Abstract
IMPORTANCE: Sex differences in Alzheimer disease (AD) neuropathology have not been examined extensively across multiple pathological constructs within broadly representative samples. OBJECTIVE: To examine sex differences in neuroimaging biomarkers of AD-related pathologies in a racially and ethnically diverse cohort. DESIGN, SETTING, AND PARTICIPANTS: Data for this cross-sectional study were collected from a community-based sample of adults without cognitive impairment aged 60 to 69 years in New York City from March 1, 2016, to September 31, 2022, and analyzed in March 2025. EXPOSURE: The primary exposure was self-reported sex (women or men). MAIN OUTCOMES AND MEASURES: The outcomes were global amyloid burden measured with florbetaben labeled with fludeoxyglucose 18 (18F) positron emission tomography (PET), tau burden in Braak stages I to VI measured with 18F-MK-6240 PET, and magnetic resonance imaging (MRI)-derived AD signature cortical thickness and white matter hyperintensity volumes. Linear regression analyses were performed to examine sex differences in the outcomes. Covariates included demographics, APOE ε4 status, and vascular health-related factors. Sex × age, sex × APOE ε4, and sex × race and ethnicity interactions were additionally examined on the outcomes. False discovery rate (FDR) correction for multiple comparisons were also performed. RESULTS: A total of 503 participants (mean [SD] age, 64.6 [2.8] years; 321 [63.8%] women; 305 [60.6%] Hispanic, 120 [23.9%] non-Hispanic Black, and 78 [15.5%] non-Hispanic White) with Aβ PET, MRI (n = 501), and tau PET (n = 355) data were studied. Compared with men, women had greater amyloid burden (B = 0.05; 95% CI, 0.02-0.07; P < .001), Braak stages III and IV (B = 0.05; 95% CI, 0.02-0.08; P = .003) and Braak stages V and VI (B = 0.09; 95% CI, 0.06-0.12; P < .001) tau burden, and AD signature thickness (B = 0.04; 95% CI, 0.02-0.05; P < .001). A significant sex × APOE ε4 interaction was observed, with women showing greater Braak stages I and II (B = 0.15; 95% CI, 0.04-0.25; P = .006) and Braak stages III and IV (B = 0.08; 95% CI, 0.02-0.14; P = .01) tau burden than men among APOE ε4 carriers. All findings remained statistically significant after FDR correction. No significant sex × age or sex × race and ethnicity interactions were observed on any outcome. CONCLUSIONS AND RELEVANCE: This cross-sectional study of community-based adults found greater AD pathology yet better preserved structural brain integrity in women compared with men. Sex differences in tau burden across early to middle Braak stages were more pronounced among APOE ε4 carriers compared with noncarriers. These findings were not modified by age or race and ethnicity. Overall, the results underscore sex-specific distinctions in AD pathology burden and brain structure at the cross-sectional level.