Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
APOE-mediated sex differences in microvascular pathology and AD-associated proteinopathies in the medial temporal lobe.
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Bax Francesco, Oltmer Jan, Auger Corinne A, Bonkhoff Anna, Coughlan Gillian T, Melloni Alexandra, Jaisa-Aad Methasit, Augustinack Jean, Serrano-Pozo Alberto, Frosch Matthew P, Greenberg Steven M, Gomez-Isla Teresa, Hyman Bradley T, van Veluw Susanne J, Perosa Valentina
Аннотация
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.
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.