indian‐enriched genetic variants are associated with cognitive function
Authors: Abu‐Amara Hasan , Zhao Wei , Li Zheng , Leung Yuk Yee , Schellenberg Gerard D. , Wang Li‐San , Moorjani Priya , Dey A.B , Dey Sharmistha , Zhou Xiang , Gross Alden L. , Lee Jinkook , Kardia Sharon L R , Smith Jennifer A 
Published: January 2025

AbstractBackgroundThe prevalence of dementia in India is approximately 7.4% among those aged 60 years and older, yet little is known about genetic risk factors for dementia in this population. Examining genetic variants at higher frequency in India than other ancestries (i.e., Indian enriched variants) presents an opportunity to detect genetic effects which might be unique to the Indian population and/or underpowered for detection in other ancestral groups. We examined associations between Indian‐enriched variants and cognitive outcomes in 2680 older adults from the Longitudinal Aging Study in India ‐ Diagnostic Assessment of Dementia (LASI‐DAD) to identify potentially novel variants that may influence cognitive aging and dementia.MethodUsing whole‐genome sequence (WGS) data, we identified 4.8M Indian‐enriched variants, including 4.2M rare variants (0.2%<MAFLASI‐DAD < 5%, and MAFLASI‐DAD/MAFEA>5; and 600K common variants (MAFLASI‐DAD≥5%, and MAFLASI‐DAD /MAFEA>3). We conducted single‐variant association tests for all Indian‐enriched variants with the Hindi Mental State Exam (HMSE) score, a general cognitive function score, and five cognitive domain scores. Given the potential for heterogeneity between sexes, we also added variant‐by‐sex interaction terms to test the joint effects of variants and variant‐by‐sex interactions. In all analyses, we controlled for age, sex, state, education, literacy, rural/urban status, the first 10 genetic principal components, and genetic relatedness.ResultAt 5% false discovery rate, 11 variants were associated with one or more cognitive outcomes, including rs118075114, an intronic variant of CA12 that is in a known risk locus for Alzheimer’s disease in European ancestry. Joint models identified an additional 17 variants with a sex‐specific association with HMSE score (11 in females and 6 in males). Although the identified variants are rarely reported in the literature, partly because they are almost absent in European populations and elsewhere, several of the loci have been associated with neuropsychiatric traits and dementia risk factors such as diabetes, blood pressure, and coronary artery disease.ConclusionThese results demonstrate the potential of LASI‐DAD WGS to identify Indian‐enriched variants that are associated with cognition at older ages. Future studies are warranted to replicate and understand the functional relevance of the identified variants.
Differential relations between depressive symptoms and everyday function in older adults using multiple modes of functional assessment
Authors: Halberstadter Kimberly , Kaplan Marina , Mckniff Moira , Holmqvist Sophia L. , Tassoni Molly B. , Simone Stephanie M. , Giovannetti Tania 
Published: January 2025

AbstractBackgroundThe impact of depressive symptoms on everyday function in older adults remains poorly understood. Depression may decrease motivation, impair cognition, and/or bias self‐reports of functional ability. The present study examined relations between depressive symptoms and everyday function as measured by self‐report, informant‐report, and an objective performance‐based measure which evaluates functional/cognitive capacity but requires only minimal motivation.Method88 community dwelling older adults with normal cognition or mild cognitive impairment completed the Geriatric Depression Scale (GDS‐15), tests of cognitive abilities, and the performance‐based Naturalistic Action Test (NAT), which requires preparation of a breakfast and lunch using real objects presented on a table. Video recordings of the NAT were scored for completion time and errors. Participants and their study partners also completed the Instrumental Activities of Daily Living – Compensation (IADL‐C) Questionnaire, which evaluates the ability to perform a range of everyday tasks in daily life. A Spearman correlation matrix was used to assess associations among measures.ResultGDS‐15 scores were significantly associated with both questionnaires (participant IADL‐C: r = .369, p < .001; informant IADL‐C: r = .265, p = .022) but did not correlate with NAT scores. Global cognitive composite scores were negatively correlated with self‐reported IADL‐C scores (r = ‐.320, p = .003) and NAT scores (completion time: r = ‐.376, p < .001; errors: r = ‐.349, p < .001), but did not correlate with informant‐reported IADL‐C scores. Ancillary analyses showed the two questionnaire measures were significantly correlated (self‐report x informant‐report IADL‐C, r = .362, p = .002) but did not correlate significantly with NAT scores, and the GDS‐15 did not correlate with the cognitive composite.ConclusionAmong community dwelling older adults, depressive symptoms were associated with participant‐reported and informant‐reported everyday function, but not with performance‐based tasks or cognitive abilities. The pattern of correlates suggests that depressive symptoms may affect function in everyday contexts by decreasing motivation to engage in daily activities without altering cognitive capacity to perform everyday tasks. Future research should investigate relations among specific depressive symptoms, such as apathy, and multiple measures of everyday function.