Alzheimer's disease (AD) is the most common cause of dementia and is characterized by accumulation of senile plaques and neurofibrillary tangles in the brain. The primary constituent of senile plaques, amyloid-beta peptide (Aß), can also be commonly found deposited in brain blood vessels, referred to as cerebral amyloid angiopathy (CAA). CAA can lead to impaired blood vessel integrity and increased risk of brain hemorrhage, and dementia. CAA and AD share common genetic risk factors, including APP mutations and APOE?4. Higher CAA levels are observed in males, while the APOE?4 allele is more significantly associated with CAA in females. These findings suggest that there may be sex- and APOE-dependent pathways that influence the development of AD and/or CAA pathology that are as yet not well understood. Our parent project (RF1 AG051504) aims to close this knowledge gap, where the overarching goal of our work is to address how sex differentially affects cerebrovascular biology, amyloid pathology and CAA formation and how APOE-related and -independent pathways contribute to these sex effects. Under Aim 2 of the parent award, we have collected genome-wide genotypes for 477 individuals, pathologically diagnosed with AD, and scored for CAA pathology. We obtained RNAseq expression measures in temporal cortex of all and in cerebellum of a subset (N=200) of these same individuals. Further, we are in the process of also collecting DNA methylation (RRBS), and histone acetylation (H3K27ac) measures from many of these same tissue samples. Biochemical measures, including brain apoE and Aß levels are likewise being collected. Thus, we are well positioned to perform integrative molecular profiling analysis on this autopsy cohort, and have already made significant progress. We completed GWAS of CAA and confirmed APOE?4 dose as a significant risk factor in our cohort (p=4.85E-14). Sex stratified analysis confirmed more significant association for APOE?4 dose in females than males. Importantly, we identified 184 independent loci with a smaller p-value than those at the APOE locus (p
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