👤 Gillian Coughlan

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. 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. 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. Our results highlight the complex effect of sex on microvascular and AD-associated pathologies in the MTL. Show less

Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression. We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis. Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men. High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD. A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design. Show less

Women face greater vulnerability to dementia and Alzheimer's disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure-endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])-and late-life vascular brain injury, AD-related atrophy, and We included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by Extended estrogen exposure throughout life-both endogenous and exogenous-appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen's longterm impact on brain health and cognition to inform personalized medicine. Show less