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APOE‐mediated sex differences in microvascular pathology and AD‐associated proteinopathies in the medial temporal lobe
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APOE‐mediated sex differences in microvascular pathology and AD‐associated proteinopathies in the medial temporal lobe
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Journal Article
APOE‐mediated sex differences in microvascular pathology and AD‐associated proteinopathies in the medial temporal lobe
2026
Overview
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. Highlights Deep learning was used to obtain quantitative measures of proteinopathies. In the medial temporal lobe, women had fewer amyloid beta (Aβ) plaques and more tau tangles compared to men. Women with more cerebral amyloid angiopathy (CAA) had fewer Aβ plaques but a higher tau tangle density. After age stratification, women younger than 75 years and ε4 carriers had higher Aβ plaque burden.
Publisher
John Wiley & Sons, Inc,Wiley
Subject
/ Aged
/ Alzheimer Disease - genetics
/ Alzheimer Disease - pathology
/ Amygdala
/ Antigens
/ APOE
/ Apolipoprotein E4 - genetics
/ Apolipoproteins E - genetics
/ Arteriolosclerosis - genetics
/ Arteriolosclerosis - pathology
/ Autopsy
/ Brain
/ Cerebral Amyloid Angiopathy - genetics
/ Cerebral Amyloid Angiopathy - pathology
/ Cerebral Small Vessel Diseases - genetics
/ Cerebral Small Vessel Diseases - pathology
/ Cloning
/ Dementia
/ Disease
/ Female
/ Genotype
/ Humans
/ Male
/ Proteins
/ pTDP‐43
/ Time
/ Women
