Testing Hypothesized Pathways Linking Infection, Physical Activity, Apoe Genotype, And Biological Sex To Low Dementia Prevalence And Reduced Brain Atrophy In Two Native American Populations - The proposed research investigates the risk of cognitive impairment, dementia and brain atrophy in relation to physical activity, infection, biological sex, and APOE genotype. We propose to continue longitudinal research with Tsimane and Moseten, two cohorts of Native South Americans whose lifestyle and environment require high levels of physical activity and expose them to high pathogen burdens, most like the human preindustrial past. Though infections are hypothesized to play a key role in the pathogenesis of Alzheimer’s Disease and Related Dementias (ADRD), this is the first population-based study of ADRD in a highly infectious context, where infection is considered as a primary contributor of risk. The current NIA project (1RF1AG054442) has revealed: 1) very low prevalence of both coronary artery disease (CAD) and AD, with a shallower cross- sectional age slope of brain atrophy than in European and US populations, but 2) a high prevalence of intracranial medial arterial calcification (MAC) associated with cognitive impairment, and 3) an almost two-fold higher risk of cognitive impairment in females. We propose the following hypotheses to explain these findings: (H1) high levels of physical activity slow brain atrophy and reduce risk of AD, in part by reducing adiposity, arteriosclerosis, and metabolically-induced inflammation; (H2) viral and bacterial infections increase brain atrophy and ADRD risk, by (H2a) affecting amyloid production and arterial disease, including pathways that affect amyloid and leukocyte trafficking across the blood brain barrier. We further hypothesize that those impacts are reduced by (H2b) high physical activity and (H2c) intestinal helminth infection, as helminths have anti-inflammatory and immuno-regulatory effects; (H3) higher cognitive impairment risk in females is due to greater upregulated innate inflammatory responses to pathogens (e.g. via increased amyloid and tau production) than in males; (H4) In a food-limited high-pathogen environment, the APOE ε4 allele has sex-specific and interactive effects with pathogen burden on immune responses, blood lipids and ADRD risk. These hypotheses will be tested with a population-based, mixed longitudinal-panel and case-control design, including two waves of cognitive assessments, family interviews, medical exams and biomarker collection, and a wave of paired chest and brain computed tomography scans for assessment of longitudinal change in brain volume and arteriosclerosis. Innovations include blood levels of amyloid and tau biomarkers, gene (mRNA) expression, and within-individual comparisons pre- versus post COVID-19 illness. The new data collection builds on a cohesive interdisciplinary leadership team to augment current cross-sectional findings with tests of causal models of longitudinal change. These populations offer a vanishing opportunity to study how risk factors operate in diverse environments, and assess the role of infection in AD and brain aging. The data collected will also constitute a biobank for future research and access to data-sharing consortia.
