Search

Cognitive resilience (CR) describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. This is especially true when information about CR is contained in the data the linear model was fitted to, either through inclusion of CR-associated variables or due to correlation. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and CR and achieves better estimation accuracy on simulated ground-truth data., Competing Interests: Declarations. Competing interests: Paul Maruff is a full-time employee of Cogstate Ltd. Samuel N. Lockhart is a full time employee of Invicro LLC. SCJ has served in the past three years as a consultant to ALZPath and Enigma Biomedical., (© 2024. The Author(s).)

Importance: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts., Objective: To determine the frequency of APOE genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases., Design: This multicohort study selected data from eight longitudinal cohort studies of normal aging and AD., Setting: Variable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples., Participants: Inclusion in our analyses required APOE genotype, that participants be age 50+, and are identified as either non-Hispanic Black or non-Hispanic White. In total, 18,080 participants were included in the present study with a total of 78,549 datapoints., Main Outcomes and Measures: Harmonized, longitudinal memory, executive function, and language scores were obtained from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). SuperAgers, controls, and AD dementia cases were identified by cognitive scores using a residual approach and clinical diagnoses across multiple timepoints when available. SuperAgers were compared to AD dementia cases and cognitively normal controls using age-defined bins (middle-aged, old, oldest-old)., Results: Across racialized groups, SuperAgers had significantly higher proportions of APOE -ε2 alleles and lower proportions of APOE -ε4 alleles compared to cases. Similar differences were observed between SuperAgers and middle-aged and old controls. Non-Hispanic White SuperAgers had significantly lower proportions of APOE- ε4 alleles and significantly higher proportions of APOE -ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE- ε4 alleles compared to cases and younger controls, and significantly higher proportions of APOE -ε2 alleles compared only to cases., Conclusions and Relevance: In the largest study to date, we demonstrated strong evidence that the frequency of APOE -ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of APOE in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.

Introduction: Accurately assessing temporal order of cognitive decline across multiple domains is critical in Alzheimer's disease (AD). Existing literature presented controversial conclusions likely due to the use of a single cohort and different analytical strategies., Methods: Harmonized composite cognitive measures in memory, language and executive functions from 13 cohorts in the ADSP-PHC data are used. A novel double anchoring events-based sigmoidal mixed model was developed using time to the incident of AD diagnosis as the time scale., Results: Decline in memory occurred before decline in language which was followed by the decline in executive function. Throughout the entire AD continuum, APOE- ε 4 non-carriers and non-Hispanic Whites showed better memory performance, respectively, in all three cognitive domains., Discussion: Using harmonized data across multiple cohorts is the key to accurately characterizing the temporal order of AD biomarkers. Time to incident AD diagnosis should be used as the time scale for reproducibility purposes., Competing Interests: Conflicts Dr. Dumitrescu reported grants from NIH during the study. Dr. Mez reported grants from NIH during the study and grants from the Department of Defense outside the submitted work. Dr. Saykin reported grants from NIH to Indiana University and support from multiple NIH grants during the conduct of the study as well as support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of PET tracer precursor); Bayer Oncology (scientific advisory board); Eisai (scientific advisory board); Siemens Medical Solutions USA (dementia advisory board); National Heart, Lung, and Blood Institute (MESA observational study monitoring board); and Springer-Nature Publishing (editorial office support as editor-in-chief for Brain Imaging and Behavior) outside the submitted work. Dr. Hohman reported grants from NIH during the study and is a member of a scientific advisory board for Vivid Genomics outside the submitted work. Dr. Liu reported grants from NIH during the study. No other disclosures were reported.

The biological mechanisms underlying women's increased Alzheimer's disease (AD) prevalence remain undefined. Previous case/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau as well as antemortem longitudinal cognition. Of 23,118 significant gene associations, 10% were significant in one sex and not the other (sex-specific). Most sex-specific gene associations were identified in females (73%) and associated with tau tangles and longitudinal cognition (90%). Four X-linked genes, MCF2 , HDAC8 , FTX , and SLC10A3 , demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant sex x gene interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, reinforcing the potential for sex-aware analyses to enhance precision medicine approaches in AD.

Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is a polygenic disorder with a prolonged prodromal phase, complicating early diagnosis. Recent research indicates that increased astrocyte reactivity is associated with a higher risk of pathogenic tau accumulation, particularly in amyloid-positive individuals. However, few clinical tools are available to predict which individuals are likely to exhibit elevated astrocyte activation and, consequently, be susceptible to hyperphosphorylated tau-induced neurodegeneration. Polygenic risk scores (PRS) aggregate the effects of multiple genetic loci to provide a single, continuous metric representing an individual's genetic risk for a specific phenotype. We hypothesized that an astrocyte activation PRS could aid in the early detection of faster clinical decline. Therefore, we constructed an astrocyte activation PRS and assessed its predictive value for cognitive decline and AD biomarkers (i.e., cerebrospinal fluid [CSF] levels of Aβ1-42, total tau, and p-tau181) in a cohort of 791 elderly individuals. The astrocyte activation PRS showed significant main effects on cross-sectional memory (β = -0.07, p = 0.03) and longitudinal executive function (β = -0.01, p = 0.03). Additionally, the PRS interacted with amyloid positivity (p.intx = 0.02), whereby indicating that amyloid burden modifies the association between the PRS and annual rate of language decline. Furthermore, the PRS was negatively associated with CSF Aβ1-42 levels (β = -3.4, p = 0.07) and interacted with amyloid status, such that amyloid burden modifies the association between the PRS and CSF phosphorylated tau levels (p.intx = 0.08). These findings suggest that an astrocyte activation PRS could be a valuable tool for early disease risk prediction, potentially enabling intervention during the interval between pathogenic amyloid and tau accumulation.

Introduction: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized., Methods: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FA FWcorr ) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status., Results: Sex differences in FA FWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced., Discussion: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted., Highlights: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The presence of multiple pathologies is the largest predictor of dementia. A major gap in the field is the in vivo detection of mixed pathologies and their antecedents. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address this gap. The ADRCs longitudinally follow ≈ 17,000 participants, ranging from cognitively unimpaired to dementia, arising from Alzheimer's disease (AD) and related dementias (ADRD; e.g., AD, Lewy body disorders, vascular). Motivated by the Alzheimer's Disease Neuroimaging Initiative's (ADNI) impact, the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) was formed. Leveraging existing ADRC infrastructure, CLARiTI will integrate standardized imaging and plasma collection to characterize mixed pathologies and use community-engaged research methods to ensure that ≥ 25% of the sample is from underrepresented populations (e.g., ethnoculturally minoritized, low education). The resulting ADRD profiles, within a more diverse sample, will provide key resources for ADRCs and an unprecedented, more generalizable publicly available imaging-plasma dataset. HIGHLIGHTS: In vivo detection of mixed pathologies is critical for Alzheimer's disease and related dementias research. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address gaps related to mixed pathologies. The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will enhance this national program by adding standardized imaging and plasma collection to existing ADRC infrastructure. This effort will provide key resources for ADRCs and an unprecedented publicly available imaging-plasma-neuropath dataset., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Plasma phosphorylated tau-181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood., Methods: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and included 1185 adults >55 years of age with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, apolipoprotein E (APOE) ε4 carrier status, age, and sex on cognitive outcomes., Results: Higher plasma p-tau181 level was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in mild cognitive impairment (MCI) or dementia, APOE ε4 carriers, women, and younger participants., Discussion: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex., Highlights: Greater plasma p-tau181 was associated with lower cognition across most domains.Associations between p-tau181 and cognition were modified by age and sex.Level of p-tau181 was more strongly associated with cognition in people with mild cognitive impairment (MCI) and apolipoprotein E ( APOE ) ε4., Competing Interests: T.J.H. is a member of the scientific advisory board for Vivid Genomics (outside the work presented herein). H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). No other authors report any relevant conflicts. Author disclosures are available in the Supporting Information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Using a single-nucleus transcriptome derived from the dorsolateral prefrontal cortex of 424 Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP) participants, we investigated the cell type-specific effect of ten vascular endothelial growth factor (VEGF) genes on Alzheimer's disease (AD) endophenotypes., Methods: Negative binomial mixed models were used for differential gene expression and association analysis with AD endophenotypes. VEGF-associated intercellular communication was also profiled., Results: Higher microglia FLT1, endothelial FLT4, and oligodendrocyte VEGFB are associated with greater amyloid beta (Aβ) load, whereas higher VEGFB expression in inhibitory neurons is associated with lower Aβ load. Higher astrocyte NRP1 is associated with lower tau density. Higher microglia and endothelial FLT1 are associated with worse cognition performance. Endothelial and microglial FLT1 expression was upregulated in clinical AD patients compared to cognitively normal controls. Finally, AD cells showed a significant reduction in VEGF signaling compared to controls., Discussion: Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons., Highlights: The prefrontal cortical expression of FLT1 and FLT4 was associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and more Alzheimer's disease (AD) neuropathology. The associations between FLT1 or FLT4 and AD endophenotypes appear to be driven by endothelial and microglial cells. VEGFB expression seems to have opposing effects on the Aβ burden in AD depending on cell types, highlighting its potential protective role in neurons., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's Disease and Related Dementias (AD/ADRD) by sequencing whole genomes of affected participants and age-matched cognitive controls from diverse populations. The Genome Center for Alzheimer's Disease (GCAD) processed whole-genome sequencing data from 36,361 ADSP participants, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4). This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 2.2 million structural variants. Annotations and quality control data are available for all variants and samples. Additionally, detailed phenotypes from 15,927 participants across 10 domains are also provided. A linkage disequilibrium panel was created using unrelated AD cases and controls. Researchers can access and analyze the genetic data via NIAGADS Data Sharing Service, the VariXam tool, or NIAGADS GenomicsDB.

Background: Limited research has explored the effect of cardiovascular risk and amyloid interplay on cognitive decline in East Asians., Methods: Vascular burden was quantified using Framingham's General Cardiovascular Risk Score (FRS) in 526 Korean Brain Aging Study (KBASE) participants. Cognitive differences in groups stratified by FRS and amyloid positivity were assessed at baseline and longitudinally., Results: Baseline analyses revealed that amyloid-negative (Aβ-) cognitively normal (CN) individuals with high FRS had lower cognition compared to Aβ- CN individuals with low FRS (p < 0.0001). Longitudinally, amyloid pathology predominantly drove cognitive decline, while FRS alone had negligible effects on cognition in CN and mild cognitive impairment (MCI) groups., Conclusion: Our findings indicate that managing vascular risk may be crucial in preserving cognition in Aβ- individuals early on and before the clinical manifestation of dementia. Within the CN and MCI groups, irrespective of FRS status, amyloid-positive individuals had worse cognitive performance than Aβ- individuals., Highlights: Vascular risk significantly affects cognition in amyloid-negative older Koreans. Amyloid-negative CN older adults with high vascular risk had lower baseline cognition. Amyloid pathology drives cognitive decline in CN and MCI, regardless of vascular risk. The study underscores the impact of vascular health on the AD disease spectrum., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We have identified FLT1 as a protein that changes during Alzheimer's disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance. Additionally, we sought to replicate FLT1 interactions in the brain. The results showed that higher levels of FLT1 in CSF and post-mortem brain tissue related to increased tau, particularly among amyloid positive individuals. These analyses help clarify the potential utility of FLT1 as a biomarker among individuals with evidence of brain amyloidosis., Competing Interests: Conflicts of interest HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work)., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker of Alzheimer's disease (AD), with higher blood GFAP levels linked to faster cognitive decline, particularly among individuals with high brain amyloid burden. However, few studies have examined brain GFAP expression to clarify if peripheral associations reflect brain changes. This study aimed to correlate region-specific GFAP mRNA expression (n = 917) and protein abundance (n=386) with diverse neuropathological measures at autopsy in the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and to characterize the interaction between brain GFAP and brain amyloid burden on downstream outcomes. We assessed GFAP gene expression in the dorsolateral prefrontal cortex, caudate nucleus, and posterior cingulate cortex with respect to core AD pathology (amyloid-β and tau), cerebrovascular (microinfarcts, macroinfarcts, and cerebral amyloid angiopathy [CAA]), proteinopathic (TDP-43, Lewy bodies), and cognitive outcomes. These associations were further examined at the protein level using tandem-mass tag proteomic measurements from the dorsolateral prefrontal cortex. We also assessed GFAP interactions with AD neuropathology on downstream outcomes. Cortical GFAP gene and protein expression were significantly upregulated in participants with a neuropathologically confirmed AD diagnosis at autopsy (all P FDR  < 3.5e-4), but not in individuals positive for tau pathology and negative for amyloid pathology (all P FDR  > 0.05). Higher cortical GFAP levels were associated with increased amyloid pathology, CAA pathology, and faster cognitive decline (all P FDR  < 3.3e-3). GFAP's associations with phosphorylated tau burden and cognition were influenced by amyloid burden, being most pronounced among amyloid-positive individuals, confirming previous in vivo biomarker observations. No associations were observed between GFAP gene expression and outcomes in the caudate nucleus. Our results support previous biomarker findings and suggest that higher brain GFAP levels are associated with higher brain amyloid burden and faster cognitive decline among amyloid-positive individuals., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval and consent to participate: This study adhered to the principles outlined in the Declaration of Helsinki. All protocols received approval from the Rush University Medical Center Institutional Review Board, and written informed consent, including the Anatomical Gift Act, was obtained from all participants. The secondary analyses were approved by the Vanderbilt University Medical Center Institutional Review Board under protocol number 170135. Consent for publication: All authors have given consent to the publication of this manuscript., (© 2024. The Author(s).)

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk., (© 2024. The Author(s).)

Objective: This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults., Methods: Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers., Results: In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004)., Interpretation: Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD., Methods: We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18] F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18] F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses., Results: GWAS of tau-SUVR revealed two significant loci: rs78636169 ( P =5.76×10 -10 ) in JARID2 and rs7292124 ( P =2.20×10 -8 ) near ISX . Gene-based analysis of tau deposition highlighted APOE ( P =2.55×10 -6 ), CTNNA3 ( P =2.86×10 -6 ) and JARID2 ( P =1.23×10 -4 ), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE -ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers., Conclusion: We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ ., (© 2024. The Author(s).)

Impaired memory formation and recall is a distinguishing feature of Alzheimer's disease, and memory requires de novo gene transcription in neurons. Rapid and robust transcription of many genes is facilitated by the formation of a poised basal state, in which RNA polymerase II (RNAP2) has initiated transcription, but is paused just downstream of the gene promoter. Neuronal depolarization releases the paused RNAP2 to complete the synthesis of messenger RNA (mRNA) transcripts. Paused RNAP2 release is controlled by positive transcription elongation factor b (P-TEFb), which is sequestered into a larger inactive complex containing Hexamethylene bisacetamide inducible protein 1 (HEXIM1) under basal conditions. In this work, we find that neuronal expression of HEXIM1 mRNA is highly correlated with human Alzheimer's disease pathologies. Furthermore, P-TEFb regulation by HEXIM1 has a significant impact on the rapid induction of neuronal gene transcription, particularly in response to repeated depolarization. These data indicate that HEXIM1/P-TEFb has an important role in inducible gene transcription in neurons, and for setting and resetting the poised state that allows for the robust activation of genes necessary for synaptic plasticity.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

Diffusion MRI derived free-water (FW) metrics show promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD). FW is sensitive to subtle changes in brain microstructure, so it is possible these measures may be more sensitive than traditional structural neuroimaging biomarkers. In this study, we examined the associations among FW metrics (measured in the hippocampus and two AD signature meta-ROIs) with cognitive performance, and compared FW findings to those from more traditional neuroimaging biomarkers of AD. We leveraged data from a longitudinal cohort (n participants = 296, n observations = 870, age at baseline: 73 ± 7 years, 40% mild cognitive impairment [MCI]) of older adults who underwent serial neuropsychological assessment (episodic memory, information processing speed, executive function, language, and visuospatial skills) and brain MRI over a maximum of four time points, including baseline (n = 284), 18-month (n = 246), 3-year (n = 215), and 5-year (n = 125) visits. The mean follow-up period was 2.8 ± 1.3 years. Structural MRI was used to quantify hippocampal volume, in addition to Schwarz and McEvoy AD Signatures. FW and FW-corrected fractional anisotropy (FAFWcorr) were quantified in the hippocampus (hippocampal FW) and the AD signature areas (Schwarz FW , McEvoy FW ) from diffusion-weighted (dMRI) images using bi-tensor modeling (FW elimination and mapping method). Linear regression assessed the association of each biomarker with baseline cognitive performance. Additionally, linear mixed-effects regression assessed the association between baseline biomarker values and longitudinal cognitive performance. A subsequent competitive model analysis was conducted on both baseline and longitudinal data to determine how much additional variance in cognitive performance was explained by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein-ε4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. All analyses were corrected for multiple comparisons using an FDR procedure. Cross-sectional results indicate that hippocampal volume, hippocampal FW, Schwarz and McEvoy AD Signatures, and the Schwarz FW and McEvoy FW metrics are all significantly associated with memory performance. Baseline competitive model analyses showed that the McEvoy AD Signature and Schwarz FW explain the most unique variance beyond covariates for memory (ΔR adj 2 = 3.47 ± 1.65%) and executive function (ΔR adj 2 = 2.43 ± 1.63%), respectively. Longitudinal models revealed that hippocampal FW explained substantial unique variance for memory performance (ΔR adj 2 = 8.13 ± 1.25%), and outperformed all other biomarkers examined in predicting memory decline (p FDR = 1.95 x 10 -11 ). This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD., Competing Interests: Timothy J. Hohman, PhD is a member of the scientific advisory board for Vivid Genomics and serves on the editorial board for Alzheimer’s & Dementia and Alzheimer’s & Dementia: Translational Research and Clinical Intervention., (© 2024 The Authors. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data., Competing Interests: Conflict of interest Paul Maruff is a full-time employee of Cogstate Ltd. Samuel N. Lockhart is a full time employee of Invicro LLC. SCJ has served in the past three years as a consultant to ALZPath and Enigma Biomedical.

Introduction: Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes., Methods: We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n = 815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk., Results: Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization., Discussion: Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration., Highlights: Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ 42/40 , GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms., Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP)., Results: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD., Discussion: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations., Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site., Competing Interests: There are no competing interests to report. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE -ɛ4, APOE -ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes ( N = 1541) and AD-PRS ( N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE -ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE - ɛ 4 with atrophy were reduced among those with higher education ( P < 0.04) and younger baseline ages ( P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD ( P = 0.035) and the hippocampus ( P = 0.014), independent of APOE -ɛ4 status. APOE -ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities ( P = 0.014). Additionally, there was an APOE -ɛ4 × AD-PRS interaction in relation to white matter hyperintensities ( P = 0.038), with greater increases in white matter hyperintensities among APOE -ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE - ɛ 4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE - ɛ 2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation., Competing Interests: The following authors declare that they have no competing interests: A.S., J.W., C.P., C.D., G.E., T.J.H., L.D., M.B., S.M.R., L.A.R.-R., R.L., T.B., J.C.M. and J.F. C.L.M. and M.S.A. are advisors to Eli Lilly. S.C.J. has served as an advisor to Roche Diagnostics. S.M.L. is a scientific advisor to Cytox Ltd., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Platelet activation of protease-activated receptor 4 (PAR4) and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption, and inflammation. We evaluated mRNA expression of the PAR4 gene F2RL3 in human brain and global cognitive performance in participants with and without cognitive impairment or dementia. Data were acquired from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). F2RL3 mRNA was elevated in AD cases and was associated with worse retrospective longitudinal cognitive performance. Moreover, F2RL3 expression interacted with clinical AD diagnosis on longitudinal cognition whereas this relationship was attenuated in individuals without cognitive impairment. Additionally, when adjusting for the effects of AD neuropathology, F2RL3 expression remained a significant predictor of cognitive decline. F2RL3 expression correlated positively with transcript levels of proinflammatory markers including TNFα, IL-1β, NFκB, and fibrinogen α/β/γ. Together, these results reveal that F2RL3 mRNA expression is associated with multiple AD-relevant outcomes and its encoded product, PAR4, may play a role in disease pathogenesis., Competing Interests: Conflict of Interest TH serves as a member of the scientific advisory board for Vivid Genomics (outside the work presented herein). No other authors have any relevant conflicts to declare., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes., Objective: To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults., Design, Setting, and Participants: This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded., Main Outcomes and Measures: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite., Results: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition., Conclusions and Relevance: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers, has served at data monitoring committees for Julius Clinical and Novartis, has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. R.M. has scientific collaborations with Alector, Nodthera and Alchemab, and has been consultant for Sanofi. B.D.S. is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. B.D.S is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics., (Published by Elsevier Inc.)

Background: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR., Methods: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women)., Results: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline., Conclusion: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity., (© 2024. The Author(s).)

Purpose: In brain diffusion magnetic resonance imaging (dMRI), the volumetric and bundle analyses of whole-brain tissue microstructure and connectivity can be severely impeded by an incomplete field of view (FOV). We aim to develop a method for imputing the missing slices directly from existing dMRI scans with an incomplete FOV. We hypothesize that the imputed image with a complete FOV can improve whole-brain tractography for corrupted data with an incomplete FOV. Therefore, our approach provides a desirable alternative to discarding the valuable brain dMRI data, enabling subsequent tractography analyses that would otherwise be challenging or unattainable with corrupted data., Approach: We propose a framework based on a deep generative model that estimates the absent brain regions in dMRI scans with an incomplete FOV. The model is capable of learning both the diffusion characteristics in diffusion-weighted images (DWIs) and the anatomical features evident in the corresponding structural images for efficiently imputing missing slices of DWIs in the incomplete part of the FOV., Results: For evaluating the imputed slices, on the Wisconsin Registry for Alzheimer's Prevention (WRAP) dataset, the proposed framework achieved PSNR b 0 = 22.397 , SSIM b 0 = 0.905 , PSNR b 1300 = 22.479 , and SSIM b 1300 = 0.893 ; on the National Alzheimer's Coordinating Center (NACC) dataset, it achieved PSNR b 0 = 21.304 , SSIM b 0 = 0.892 , PSNR b 1300 = 21.599 , and SSIM b 1300 = 0.877 . The proposed framework improved the tractography accuracy, as demonstrated by an increased average Dice score for 72 tracts ( p < 0.001 ) on both the WRAP and NACC datasets., Conclusions: Results suggest that the proposed framework achieved sufficient imputation performance in brain dMRI data with an incomplete FOV for improving whole-brain tractography, thereby repairing the corrupted data. Our approach achieved more accurate whole-brain tractography results with an extended and complete FOV and reduced the uncertainty when analyzing bundles associated with Alzheimer's disease., (© 2024 The Authors.)

Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression and vascular disease, do not affect all individuals in the same way, likely due to inter-individual differences in genetics. However, the precise nature of how genetic risk profiles interact with modifiable risk factors to affect brain health is poorly understood. Here we combine multiple data resources, including genotyping and postmortem gene expression, to map the genetic landscape of brain structure and identify 367 loci associated with cortical thickness and 13 loci associated with white matter hyperintensities (P < 5×10 -8 ), with several loci also showing a significant association with cognitive function. We show that among 220 unique genetic loci associated with cortical thickness in our genome-wide association studies (GWAS), 95 also showed evidence of interaction with depression or cardiovascular conditions. Polygenic risk scores based on our GWAS of inferior frontal thickness also interacted with hypertension in predicting executive function in the Canadian Longitudinal Study on Aging. These findings advance our understanding of the genetic underpinning of brain structure and show that genetic risk for brain and cognitive health is in part moderated by treatable mid-life factors., (© 2024. The Author(s).)

Introduction: The effects of sex, race, and Apolipoprotein E ( APOE ) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized., Methods: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FA FWcorr ) were used to assess differences in white matter microstructure by sex, race, and APOE -ε4 carrier status., Results: Sex differences in FA FWcorr in association and projection tracts, racial differences in FA FWcorr in projection tracts, and APOE -ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced., Discussion: There are prominent differences in white matter microstructure by sex, race, and APOE -ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted., Competing Interests: SCJ has served on advisory boards for Enigma Biomedical and ALZPath in the past two years. AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, U19 AG074879, and U24 AG074855). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as External Advisory Committees for multiple NIA grants. He also serves as Editor-in-Chief of Brain Imaging and Behavior, a Springer-Nature Journal.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD., Competing Interests: DY, BH, BD, SM, BK, YD, LD, YW, AN, AK, YZ, HK, SJ, CC, TH, PC, CE, QL No competing interests declared, (© 2023, Yan, Hu et al.)

The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP) to investigate the effect of 10 VEGF genes ( VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1 , and NRP2 ) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with β-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical FLT1 expression was upregulated in AD brains in both endothelial and microglial cells. Higher FLT1 expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and β-amyloid load. Similarly, higher endothelial FLT4 expression was associated with more β-amyloid load. In contrast to the receptors, VEGFB showed opposing effects on β-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.

Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ 40 , worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ 40 (β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ 1-38 , β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future., (© 2024. The Author(s).)

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE-ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE-ε4 status on cross-sectional naming performance (β = -0.002, p = 0.002), and executive function excluding outliers (β = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (β = 0.002, p = 0.05). While cross-sectional models stratified by APOE-ε4 status indicated greater ePVS related to worse cognition mostly in APOE-ε4 carriers, longitudinal models stratified by APOE-ε4 status showed greater ePVS volume related to worse cognition among APOE-ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE-ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE-ε4 non-carriers, possibly due to the deleterious effects of APOE-ε4 on cognition across the lifespan., Competing Interests: Declaration of Competing Interest TJH serves on the Scientific Advisory Board for Vivid Genomics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete., Methods: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43., Results: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility., Discussion: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies., Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Purpose: Adverse neurological effects after cancer therapy are common, but biomarkers to diagnose, monitor, or risk stratify patients are still not validated or used clinically. An accessible imaging method, such as fluorodeoxyglucose positron emission tomography (FDG PET) of the brain, could meet this gap and serve as a biomarker for functional brain changes. We utilized FDG PET to evaluate which brain regions are most susceptible to altered glucose metabolism after chemoradiation in patients with head and neck cancer (HNCa)., Methods: Real-world FDG PET images were acquired as standard of care before and after chemoradiation for HNCa in 68 patients. Linear mixed-effects voxelwise models assessed changes after chemoradiation in cerebral glucose metabolism quantified with standardized uptake value ratio (SUVR), covarying for follow-up time and patient demographics., Results: Voxelwise analysis revealed two large clusters of decreased glucose metabolism in the medial frontal and polar temporal cortices following chemoradiation, with decreases of approximately 5% SUVR after therapy., Conclusions: These findings provide evidence that standard chemoradiation for HNCa can lead to decreased neuronal glucose metabolism, contributing to literature emphasizing the vulnerability of the frontal and anterior temporal lobes, especially in HNCa, where these areas may be particularly vulnerable to indirect radiation-induced injury. FDG PET shows promise as a sensitive biomarker for assessing these changes., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Purpose: Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that provides unique information about white matter microstructure in the brain but is susceptible to confounding effects introduced by scanner or acquisition differences. ComBat is a leading approach for addressing these site biases. However, despite its frequent use for harmonization, ComBat's robustness toward site dissimilarities and overall cohort size have not yet been evaluated in terms of DTI., Approach: As a baseline, we match N = 358 participants from two sites to create a "silver standard" that simulates a cohort for multi-site harmonization. Across sites, we harmonize mean fractional anisotropy and mean diffusivity, calculated using participant DTI data, for the regions of interest defined by the JHU EVE-Type III atlas. We bootstrap 10 iterations at 19 levels of total sample size, 10 levels of sample size imbalance between sites, and 6 levels of mean age difference between sites to quantify (i)  β AGE , the linear regression coefficient of the relationship between FA and age; (ii)  γ ^ s f * , the ComBat-estimated site-shift; and (iii)  δ ^ s f * , the ComBat-estimated site-scaling. We characterize the reliability of ComBat by evaluating the root mean squared error in these three metrics and examine if there is a correlation between the reliability of ComBat and a violation of assumptions., Results: ComBat remains well behaved for β AGE when N > 162 and when the mean age difference is less than 4 years. The assumptions of the ComBat model regarding the normality of residual distributions are not violated as the model becomes unstable., Conclusion: Prior to harmonization of DTI data with ComBat, the input cohort should be examined for size and covariate distributions of each site. Direct assessment of residual distributions is less informative on stability than bootstrap analysis. We caution use ComBat of in situations that do not conform to the above thresholds., (© 2024 The Authors.)

Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimer's Disease (AD). Protective and cognitive-enhancing roles for the nicotinic α5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic α5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to increased expression of CHRNA5 (rs1979905A2) predicts significantly reduced cortical β-amyloid load. Intriguingly, co-expression analysis suggests CHRNA5 has a distinct cellular expression profile compared to other nicotinic receptor genes. Consistent with this prediction, single nucleus RNA sequencing from 22 individuals reveals CHRNA5 expression is disproportionately elevated in chandelier neurons, a distinct subtype of inhibitory neuron known for its role in excitatory/inhibitory (E/I) balance. We show that chandelier neurons are enriched in amyloid-binding proteins compared to basket cells, the other major subtype of PVALB-positive interneurons. Consistent with the hypothesis that nicotinic receptors in chandelier cells normally protect against β-amyloid, cell-type proportion analysis from 549 individuals reveals these neurons show amyloid-associated vulnerability only in individuals with impaired function/trafficking of nicotinic α5-containing receptors due to homozygosity of the missense CHRNA5 SNP (rs16969968A2). Taken together, these findings suggest that CHRNA5 and its nicotinic α5 subunit exert a neuroprotective role in aging and Alzheimer's disease centered on chandelier interneurons., (© 2024. The Author(s).)

Background: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear., Methods: We conducted the largest sex-aware genetic study on late-life memory to date (N males  = 11,942; N females  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants., Results: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits., Discussion: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory., Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline., Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts., Results: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits., Discussion: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline., Highlights: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)