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

在两个美洲原住民群体中测试感染、体力活动、Apoe 基因型和生物性别与低痴呆症患病率和减少脑萎缩之间的假设途径

• 批准号: 10369546
• 负责人: CALEB E FINCH
• 金额: $ 319.97万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369546
• 关键词: 2019-nCoV; Adult; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Antibodies; Antigens; Aorta; Apolipoprotein E; Apolipoproteins; Arteriosclerosis; Atherosclerosis; Atrophic; Bacterial Antigens; Bacterial Infections; Basal Ganglia; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Carotid Arteries; Chest; Cognition; Cognitive; Collection; Coronary Arteriosclerosis; Coronary artery; Data; Data Collection; Dementia; Developing Countries; Diet; Disease; Disease Outcome; Environment; Europe; European; Exposure to; Family; Fatty acid glycerol esters; Female; Food; Gene Expression; Gene Expression Profile; Genes; Genotype; Helminths; Hematological Disease; High Prevalence; Human; Immune; Immune response; Impaired cognition; In Vitro; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory Response; Interview; Intestinal parasite; Intestines; Leadership; Leukocyte Trafficking; Life Style; Link; Longitudinal Studies; Low Prevalence; Measures; Medial; Mediator of activation protein; Medical; Metabolic; Native Americans; Neurologic; Neuropathy; Obesity; Parasites; Parasitic infection; Pathogenesis; Pathway interactions; Physical activity; Play; Population; Population Study; Prevalence; Production; Research; Risk; Risk Factors; Role; Sampling; Scanning; Severities; Sex Differences; Signal Transduction; South American; Specimen; Testing; Variant; Vascular Endothelial Growth Factors; Viral; Viral Antigens; Virus Diseases; Whole Blood; X-Ray Computed Tomography; aged; aging brain; amyloid peptide; biobank; biological sex; blood lipid; brain volume; calcification; case control; causal model; cerebral atrophy; cognitive testing; cohesion; cohort; dementia risk; design; differential expression; gene network; genotypic sex; gray matter; helminth infection; high risk; immunoregulation; innovation; mRNA Expression; male; mild cognitive impairment; neurofilament protein L; pathogen; population based; post-COVID-19; screening; sex; tau Proteins; transcriptome; transcriptomics; white matter

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.

拟议的研究调查了认知障碍，痴呆和脑萎缩的风险 体育活动，感染，生物学和APOE基因型。我们建议继续纵向研究 与Tsimane和Moseten一起，两名南美本地人的生活方式和环境需要 高水平的体育锻炼并将其暴露于高病原体伯良，最喜欢工业前的人 过去的。尽管假设感染在阿尔茨海默氏病和 相关痴呆症（ADRD），这是在高度感染力的情况下对ADRD的首次基于人群的研究， 感染被认为是风险的主要因素。当前的NIA项目（1RF1AG054442） 揭示：1）冠状动脉疾病（CAD）和AD的患病率很低 大脑萎缩的分裂年龄斜率比欧洲和美国人群 与认知障碍相关的颅内内侧动脉钙化（MAC）和3） 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）高水平的体育活动缓慢脑萎缩并降低AD的风险，部分原因是降低肥胖， 动脉硬化和代谢诱发的炎症； （H2）病毒和细菌感染会影响淀粉样蛋白产生的（H2A）增加脑萎缩和ADRD风险 和动脉疾病，包括影响淀粉样蛋白和白细胞流量的途径 障碍。我们进一步假设这些影响通过（H2B）高体育锻炼和（H2C）降低 肠蠕虫感染，因为蠕虫具有抗炎和免疫调节作用； （H3）女性的认知障碍风险更高，是由于先天性炎症反应的上调较高 与男性相比，病原体（例如，通过淀粉样蛋白和TAU产生增加）； （H4）在食物有限的高病原体环境中，APOEε4等位基因具有性别特异性和互动效果 病原体伯嫩的免疫反应，血脂和ADRD风险。 这些假设将通过基于人群的混合纵向面板和病例对照设计进行检验， 包括两次认知评估，家庭访谈，体检和生物标志物收集，以及 一波配对的胸部和大脑计算机断层扫描，以评估大脑的纵向变化 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） 表达和个人内部比较在Covid-19-19疾病后发生前反面。新数据收集 建立在一个有凝聚力的跨学科领导团队的基础上，以增强当前的横断面调查结果 纵向变化的因果模型。这些人群提供了一个消失的机会来研究风险因素如何 在潜水员环境中运行，并评估感染在AD和大脑衰老中的作用。收集的数据将 这也构成了一个生物库，用于未来的研究并获得数据共享财团。