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

这项拟议的研究调查了认知障碍、痴呆症和脑萎缩的风险与 体力活动、感染、生物学性别和载脂蛋白E基因。我们建议继续进行纵向研究 与Tsimane和Moseten一起，两个南美洲原住民群体的生活方式和环境要求 高水平的体力活动，使他们暴露在高病原体负担下，最像工业前人类 过去时。尽管感染被认为在阿尔茨海默病的发病机制中起着关键作用，但 相关痴呆症(ADRD)，这是第一次在高传染性背景下对ADRD进行基于人群的研究， 感染被认为是风险的主要贡献者。当前的NIA项目(1RF1AG054442)具有 显示：1)冠状动脉疾病(CAD)和阿尔茨海默病(AD)的患病率非常低，交叉症状较浅。 脑萎缩的分段年龄斜率高于欧洲和美国人群，但2)高患病率 与认知损害相关的颅内内动脉钙化(MAC)，以及3)几乎两倍 女性患认知障碍的风险更高。我们提出以下假设来解释这些发现： (H1)高水平的体力活动减缓大脑萎缩，降低阿尔茨海默病的风险，部分是通过减少肥胖， 动脉硬化和代谢性炎症； (H2)病毒和细菌感染通过(H2A)影响淀粉样蛋白的产生，增加脑萎缩和ADRD的风险 和动脉疾病，包括影响淀粉样蛋白和白细胞跨血脑运输的途径 障碍。我们进一步假设，这些影响可以通过(H_2b)高体力活动和(H_2c)减少。 肠道蠕虫感染，由于蠕虫具有抗炎和免疫调节作用； (H3)女性认知障碍风险较高是由于先天炎症反应上调 对病原体(例如，通过增加淀粉样蛋白和tau的产生)的作用大于男性； (H4)在食物受限的高致病菌环境中，apoEε4等位基因具有性别特异性和交互作用。 病原体负担对免疫反应、血脂和ADRD风险的影响。 这些假设将通过以总体为基础的混合纵向面板和病例对照设计进行检验， 包括两波认知评估、家庭访谈、体检和生物标记物收集，以及 一组配对的胸部和脑计算机断层扫描用于评估大脑的纵向变化 体积和动脉硬化。创新包括血液淀粉样蛋白和tau生物标记物的水平，基因(MRNA) 表达，以及新冠肺炎患病前后的个体内比较。新的数据收集 建立在一个有凝聚力的跨学科领导团队的基础上，通过测试 纵向变化的因果模型。这些人群提供了一个正在消失的机会来研究风险因素 在不同的环境中运行，并评估感染在AD和脑老化中的作用。收集到的数据将 也构成了未来研究和获取数据共享联合体的生物库。

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.