From aging to Alzheimer’s disease: concordant brain DNA methylation changes in late life
Year: 2026
Type: article
Abstract: BACKGROUND: Aging is the strongest risk factor for Alzheimer's disease (AD), but the molecular connections between aging and AD remain unclear. DNA methylation (DNAm) is implicated in both processes. METHODS: We conducted a meta-analysis of DNAm in prefrontal cortex from two independent postmortem cohorts: the Religious Orders Study and Memory and Aging Project (ROSMAP) and Brains for Dementia Research (BDR). Age-associated CpG sites were identified using cohort-specific linear models adjusted for neuronal proportion, sex, and batch, followed by meta-analysis. We computed epigenetic age acceleration in brain samples as delta-age (DNAmAge - chronological age), and compared clinically diagnosed AD with cognitively unimpaired participants. Functional analyses included genomic feature enrichment, pathway analysis, brain-blood DNAm correlation, and colocalization with genome-wide association study (GWAS) loci. Prognostic relevance of age-associated CpGs was tested in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset using Cox proportional hazards models for disease progression. RESULTS: We identified 3264 CpG sites associated with aging; most were hypermethylated and enriched in promoters and CpG islands, and involved genes related to immune regulation and metabolism. Comparison with AD neuropathology-associated methylation showed substantial overlap, with nearly all shared CpGs and regions showing concordant directional changes. Cortical epigenetic age acceleration was higher in ROSMAP participants with clinical AD than in cognitively unimpaired individuals after covariates adjustment, and this association persisted when the cortical clock was restricted to the aging-associated CpGs identified here, suggesting that acceleration in AD is attributable to age-related CpGs. Several CpGs showed significant brain-blood methylation correlations or were linked to AD GWAS risk loci through colocalization analyses. In ADNI, among 33 candidate CpGs selected for concordant aging- and AD-associated changes in cortex and significant brain-blood methylation correlations, baseline methylation at one CpG (cg10752406 in AZU1 promoter) was associated with progression at a 5% false discovery rate after covariate adjustment. CONCLUSIONS: Aging-associated DNAm changes in prefrontal cortex overlap with AD neuropathology-related changes and are involved in accelerated epigenetic aging in clinical AD. Our study provides valuable insights into the epigenetic landscape of aging and its implications for AD.
Source: Genome Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,290
Funders: U.S. Department of Defense, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, Rush University, Northern California Institute for Research and Education, Eisai, Servier, H. Lundbeck A/S, IXICO, National Institutes of Health, Genentech, Canadian Institutes of Health Research, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G104586243, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, G1298807586, G1554142629, G1593117279, G1650819308, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, G1763712247, G1880935189, Alzheimer's Disease Neuroimaging Initiative, G2100670906, G2105457377, G2152643862, G2189010064, G2340207221, G2423387114, G2471646051, G2522063444, G2823913939, G2835601961, G29951154, Exploring the Role of the Brain Transcriptome in Cognitive Decline, G3131374986, G3146424788, G3159755494, G3216574877, G3553156159, G3710456697, G3752451908, Pathway discovery, validation and compound identification for Alzheimer's disease, G3870774570, G3908963977, New computational tools for understanding and predicting AD via age-associated DNA methylation changes, G4119534169, G43180419, G4475667458, G4501223628, G4800177743, G4871541374, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, G5207404921, G5209990037, Alzheimer's Disease Genetics Consortium, G528601746, G5365730499, EFFECTS OF TRAUMATIC BRAIN INJURY (TBI) AND POST TRAUMATIC STRESS DISORDER (PTSD) ON ALZHEIMER'S DISEASE (AD) IN VETERANS USING IMAGING AND BIOMARKERS IN THE AD NEUROIMAGING INITIATIVE (ADNI)", G5654639750, G5740349702, G5850682332, G613619302, G6173816828, G6210868510, G6371410416, G6412110892, G6447063303, G6719828067, G6792506723, G6899163935, G72415811, G7298697282, G764699806, New DNA methylation biomarkers for predicting AD and cognitive decline, G7799614282, G781725486, G8228018387, G8281378126, G832434733, G839208290, Integrative Genomic Approaches for Understanding Sex Differences in Alzheimer's Disease, G8852128998, G8895907669, G8897063270, G8957659042, G9000039018, G9000122335, New computational tools for understanding and predicting AD via age-associated DNA methylation changes, Rush Alzheimer's Disease Research Center, G949825395
OpenAlex ID: W4411410983