Contextualizing molecular and structural aging across human organs

medRxiv · 2025-05-27

Organ-specific aging clocks have shown promise as predictors of disease risk and aging trajectories; however, the underlying biological mechanisms they reflect remain largely unexplored. Here, we use large-scale proteomic and imaging data to investigate the relationships among organ-specific and modality-specific aging clocks and to uncover the biological processes they represent. By estimating paired protein-based and imaging-based aging clocks across 8 major organs, we demonstrate that these omics and structural profiles exhibit distinct phenotypic and genetic signatures, each potentially quantifying different stages and playing complementary roles within a unified biological aging process. Furthermore, context-specific aging clocks from multiple organs often converge and jointly capture established biological and disease pathways. For example, 65.7% of the KEGG Alzheimer's disease pathway is enriched by at least one of 11 protein- and imaging-based aging clocks, with each clock representing different components of the pathway. These results underscore the importance of a pan-organ multi-modal perspective for quantifying the mechanisms underlying age-related diseases. Additionally, we identify modality-specific links between aging clocks and complex diseases and lifestyle factors. In summary, we uncover intricate relationships among molecular and structural aging clocks across human organs, providing novel insights into their context-specific roles in capturing consequences of aging biology and their implications for disease risk.

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Molecular Neurodegeneration · 2025-12-01 · 1 citations

Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Integrated genomic analysis and CRISPRi implicates <i>EGFR</i> in Alzheimer’s disease risk

medRxiv · 2025-06-26 · 1 citations

Abstract Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer’s disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci. We identified 42 candidate causal variant-effector gene pairs and assessed their impact using enhancer-promoter interaction data, variant annotations, and brain cell-type-specific gene expression. Notably, the LOAD risk allele of rs74504435 at the SEC61G locus was computationally predicted to increase EGFR expression in LOAD related cell types: microglia, astrocytes, and neurons. Functional validation using promoter-focused Capture C, ATAC-seq, and CRISPR interference in the HMC3 human microglia cell line confirmed this regulatory relationship. Our findings reveal a microglial enhancer regulating EGFR in LOAD, suggesting EGFR inhibitors as a potential therapeutic avenue for the disease.

Region-Based Analysis with Functional Annotation Identifies Genes Associated with Cognitive Function in South Asians from India

Genes · 2025-05-27 · 2 citations

Background/Objectives: The prevalence of dementia among South Asians across India is high among those who are 65 years and older, yet little is known about genetic risk factors for dementia in this population. Methods: Using whole-genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD), we performed a gene-based analysis on the missense/loss-of-function (LoF) and brain-specific promoter/enhancer variants of 84 genes, previously associated with AD in European Ancestry (EA). These analyses were performed separately, both with and without incorporating additional annotation weights (e.g., deleteriousness, conservation scores), using the variant-Set Test for Association using Annotation infoRmation (STAAR). We investigated associations with the Hindi Mental State Examination (HMSE) score and factor scores for general cognitive function and five cognitive domains. Results: In the missense/LoF analysis, without annotation weights and controlling for age, sex, state/territory, and genetic ancestry, three genes were associated with at least one measure of cognitive function (FDR q &lt; 0.1). APOE was associated with four measures of cognitive function, PICALM was associated with HMSE score, and TSPOAP1 was associated with executive function. The most strongly associated variants in each gene were rs429358 (APOE ε4), rs779406084 (PICALM), and rs9913145 (TSPOAP1). Rs779406084 is a rare missense mutation that is enriched in LASI-DAD compared to EA (minor allele frequency = 0.075% vs. 0.0015%). Conclusions: Missense/LoF variants in some genes previously associated with AD in EA are associated with measures of cognitive function in South Asians from India. Analyzing genome sequence data allows the identification of potential novel causal variants enriched in South Asians.

Alzheimer's Disease Sequencing Project release 4 whole genome sequencing dataset

Alzheimer s & Dementia · 2025-05-01 · 19 citations

INTRODUCTION: The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's disease and related dementias (ADRD) by integrating whole genome sequencing (WGS) with other genetic, phenotypic, and harmonized datasets from diverse populations. METHODS: The Genome Center for Alzheimer's Disease (GCAD) uniformly processed WGS from 36,361 ADSP samples, 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). RESULTS: This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 6.8 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. DISCUSSION: Researchers can access and analyze the genetic data via the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) Data Sharing Service, the VariXam, or NIAGADS GenomicsDB. HIGHLIGHTS: We detailed the genetic architecture and quality of the Alzheimer's Disease Sequencing Project release 4 whole genome sequences. We identified 435 million single nucleotide polymorphisms, insertions and deletions, and structural variants from diverse genomes. We harmonized extensive phenotypes, linkage disequilibrium reference panel on subset of samples. Data is publicly available at NIAGADS Data Storage Site, variants and annotations are browsable on two different websites.

Integrated genomic analysis and CRISPRi implicates EGFR in Alzheimer’s disease risk

npj Dementia · 2025-12-16

Abstract Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer’s disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci. We identified 41 candidate causal variant-effector gene pairs and assessed their impact using enhancer–promoter interaction data, variant annotations, and brain cell-type-specific gene expression. Notably, the LOAD risk allele of rs74504435 at the SEC61G locus was computationally predicted to increase EGFR expression in LOAD-related cell types: microglia, astrocytes, and neurons. Functional validation using promoter-focused Capture C, ATAC-seq, and CRISPR interference in the HMC3 human microglia cell line confirmed this regulatory relationship. Our findings reveal a microglial enhancer regulating EGFR in LOAD, suggesting EGFR inhibitors as a potential therapeutic avenue for the disease.

NIAGADS: A data repository for Alzheimer's disease and related dementia genomics

Alzheimer s & Dementia · 2025-06-01 · 3 citations

The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is the National Institute on Aging-designated national data repository for human genetics research on Alzheimer's disease and related dementias (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis, including whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project and other genotype/phenotype data, encompassing 211,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a Federal Information Security Modernization Act moderate compliant cloud-based platform that fully supports the National Institutes of Health Genomic Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. As a one-stop access portal for Alzheimer's disease (AD) genetics, NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of AD. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a data repository for the storage of genetics and genomics data. NIAGADS houses data for Alzheimer's disease, related dementias, and healthy aging. NIAGADS offers open and qualified access data and knowledgebases to explore open access data. The Alzheimer's Disease Sequencing Project dataset is the largest Alzheimer's disease and related dementias joint called whole genome sequencing dataset (≈ 58,000 whole genomes).

Evaluating the association of <i>APOE</i> genotype and cognitive resilience in SuperAgers

medRxiv · 2025-01-07 · 1 citations

Abstract INTRODUCTION “SuperAgers” are oldest-old adults (ages 80+) whose memory performance more closely resembles middle-aged adults. The present study examined APOE allele frequency in non-Hispanic Black (NHB) and non-Hispanic White (NHW) SuperAgers compared to controls and Alzheimer’s disease dementia cases. METHODS In 18,080 participants from eight cohorts, harmonized clinical diagnostics and memory, executive function, and language domain scores were used to identify SuperAgers, cases, and controls across age-defined bins. RESULTS NHW SuperAgers had significantly lower frequency of APOE- ε4 alleles and higher frequency of APOE -ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. DISCUSSION We demonstrated strong evidence that APOE allele frequency relates to SuperAger status. Further research is needed with a larger sample of NHB SuperAgers to determine if mechanisms conferring resilience differ across race groups.

Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures

medRxiv · 2025-02-13 · 1 citations

Abstract Background Genome-wide association studies (GWAS) have identified over 1,000 blood pressure (BP) loci and over 80 loci for Alzheimer’s disease (AD). Considering BP is an AD risk factor, identifying pleiotropy in BP and cognitive performance measures may indicate mechanistic links between BP and AD. Methods Genome-wide scans for pleiotropy in BP variables—systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse pressure (PP)—and co-calibrated scores for cognitive domains (executive function, language, and memory) were performed using generalized linear mixed models and 116,075 longitudinal measures from 25,726 participants of clinic-based and prospective cohorts. GWAS was conducted using PLACO to estimate each SNP’s main effect and interaction with age, and their joint effect on pleiotropy. Effects of genome-wide significant (GWS) pleiotropic SNPs on cognition as direct or mediated through BP were evaluated using Mendelian randomization. Potential contribution of genes in top-ranked pleiotropic loci to cognitive resilience was assessed by comparing their expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms. Results Pleiotropy GWAS identified GWS associations with APOE and 11 novel loci. In the total sample, pleiotropy was identified for SBP and language with JPH2 ( P Joint =6.09×10 -9 ) and GATA3 ( P G×Age =1.42×10 -8 ), MAP and executive function with PAX2 ( P G×Age =4.22×10 -8 ), MAP and language with LOC105371656 ( P G×Age =1.75×10 -8 ), and DBP and language with SUFU ( P G =2.10×10 -8 ). In prospective cohorts, pleiotropy was found for SBP and language with RTN4 ( P G×Age =1.49×10 -8 ), DBP and executive function with ULK2 ( P Joint =2.85×10 -8 ), PP and memory with SORBS2 ( P G =2.33×10 -8 ), and DBP and memory with LOC100128993 ( P G×Age =2.81×10 -8 ). In clinic-based cohorts, pleiotropy was observed for PP and language with ADAMTS3 ( P G =2.37×10 -8 ) and SBP and memory with LINC02946 ( P G×Age =3.47×10 -8 ). Five GWS pleiotropic loci influence cognition directly, and genes at six pleiotropic loci were differentially expressed between pathologically confirmed AD cases with and without clinical symptoms. Conclusion Our results provide insight into the underlying mechanisms of high BP and AD. Ongoing efforts to harmonize BP and cognitive measures across several cohorts will improve the power of discovering, replicating, and generalizing novel associations with pleiotropic loci.

Mosaic chromosomal alterations in blood are associated with an increased risk of Alzheimer’s disease

medRxiv · 2025-06-04 · 3 citations

Abstract Mosaic chromosomal alterations (mCAs) in blood, a form of clonal hematopoiesis, have been linked to various diseases, but their role in Alzheimer’s disease (AD) remains unclear. We analyzed blood whole-genome sequencing (WGS) data from 24,049 individuals in the Alzheimer’s Disease Sequencing Project and found that autosomal mCAs were significantly associated with increased AD risk (odds ratio = 1.27; P = 1.3 × 10 −5 ). This association varied by ancestry, mCA subtype, APOE ε4 allele status, and chromosomal location. Using matched blood WGS and brain single-nucleus RNA-seq data, we identified microglia-annotated cells in the brain carrying the same mCAs found in blood. These findings suggest that blood mCAs may contribute to AD pathogenesis, potentially through infiltration into the brain and influencing local immune response.