APOE ‐mediated sex differences in microvascular pathology and AD‐associated proteinopathies in the medial temporal lobe

INTRODUCTION Cerebral small vessel disease (CSVD) contributes to the development of Alzheimer's disease (AD) dementia and co‐occurs with AD‐associated proteinopathies. However, how sex modulates the interaction between CSVD and AD‐associated proteinopathies in the medial temporal lobe (MTL) remains unclear. METHODS One hundred fifty‐two autopsy cases from the Massachusetts Alzheimer's Disease Research Center were included. Deep‐learning and semiquantitative scores were applied to MTL histological sections to obtain quantitative measures of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis). The effect of sex on AD‐associated proteinopathies and the interaction between sex, CSVD, and apolipoprotein E ( APOE ) genotype were analyzed using linear mixed‐effect models. RESULTS In women, higher CAA burden was associated with lower amyloid beta (Aβ) plaques but higher tau tangles density. No interaction effect was found for arteriolosclerosis. Women <75 years of age carrying the APOE ε4 allele had higher Aβ plaque burden than ε4 non‐carriers. DISCUSSION Our results highlight the complex effect of sex on microvascular and AD‐associated pathologies in the MTL.