Basic Science and Pathogenesis

Abstract

Background: Alzheimer's disease (AD) related pathologies (i.e., neurofibrillary tangles [NFTs], amyloid-β plaques, and phosphorylated-TAR-DNA-binding-protein-43 [pTDP-43]) differ across sexes. However, the interaction between sex and cerebral small vessel disease (CSVD) (i.e., cerebral amyloid angiopathy [CAA] and arteriolosclerosis) on AD-related pathologies has been less well characterized. The medial temporal lobe (MTL) is a crucial region in AD pathophysiology which harbors AD-pathologies at an early disease stage and is vascularized by small vessels prone to CSVD. We therefore aimed to analyze the relationship between sex and CSVD on AD-related pathologies in the MTL of a pathological AD cohort.

Methods: The study included autopsy cases from the Massachusetts AD Research Center. One hemisphere was formalin-fixed, samples from pre-defined regions (hippocampal body and entorhinal cortex) were stained for luxol fast blue with hematoxylin&eosin, amyloid-b, At8, and pTDP-43. Deep-learning models (Aiforiaâ) were used to obtain quantitative measures for burden of CAA, NFTs, and pTDP-43 inclusions. Arteriolosclerosis (grade 0-3) was determined in vessels >20mm Ø. Mixed effect models explored age and sex (fixed terms) across regions of interest (ROIs: hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala) of the MTL on CSVD subtypes. Furthermore, interactions between sex and CSVD subtypes on AD-related pathologies were tested. Finally, ApoE effect was evaluated in a subgroup with available genotyping.

Results: 157 autopsy cases (80.8±12.6y, 91 females) were included, ApoE status was available in 66/157. Females had higher arteriolosclerosis severity (odds ratio for grade 2/3 = 1.56, 95% confidence interval [CI] 1.11; 2.20, p = 0.01) and lower CAA burden (b = -0.08, 95%CI -0.12; -0.04, p<0.001), when adjusting for age and ROIs. Moreover, females had lower burden of amyloid-b plaques (b = -0.25, 95%CI -0.46; -0.04, p = 0.02) and higher density of NFTs (b = 5.16, 95%CI 1.90; 8.41, p = 0.002). Inclusion of ApoE-status confirmed these findings with higher effect-size, and ApoE4 genotype interacted with female sex predicting higher NFT density when adjusting for arteriolosclerosis and CAA respectively (b = 16.2, 95%CI 4.2; 28.2, p = 0.008 and b = 16.3, 95%CI 3.37; 29.22, p = 0.01). No interaction effect was found between sex and CSVD on AD-pathology.

Conclusions: In this cohort, sex differentially affected microvascular and AD-related pathologies in the MTL. ApoE4 genotype might act as an effect modifier of sex.