Basic Science and Pathogenesis.

Background: Cerebrovascular pathology frequently co-occurs with Alzheimer's disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.

Method: Sex-specific Polygenic Risk Scores (PRS) of the sex hormones testosterone (N: 146,339; N: 142,778) and estradiol N 147,690; N 163,985) were built using a linkage-disequilibrium (LD) clumping method from published sex-stratified GWAS from UK Biobank, using individuals with an age range of 40-69 years old. Each PRS was scaled before analysis. Genetic data and harmonized cerebrovascular pathology data were leveraged from non-Hispanic White autopsy participants from three independent studies of aging and AD: Adult Changes in Thought (ACT), the National Alzheimer's Coordinating Center (NACC), and the Religious Orders Study/Rush Memory and Aging Project (ROSMAP) (N: 4,269; N: 4,609). Characteristics of the participants are described in Table 1. Sex-specific logistic regression models were used to evaluate whether each PRS relate to cerebrovascular disease (CVD) outcomes, including presence or absence of macroscopic infarcts, microinfarcts, atherosclerosis, or arteriolosclerosis. Covariates included age at death, last clinical diagnosis before death, and education.

Result: Higher genetically predicted levels of testosterone in males were associated with the presence of macroscopic infarcts (Table 2; b = 0.11, p = 0.03). Interestingly, higher genetically predicted levels of estradiol in males were associated with the presence of arteriolosclerosis (Table 2; b = 0.13, p = 0.02). No significant associations were observed for the other CVD outcomes in men and none in women. Significant results did not survive corrections for multiple comparisons.

Conclusion: The results show that a PRS of sex hormones can be used to explore the effect of sex hormone levels on cerebrovascular pathology as it pertains to AD. The results also support the need for more studies investigating the role of sex hormones on sex-specific phenotypes of cerebrovascular pathology in the presence of AD. Future work is needed to better understand the mechanisms behind the observed associations.