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

这项拟议中的研究调查了认知障碍、痴呆和脑萎缩的风险， 体力活动、感染、生物性别和APOE基因型。我们建议继续进行纵向研究 与Tsimane和Moseten一起，这两群南美洲原住民的生活方式和环境需要 高水平的体力活动，使他们暴露在高病原体负担，最像人类前工业化 过去虽然感染被假设在阿尔茨海默病的发病机制中起关键作用， 相关痴呆症（ADRD），这是第一个在高传染性背景下对ADRD进行的基于人群的研究， 感染被认为是主要的风险因素。当前的NIA项目（1 RF 1AG 054442） 结果显示：1）冠状动脉疾病（CAD）和AD的患病率非常低， 脑萎缩的分段年龄斜率高于欧洲和美国人群，但2）脑萎缩的患病率很高 颅内内侧动脉钙化（MAC）与认知功能障碍有关，3）几乎是双重的 女性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)高水平体力活动可以减缓脑萎缩，降低AD的风险，部分是通过减少肥胖， 动脉硬化和代谢诱导的炎症; (H2)病毒和细菌感染通过（H2 a）影响淀粉样蛋白的产生而增加脑萎缩和ADRD的风险 和动脉疾病，包括影响淀粉样蛋白和白细胞通过血脑运输的途径 屏障我们进一步假设，这些影响被（H2 b）高体力活动和（H2 c） 肠道蠕虫感染，因为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性炎症反应上调较多 病原体（例如通过增加淀粉样蛋白和tau蛋白的产生）比男性; (H4)在食物限制的高病原体环境中，APOE ε4等位基因具有性别特异性和交互作用 病原体负荷对免疫反应、血脂和ADRD风险的影响。 这些假设将采用基于人群的混合样本组和病例对照设计进行检验， 包括两波认知评估、家庭访谈、医学检查和生物标志物收集， 一波成对的胸部和脑部计算机断层扫描，用于评估脑部纵向变化 体积和动脉硬化。创新包括淀粉样蛋白和tau生物标志物的血液水平，基因（mRNA） 表达，以及COVID-19疾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，以增强当前的横截面结果与测试， 纵向变化的因果模型。这些人群提供了一个消失的机会，研究风险因素如何 在不同的环境中操作，并评估感染在AD和脑老化中的作用。收集的数据将 还构成了一个生物库，供今后研究和进入数据共享联盟。

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.