Sex-based contributors to vulnerability to Alzheimer's disease: a multimodal imaging study - Project Summary / Abstract Nearly 2/3 of people with Alzheimer's disease (AD) are women, and AD has a more aggressive phenotype in women. Women with AD suffer a faster rate of cognitive and functional decline than do men, and women are more impacted than men by common genetic variants such as APOE-ε4 which increase AD risk. The first signs of AD pathology are present decades prior to symptom onset, and multiple lines of research have implicated the menopausal transition as a time of emerging vulnerability to AD for women. However, we lack a fundamental understanding of sex differences in the brain circuitry most vulnerable to AD and how these differences relate to the onset and spread of AD pathology. The proposed research uses a multimodal imaging approach to understand the impact of both sex and major sex-based factors on brain circuitry and AD pathology, with two overarching aims. Our first aim leverages a new prospective cohort study of women and men with early-stage amnestic and non-amnestic AD, as well as healthy controls, to test hypotheses related to the impact of sex on functional networks in the brain and the extent to which this mediates faster tau progression in women. We also assess the impact of sex-based factors, including reproductive period and APOE genotype, on these metrics. We use innovative task-based functional neuroimaging techniques, plasma AD biomarkers, and ultra-high resolution second-generation tau PET longitudinally to accomplish these goals. Our second aim evaluates the relationship between sex, sex-based factors, tau, and functional connectivity, both in healthy aging and in preclinical and symptomatic AD. We leverage three large open- source datasets to evaluate specific hypotheses relating sex-based factors to changes in the functional circuitry targeted in amnestic AD. We then examine associations between functional circuitry changes, plasma p-tau, and tau PET signal. Finally, we use predictive modeling to identify brain connections which predict focal early-stage tau pathology, define sex differences in these predictors, and pinpoint the extent to which these connections mediate the relationship between tau and changes in cognitive performance. In order to address the disproportionate impact of AD on women, we must first understand the biological basis for sex differences in AD risk and progression, including the role of the functional connectome in promoting accelerated tau deposition in vulnerable groups. Successful completion of this work will fill key gaps in our knowledge of how both sex and specific sex-related factors impact functional circuitry, and in turn the progression of tau pathology.
