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We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This cross\u2010sectional cohort study included 1,290 CU participants (aged 48\u201377) from the ALFA cohort with SLE, lumbar puncture (n\u2009=\u2009393), and\/or structural magnetic resonance imaging (n\u2009=\u20091,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)\u2010tau<jats:sub>181<\/jats:sub> and A\u03b2<jats:sub>1\u201342<\/jats:sub>\/<jats:sub>1\u201340<\/jats:sub> ratio, (2) interleukin 6 (IL\u20106), and (3) GM volumes voxel\u2010wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p\u2010tau<jats:sub>181<\/jats:sub> and IL\u20106. Participants with history of psychiatric disease and men, showed lower A\u03b2<jats:sub>1\u201342\/1\u201340<\/jats:sub> with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. 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