Assessing the Role of Sex-Specific Genetic Drivers of Cerebrovascular Disease in the Alzheimer's Disease Brain

ABSTRACT Alzheimer's disease (AD) disproportionately affects women, yet the underlying biological and genetic factors contributing to this sex disparity remain poorly understood. This proposal addresses this critical gap by focusing on the intricate interplay between sex-specific genetic factors, cerebrovascular disease (CVD), and AD pathogenesis. Building on our groundbreaking research revealing sex-specific genetic associations in AD- related endophenotypes, we aim to extend this paradigm to explore the role of genetics in the development and progression of CVD within the AD-affected brain and to investigate whether or not these relationships present in a sex-specific manner. Our research team, with expertise spanning statistical genetics, sex differences in Alzheimer's and related dementias, neuropathology, and neuropsychiatry, will harness the vast resources of the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Sequencing Project. With autopsy data from over 9,600 well-characterized participants, including measures of CVD, amyloid and tau burden, and longitudinal cognitive scores, we are uniquely positioned to conduct the most extensive sex- specific genome-wide analyses of CVD endophenotypes in the context of AD to date. The specific aims of this proposal are threefold: [1] identify sex-specific genetic markers of autopsy measures of brain vessel disease (i.e., atherosclerosis and arteriolosclerosis), [2] identify sex-specific genetic markers of autopsy measures of vascular brain injury (i.e., macroscopic and microscopic infarction), and [3] characterize the degree to which known genetic drivers of CVD affect cognitive decline in a sex-specific manner. The outcome of this project will highlight new candidate pathways and begin the process of characterizing the mechanisms by which genetic variation among males and females affects the risk of CVD and clinical symptoms of AD. It also holds the promise of identifying novel therapeutic targets and of moving the field towards personalized interventions that consider an individual’s sex and neuropathological presentation.