Examining the impact of sex and hormones on the progression of autosomal dominant Alzheimer's disease

Summary Females may be more susceptible to Alzheimer’s disease (AD)-pathology, yet, in the early stages of AD, females perform better on verbal memory tests than males with similar levels of pathology. Nonetheless, despite this early verbal memory advantage, as disease progresses, females show faster cognitive decline. Thus, more research is needed to better characterize sex differences in AD biomarker progression, and to clarify potential mechanisms of cognitive resiliency or vulnerability to AD-pathology across the disease spectrum. To address these critical knowledge gaps, I will capitalize on our ongoing longitudinal biomarker study with the largest autosomal dominant AD kindred due to a single mutation (E280A) in the Presenilin-1 gene (PSEN1). PSEN1 mutation carriers are genetically determined to develop early-onset dementia, with mild cognitive impairment emerging at a median age of 44 and dementia at age 49. This extraordinary cohort offers the opportunity to examine sex differences in AD with few age-related confounds and methodological challenges. To this end, the candidate proposes: (1) training objectives to establish expertise in sex biology, longitudinal and multivariate modeling, and multimodal neuroimaging data, which together will further career development into an independent clinical researcher in AD; (2) a research objective to examine sex differences in the accumulation of AD-related pathology, neurodegeneration, and cognitive decline, and the potential role of steroid hormones in autosomal dominant AD; (3) a team of mentors and advisors to ensure the candidate’s success, with expertise in autosomal dominant AD (Dr. Yakeel Quiroz), biological sex differences (Dr. Jill Goldstein), sporadic AD (Dr. Reisa Sperling), multimodal neuroimaging (Dr. Chen), sex-specific differences and risk in AD (Dr. Michelle Mielke), and longitudinal and multivariate modeling (Dr. Hui Zheng). The proposed specific aims are to determine the: (1) effect of sex on AD-related pathology and neurodegeneration in PSEN1 mutation carriers; (2) effect of sex and AD biomarkers on cognitive decline in PSEN1 mutation carriers; (3) effect of steroid hormones on AD biomarker accumulation and cognitive decline in PSEN1 mutation carriers. This proposed research is innovative for investigating longitudinal sex differences in autosomal dominant AD using multimodal neuroimaging and examining the role of steroid hormones in AD biomarker abnormalities and cognitive decline. The proposed research is significant because further understanding of sex differences is crucial to inform research on prevention, early detection, design of clinical trials, and development of treatments. Overall, this project and training plan will promote the candidate’s career development by facilitating an independent program of research examining sex differences in AD and elucidating mechanisms of AD risk and resilience to inform precision interventions and treatments.