Sex Differences in Alzheimer's disease-Related Pathology: Role of Mitochondrial Function and Metabolic Health

Project Summary/Abstract My career goal is to become a leading researcher in the field of sex differences in Alzheimer’s disease (AD), with a specific focus on metabolic mediators and mitochondrial function. To this end, my specific training goals in this K01 proposal include: 1) Increasing expertise and knowledge around sex differences in the brain, 2) Expanding my knowledge in metabolic and mitochondrial function in relation to AD and obtain training in biomarker research, and 3) Developing proficiency in translational research and biostatistics for data analysis. The NIA K01 Mentored Research Scientist Development Award will support my training and provide me with the knowledge base and skills needed to become an independent investigator. These training goals will be achieved in conjunction with the testing of my specific aims, which are built on promising preliminary data showing that metabolic health impacts memory circuitry function over the menopausal transition, potentially through mechanisms of oxidative stress. Two-thirds of patients with AD are women. Beyond life expectancy rates, there are sex-specific and sex-dependent genetic and physiologic factors that contribute to the higher frequency of AD in women. Midlife metabolic dysfunction, which significantly differs by sex, has long been recognized as a risk factor for AD. Despite this, the pathophysiology underlying this relationship remains largely unknown. I will test that hypothesis that mitochondrial function plays a critical role in understanding sex differences in memory circuitry function and the early emergence of AD-related pathology. Data will be leveraged from the unique New England Family Study (NEFS) prenatal cohort (N=212; 106M:106F), born between 1959-1966 and followed for >60 years. Detailed medical/reproductive histories, metabolic assessments, memory assessments, and stored blood samples were collected from offspring at ages 45-55 (T1 in R01MH090291). These same individuals are currently being assessed in an 8-year follow up, at ages 52-65 (T2 in R01AG067019), using the same T1 measures with additional brain imaging modalities. I have a unique window of opportunity to examine how mitochondrial function affects memory circuitry and AD-related pathology in a sex-dependent manner. Further, from T1 to T2, some women transitioned to menopause and thus I will be able to prospectively explore the longitudinal impact of reproductive aging, metabolic health, and mitochondrial function on memory decline and the accumulation of AD-related pathology. This proposal will examine mitochondrial function as a pathophysiological mechanism for sex differences in memory circuitry and risk for AD. Findings will have significant long-term implications for the co-occurrence of brain and metabolic disorders and highlight potential mechanistic targets for therapeutic strategies.