{"doi":"10.1002/alz.12885","title":"AD and non‐AD mediators of the pathway between the <i>APOE</i> genotype and cognition","abstract":"INTRODUCTION: The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late-life cognition through Alzheimer's disease (AD) and non-AD neuropathologies. METHODS: We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aβ), neurofibrillary tangles), vascular (athero/arteriolo-sclerosis, micro-infarcts/macro-infarcts), and non-AD neurodegenerative neuropathologies (TAR DNA protein 43 [TDP-43], Lewy bodies, amyloid angiopathy, hippocampal sclerosis). RESULTS: The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non-AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men. DISCUSSION: The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia. HIGHLIGHTS: Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late-life cognition are mediated by AD neuropathology. The estimated mediated effects of most measures of AD neuropathology were similar. Non-Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD. Non-AD vascular pathologies did not mediate the effect of the APOE genotype on cognition. The protective effect of APOE ε2 on cognition was stronger in women.","journal":"Alzheimer s & Dementia","year":2022,"id":258169,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9377,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":270469,"name":"Adam M. Brickman","orcid":"0000-0002-5125-8226","position":1,"is_corresponding":false},{"id":329465,"name":"Kaitlin B. Casaletto","orcid":"0000-0001-5000-7604","position":2,"is_corresponding":false},{"id":27686,"name":"Kristen Dams-O'Connor","orcid":"0000-0002-2506-0216","position":3,"is_corresponding":false},{"id":328344,"name":"Kristen M. George","orcid":"0000-0001-8773-7678","position":4,"is_corresponding":false},{"id":406764,"name":"Raj G. Kumar","orcid":"0000-0002-0858-3533","position":5,"is_corresponding":false},{"id":370391,"name":"Priya Palta","orcid":null,"position":6,"is_corresponding":false},{"id":443329,"name":"Jennifer S. Rabin","orcid":"0000-0003-4754-2221","position":7,"is_corresponding":false},{"id":245362,"name":"Claudia L. Satizábal","orcid":"0000-0002-1115-4430","position":8,"is_corresponding":false},{"id":7426,"name":"Julie A. Schneider","orcid":"0000-0002-9482-1752","position":9,"is_corresponding":false},{"id":288641,"name":"Judy Pa","orcid":"0000-0002-5788-9352","position":10,"is_corresponding":false},{"id":260103,"name":"Renaud La Joie","orcid":"0000-0003-2581-8100","position":11,"is_corresponding":false},{"id":61294,"name":"Emma Nichols","orcid":"0000-0002-9005-3872","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T00:25:38.634785Z","pmid":"36516004","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":[]}