From aging to Alzheimer’s disease: concordant brain DNA methylation changes in late life
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.003 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".