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Previous studies using the National Alzheimer\u2019s Coordinating Center (NACC) have not investigated the association between age at death and apolipoprotein E (<jats:italic>APOE<\/jats:italic>) \u03b54 and the prevalence of neuropathologies found at autopsy. We used autopsy confirmed neuropathology data from the NACC to examine the interactive effects of age and <jats:italic>APOE<\/jats:italic> \u03b54 on various neuropathologies (N\u2009=\u20095,843) using modified Poisson regression to estimate the prevalence ratios. Significant interactions between <jats:italic>APOE<\/jats:italic> \u03b54 and age at death were observed for neuritic plaques, Braak staging, diffuse neuritic plaques, and Lewy body disease pathology, with the effect of <jats:italic>APOE<\/jats:italic> \u03b54 decreasing at older ages. In contrast, a significant positive interaction was found for hemorrhages\/microbleeds, indicating that the association between <jats:italic>APOE<\/jats:italic> \u03b54 and microbleeds strengthens with increasing age. These findings suggest that future therapeutic strategies should consider both genetic risk and age to effectively target AD progression.<\/jats:p>","DOI":"10.1186\/s40478-025-02012-0","type":"journal-article","created":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T09:41:45Z","timestamp":1747474905000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Age-dependent interactions of APOE isoform 4 and Alzheimer\u2019s disease neuropathology: findings from the NACC"],"prefix":"10.1186","volume":"13","author":[{"given":"Cellas A.","family":"Hayes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Roland J.","family":"Thorpe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle C.","family":"Odden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,17]]},"reference":[{"issue":"12","key":"2012_CR1","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1038\/ng.2802","volume":"45","author":"European Alzheimer\u2019s Disease Initiative (EADI)","year":"2013","unstructured":"European Alzheimer\u2019s Disease Initiative (EADI) et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer\u2019s disease. 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