Population neuroscience of sex differences in the Alzheimer's disease biomarker cascade: The role of cerebral small vessel disease

ABSTRACT The purpose of this proposed Mentored Research Scientist Career Development (K01) Award is to support the Candidate’s long-term career goal of leading a research program to elucidate sex-specific vascular contributions to AD and related dementias (ADRD) by applying the most cutting-edge assess- ments of cerebrovascular integrity and advanced epidemiologic methods. Whether there are sex differ- ences in the cerebral small vessel disease (cSVD)-to-Alzheimer’s disease (AD) pathophysiological cas- cade is currently unknown. The first aim of this proposal is to test for sex differences in tissue-based cSVD markers, Aβ, tau, and the cSVD-AD pathway. The second aim is to evaluate the role of vessel- based cSVD markers, measured by ultra-high field MRI, in the AD cascade and whether there are sex- related differences. To successfully achieve the Candidate’s career development goals and research objectives, the proposed K01 Award builds upon the Candidate's training in population neuroscience of aging and state of the art methods of ultra-high field small vessel imaging in older adults and adds four key areas of new training in addition to career and leadership development: 1) cohort harmoniza- tion methods; 2) causal inference methods to address external validity of highly selected study samples; 3) PET neuroimaging of AD pathology; and 4) sex and gender effects on cerebral pathophysiology of AD. This proposal incorporates several innovations that will allow the Candidate to better assess the importance of cSVD for sex differences in the AD biomarker cascade in the population at large: 1) application of state-of-the-art ultra-high field MRI to obtain direct vessel measures of early cSVD and 2) use of innovative neuroimaging harmonization and causal inference analytic approaches to over- come the “catch 22” obstacle that typical neuroimaging biomarker studies are not high in external va- lidity, but collecting neuroimaging in large, population representative cohorts is typically not feasible. The application is also innovative in relation to the current theoretical framework guiding AD research, testing boundaries of the extant dynamic AD biomarker model which does not include cerebrovascular biomarkers. Achieving these training and research objectives will support the Candidate's development as an independent investigator and a leader in sex-specific trajectories of AD. Ultimately, the Candi- date’s broader career goal is to develop an impactful research program which identifies sex-specific intervention targets and improves the lives of older men and women.