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: 10682379
• 负责人: CALEB E FINCH
• 金额: $ 331.62万
• 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/10682379
• 关键词: 2019-nCoV; Adult; Affect; Age; Alleles; Alzheimer' s Disease; 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 region; 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; Industrialization; Infection; Inflammasome; Inflammation; Inflammatory Response; Interview; Intestinal parasite; Intestines; Leadership; Leukocyte Trafficking; Life Style; Link; Longitudinal Studies; Low Prevalence; Measures; Medial; Mediator; Medical; Messenger RNA; Metabolic; Native Americans; Neurologic; Neuropathy; Obesity; Parasites; Parasitic infection; Pathogenesis; Pathway interactions; Physical activity; Play; Population; Population Study; Prevalence; Production; Research; Risk; Risk Factors; Risk Reduction; 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; cohort; dementia risk; design; differential expression; gene network; genotypic sex; gray matter; helminth infection; high risk; immunoregulation; innovation; 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.

拟议的研究调查了与认知障碍、痴呆和脑萎缩相关的风险 我们建议继续进行纵向研究。 提斯曼 (Tsimane) 和莫塞滕 (Moseten) 是两群南美原住民，他们的生活方式和环境要求 高水平的体力活动使他们面临高病原体负担，就像工业化前的人类一样 尽管感染在阿尔茨海默病和阿尔茨海默病的发病机制中发挥着关键作用。 相关痴呆症 (ADRD)，这是第一个在高度传染性背景下进行的基于人群的 ADRD 研究， 当前的 NIA 项目 (1RF1AG054442) 已将感染视为主要风险因素。 研究表明：1) 冠状动脉疾病 (CAD) 和 AD 的患病率都非常低，且交叉程度较浅 脑萎缩的年龄分段斜率高于欧洲和美国人群，但 2) 患病率较高 颅内内侧动脉钙化 (MAC) 与认知障碍相关，3) 几乎是认知障碍的两倍 我们提出以下假设来解释这些发现： (H1) 高水平的体力活动可减缓脑萎缩并降低 AD 风险，部分是通过减少肥胖来实现的， 动脉硬化和代谢引起的炎症； (H2) 病毒和细菌感染通过 (H2a) 影响淀粉样蛋白的产生而增加脑萎缩和 ADRD 风险 和动脉疾病，包括影响淀粉样蛋白和白细胞跨血脑运输的途径 我们进一步追求通过（H2b）高体力活动和（H2c）来减少这些影响。 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炎症反应上调更大 与男性相比，对病原体的抵抗力更强（例如，通过增加淀粉样蛋白和 tau 蛋白的产生）； (H4) 在食物有限的高病原体环境中，APOE ε4 等位基因具有性别特异性和交互作用 病原体对免疫反应、血脂和 ADRD 风险的负担。 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， 包括两波认知评估、家庭访谈、体检和生物标志物收集，以及 一系列配对的胸部和大脑计算机断层扫描，用于评估大脑的纵向变化 体积和动脉硬化的创新包括淀粉样蛋白和 tau 生物标志物、基因 (mRNA) 的血液水平。 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，通过测试来增强当前的横截面发现 这些人群为研究风险因素如何影响提供了一个正在消失的机会。 在不同的环境中进行操作，并评估感染在 AD 和大脑衰老中的作用。 还建立了一个生物库，用于未来的研究和访问数据共享联盟。