Abstract
<title>Abstract</title> <p> <bold>Importance:</bold> <italic>APOE-ε4</italic> is an established risk factor for Alzheimer’s disease (AD) and confers greater risk in women than in men. Earlier age at menopause also increases AD risk in women. Yet whether menopause timing influences <italic>APOE-ε4</italic> -related AD risk remains unclear. <bold>Objective:</bold> To examine whether age at menopause modifies the association of <italic>APOE-ε4</italic> with AD risk. <bold>Design, setting and participants:</bold> Data were analyzed from postmenopausal women free from known dementia at study entry in two longitudinal datasets: (1) the harmonized data from the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS), and (2) the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Data were collected between 1994-2025. <bold>Main outcomes and measures:</bold> In both datasets, neuropsychological tests assessed longitudinal memory performance, and MRI quantified cortical thickness and brain volume in AD vulnerable regions. In WRAP, which included <italic>in vivo</italic> AD biomarkers, AD pathology was assessed using longitudinal plasma p-tau217 and cross-sectional beta-amyloid (Aβ) PET. Menopause history was self-reported, and <italic>APOE</italic> status was classified as <italic>ε4</italic> carrier vs. non-carrier. Linear mixed-effects or linear regression models were used, as appropriate, to test interactions between <italic>APOE-ε4</italic> carrier status and age at menopause on memory decline, brain atrophy, p-tau217 accumulation, and Aβ-PET burden, adjusting for relevant covariates. <bold>Results:</bold> The study included 2,625 women in ROS/MAP/MARS (mean [ <italic>SD</italic> ] age=77.4 [7.77], mean [SD] age at menopause=47.9 [7.10]) and 512 women in WRAP (mean [SD] age=60.2 [5.57], mean [SD] age at menopause=50.1 [6.29]). In both datasets, earlier age at menopause strengthened associations of <italic>APOE-ε4</italic> with memory decline (ROS/MAP/MARS: β=0.068, <italic>p</italic> =.02; WRAP: β=0.092, <italic>p</italic> =.03) and MRI measures of brain atrophy (ROS/MAP/MARS: β=0.071, <italic>p</italic> =.05; WRAP: β=0.256, <italic>p</italic> =.03). In WRAP, earlier menopause also amplified associations of <italic>APOE-ε4</italic> with p-tau217 accumulation (β=-0.029, <italic>p</italic> =.05) and global Aβ-PET burden (β=-0.146, <italic>p</italic> =.01). <bold>Conclusions and relevance:</bold> Earlier menopause strengthened the associations between <italic>APOE</italic> -ε4 and key AD outcomes. These findings suggest that menopause timing may influence <italic>APOE</italic> -ε4-related susceptibility to AD, highlighting midlife endocrine processes as potential targets for prevention in women. </p>