{"doi":"10.1101/2025.05.15.654279","title":"Sex-Specific Differential DNA Methylation in Mild Cognitive Impairment and Alzheimer’s Disease","abstract":"Abstract Sex differences in late-onset Alzheimer’s disease (AD) progression include accelerated decrements in cognitive status and greater amyloid and tau biomarker burdens in females. To identify sex-specific differentially methylated positions (DMPs) and genes in persons with mild cognitive impairment (MCI) and AD, we analyzed whole genome methylation sequencing on blood samples from participants with MCI (N=99, 52% female), AD (N=109, 43% female), and those cognitively unimpaired (CU; N=174, 52% female). Ninety-four percent of DMPs from MCI vs . CU, AD vs . CU, and AD vs . MCI pairwise comparisons were sex-specific. Female-specific DMPs were enriched in neurologic gene sets ( e.g ., synaptic membrane, ion channel complex), while male-specific DMPs showed limited enrichment. Sex-specific DMPs overlapped blood-specific enhancers, promoters, and transcription factor binding motifs, highlighting divergent epigenetic regulation by sex. These findings identify sex-specific genes and molecular pathways in MCI and AD and support that blood DNA methylation levels can distinguish cognitive status.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557950,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9262,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":510443,"name":"Andy Madrid","orcid":"0000-0001-8612-5995","position":1,"is_corresponding":false},{"id":510445,"name":"Ligia A. Papale","orcid":"0000-0002-6457-0358","position":2,"is_corresponding":false},{"id":289690,"name":"Lindsay R. Clark","orcid":"0000-0003-4837-7627","position":3,"is_corresponding":false},{"id":289695,"name":"Sanjay Asthana","orcid":"0000-0002-3998-4479","position":4,"is_corresponding":false},{"id":230038,"name":"Sterling C. Johnson","orcid":"0000-0002-8501-545X","position":5,"is_corresponding":false},{"id":43259,"name":"Sündüz Keleş","orcid":"0000-0001-9048-0922","position":6,"is_corresponding":false},{"id":395766,"name":"Kirk J. Hogan","orcid":"0000-0001-6329-2651","position":7,"is_corresponding":false},{"id":510446,"name":"Reid S. Alisch","orcid":"0000-0003-0637-4137","position":8,"is_corresponding":false},{"id":1067468,"name":"Phillip E. Bergmann","orcid":"0000-0002-1049-8661","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40475551","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":[]}