Impact of sex differences in immune function on shared risk for cardiometabolic disorder & Alzheimer's disease

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Summary By 2050, approximately 13.8 million people in the U.S. are projected to have Alzheimer's disease (AD), two- thirds of whom will be women. Secondary to genetics, cardiometabolic diseases (CMD), such as hypertension and diabetes, are major independent risk factors for AD. There are significant sex differences in pathology, timing, and clinical presentation of these diseases in early midlife. Despite this, the shared pathophysiology underlying CMD and AD, and sex differences therein, are largely unexplored. Here, we will test the hypothesis that sex differences in immune pathophysiology, in part, underlies the sex-dependent impact of cardiometabolic dysfunction on AD risk in midlife. We propose to recruit 240 people, ages 50- 75, equally divided by sex, that are “high and low risk” (HR & LR) for AD, defined as those with genetic risk and CMD vs. those without. Currently, we are recruiting 100 people (ages 50-70), whom we will re-recruit in the current study at ages 55-75. We will develop a general AD polygenic risk score (PRS) and a sex-stratified PRS to select HR and LR individuals along with presence or absence of CMD. We are conducting extensive in-clinic assessments to characterize structural and functional MRI (s/fMRI), cognitive function, hormone and immune profiling, cardiophysiology, neurovascular structure/function, genotype, RNA transcription and cell metabolism of monocyte cells, Aβ PET imaging, and AD blood-based biomarkers. Here, we propose to recruit an additional 140 HR and LR subjects, equally divided by sex, in order to obtain adequate statistical power to test for the shared sex-dependent impact of immune dysregulation underlying the association between CMD and AD- related pathology. Further, we will follow the current 100 subjects to evaluate the longitudinal impact of immune dysregulation on 5-year change in AD-related pathology by sex. We predict that HR vs. LR individuals will express significantly greater AD-related pathology [blood-based & PET AD biomarkers and memory circuitry deficits in entorhinal cortex, temporoparietal, cingulate, medial prefrontal cortex, locus coeruleus, and paraventricular hypothalamic nucleus], metabolic and neurovascular deficits, and dysregulation of immune pathway genes, cellular metabolism, and increased pro-inflammatory markers, with postmenopausal women worse than men. Further, we predict immune dysregulation will mediate (i.e., in part, explain) the relationship between HR vs. LR and AD-related pathology, and that this mediation will be stronger (larger effect sizes) in postmenopausal women versus men. Finally, in exploratory analyses, we predict that the presence of CMD will exacerbate the effects of genetic risk alone on AD-related pathology, with women experiencing worse outcomes than men. Overall, identifying sex-dependent mechanisms will have substantial implications for developing neuroimmune therapeutics that may differ by sex and targeted early for prevention.