Sex-specific cognitive expression and risk in preclinical Alzheimer's disease

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Men and women experience Alzheimer's differently, but we do not know why. When healthy, women tend to perform better on verbal memory tasks, but then decline more quickly than men on these tasks once AD takes hold. There are sex differences in other cognitive domains too. Despite these know differences in cognitive ability and trajectories of decline, our tools to measure change in AD do not adequately take sex differences into account. In addition, risk factors including genetic and vascular risk differ by sex. Again this is largely ignored in research, yet may represent important differences which could have a role in precision medicine. Furthermore, we know from autopsy and biomarker studies that the amount and distribution of tau in the brains of women exceeds and differs from men. The proposed project will respond to PAR‐19‐070: Research on Current Topics in Alzheimer's Disease and Its Related Dementias, in combination with NOT‐AG‐18‐053: Major Opportunities for Research in Epidemiology of Alzheimer's Disease and Related Dementias and Cognitive Resilience. We will approach these known differences in cognitive expression, genetic and vascular risk, and pathophysiology to better understand AD in women and men at the earliest stages of the disease. We expect to reveal similarities and differences, which might be of central importance in the development of novel therapeutics and approaches to test them. In Aims 1 and 2 we will employ two existing datasets to create new tools, sex‐specific composites, derived from longitudinal data. These empirically derived, optimally weighted composites can be used to assess change over time in clinical trials and observational studies. Since the cohorts use different cognitive test batteries, we will learn which tests might be more sex‐agnostic compared to those which might be more sex‐biased. We will learn about genetic risk, applying newly developed sex‐specific polygenic hazard scores to assess how well these contribute to predict cognitive change in men and women across the datasets, and we will approach vascular risk similarly, with distinct scores for men and women. In Aim 3, we will assess sex differences in tau and specifically how cognition relates to tau quantity and distribution in men and women. The datasets we will use both employ tau PET, allowing us to investigate regional distribution in relation to cognition. We expect to find important and intertwined differences in cognitive expression, and risk, and for these to be related to underlying pathophysiology. By taking advantage of existing cohort data we hope to pave the way for future studies extending our research into more diverse cohorts and a deeper understanding of the disease. This project will have direct public health impact, identifying how a sex‐specific approach can enrich our understanding of the symptomatology, course, risk factors and pathophysiology in AD. This can be translated for use in clinical trials, epidemiologic and observational studies, and even potentially the development of new sex‐targeted treatments.