{"doi":"10.1016/j.jalz.2012.05.1829","title":"P4‐126: Genome‐wide exploration of DNA methylation in the aging brain and its relation to Alzheimer's disease","abstract":"Alterations in DNA methylation have been suggested to occur at a global, nuclear scale or in certain loci in the context of Alzheimer's disease. Here, leveraging new technology for DNA methylation profiling, we rigorously explore the role of the brain's chromatin conformation in the pathophysiology of Alzheimer's disease (AD) on a genome-wide scale. Clinical and post-mortem data come from two prospective clinical-pathologic cohort studies of aging: the Memory and Aging Project and the Religious Order Study. Each subject is non-demented at the time of entry. Post-mortem indices include quantitative measures of AD pathology and NIA-Reagan pathologic diagnosis. We interrogated the Methylome in frozen dorsolateral prefrontal cortex from 759 subjects with the Illumina Humanmet 450K platform, generating data for 486,428 CpG sites distributed throughout the genome. Regression adjusting for sex and age were used to examine the relation of the methylome to neuropathologic indices. In our primary analysis, methylation levels at 163 CpG dinucleotides demonstrate evidence of association with a quantitative measure of AD-related neuritic amyloid plaque burden (P<10^-7). In a secondary analysis, all 163 CpG also demonstrate strong evidence of association with a pathological diagnosis of AD, and 95% of the dinucleiotides are hypermethylated in AD subjects. Further, when the analysis is limited to 230 subjects with normal cognition at the time of death, association with neuritic plaque burden persists, suggesting that changes in methylation are an early feature of AD. We validate these results using an independent collection of AD and control brains: 58.5% of the genes near these 163 CpGs demonstrate altered transcription levels in AD brains. Finally, using a novel chromatin state map of the frontal cortex, we see that the 163 CpGs are distributed in a number of different chromatin states but appear to be enriched in gene bodies, particularly those that are not transcriptionally active. Robust changes in DNA methylation are found in the brains of subjects who display evidence of AD-associated neuritic plaque pathology. Most sites are hypermethylated in AD subjects, suggesting a coordinated AD-associated chromatin remodeling in aging brains that is present even in individuals with no cognitive impairment.","journal":"Alzheimer's &amp; Dementia","year":2012,"id":101,"datarank":0.27807996682948494,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.03666427996436984,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.03666427996436984,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":2,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.3281,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2012-07-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":759,"name":"Gyan Srivastava","orcid":"0000-0002-3999-2145","position":1,"is_corresponding":false},{"id":7783,"name":"Richard S. Sandstrom","orcid":null,"position":2,"is_corresponding":false},{"id":763,"name":"Fangeng Zou","orcid":null,"position":5,"is_corresponding":false},{"id":764,"name":"High Song","orcid":null,"position":6,"is_corresponding":false},{"id":765,"name":"Curtis Younkin","orcid":null,"position":7,"is_corresponding":false},{"id":92336,"name":"Nilufer Ertekin-Taner","orcid":null,"position":9,"is_corresponding":false},{"id":768,"name":"Brad Bernstein","orcid":null,"position":10,"is_corresponding":false},{"id":769,"name":"Alexander Meissner","orcid":"0000-0001-8646-7469","position":11,"is_corresponding":false},{"id":14693,"name":"Sharon L. R. Kardia","orcid":"0000-0002-9853-3379","position":12,"is_corresponding":false},{"id":771,"name":"Philip L. De Jager","orcid":"0000-0002-8057-2505","position":14,"is_corresponding":false},{"id":772,"name":"Matthew L. Eaton","orcid":"0000-0002-3447-8059","position":15,"is_corresponding":false},{"id":773,"name":"Lori B. Chibnik","orcid":"0000-0001-6293-806X","position":16,"is_corresponding":false},{"id":774,"name":"Brendan T Keenan","orcid":"0000-0002-9070-847X","position":17,"is_corresponding":false},{"id":775,"name":"Steven G. Younkin","orcid":null,"position":18,"is_corresponding":false},{"id":776,"name":"Nilüfer Ertekin‐Taner","orcid":"0000-0003-4436-8889","position":19,"is_corresponding":false},{"id":42925,"name":"Louis Philip Benoit Bouvrette","orcid":"0000-0003-2726-5669","position":20,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":21,"is_corresponding":false},{"id":95160,"name":"Adrian J. Ivinson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}