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Microbial Impact on NeuroDegeneration in Alzheimer's Dementia: MIND-AD

微生物对阿尔茨海默氏痴呆症神经退行性变的影响：MIND-AD

基本信息

批准号：
10380937
负责人：
Brion S Maher
金额：
$ 76.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380937
关键词：
2019-nCoV Affect Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid beta-Protein Antibodies Anxiety Disorders Apolipoprotein E Area Attention Baltimore Biological Biological Aging Biological Assay Biology of Aging Blood Blood specimen Brain CD8-Positive T-Lymphocytes CDKN2A gene COVID-19 Catchment Area Cell Aging Chronic Cognitive Cognitive aging Communicable Diseases Cyclin-Dependent Kinase Inhibitor Cytomegalovirus Data Data Collection Dementia Development Diagnosis Diagnostic Disease Elderly Epidemiology Epigenetic Process Etiology Event Exhibits Follow-Up Studies Future Genetic Genetic Risk Genotype Growth Health Healthcare Systems Herpes Simplex Infections Herpesviridae Herpesvirus 1 Human Human Herpesvirus 2 Human Herpesvirus 4 Immune response Impaired cognition Individual Infection Inflammation Interview Length Life Life Style Light Link Longitudinal cohort Measures Mental disorders Methylation Modification Nerve Degeneration Neuropsychology Neurovirology Older Population Outcome Participant Pathway interactions Performance Persons Phenotype Physiological Plasma Prevalence Prevention Preventive Public Health Reporting Research Risk Risk Factors Role SARS-CoV-2 infection Sampling Simplexvirus Stress Structure Subgroup Symptoms T cell differentiation T cell response Telomere Shortening Testing Therapeutic Time Toxoplasma gondii Viral Virus Woman Work Wrist abeta deposition actigraphy adjudicate anxiety symptoms base blood-based biomarker brain health cognitive performance cognitive testing cohort dementia risk depressive symptoms epidemiologic data functional decline genome-wide genomic data interest latent infection microbial mild cognitive impairment modifiable risk mouse model neurofilament neuroinflammation novel novel therapeutics pathogen poor sleep reactivation from latency risk variant senescence seropositive sex stressor tau Proteins telomere traumatic event

项目摘要

Alzheimer’s disease is a major threat to public health. Because Alzheimer’s disease has no cure, it is critical to identify its modifiable risk factors that can be targeted to reduce its burden. Although initial evidence suggests its plausibility, relatively little attention has been paid to the role of common infections in Alzheimer’s disease etiology. We propose to investigate the association of infection with common pathogens—Herpes Simplex Virus Types 1 and 2, Cytomegalovirus, Epstein-Barr Virus, Toxoplasma gondii—measured four times over ~25 years, and SARS-CoV-2 (the virus that causes COVID-19), with: (a) cognitive decline, and adjudicated mild cognitive impairment (MCI) and dementia diagnoses; (b) plasma biomarkers of Alzheimer’s disease; and (c) markers of physiological aging (telomere shortening, cyclin-dependent kinase inhibitor p16INK4a, plasma-derived senescence-associated secretory phenotypes, and epigenetic clocks). We will also explore sex, Alzheimer’s disease risk genes, and stress-related exposures (mental disorders and their symptoms, stressful life events, and poor sleep) as moderators that amplify the risk of adverse infection-induced cognitive, brain health, and physiological aging outcomes. Inclusion of viral specific CD8 T-cell differentiation in combination with antibody levels measured serially in the same individuals will allow us to distinguish between long-term infections and reactivation and to evaluate the influence of the course of both infection and immune response to infection, on our outcomes. Senescence-associated secretory phenotypes will point to novel senescent pathways by which infections affect brain health. We will accomplish this using existing data and collecting new data from participants in the Baltimore Epidemiological Catchment Area (ECA) Study Follow-up, which has been assessed five times for >35 years (mean age = 70 years, range 58-100). Blood specimens have been collected three times over ~25 years in the ECA, and we will collect an additional blood draw to obtain infection status at four time points, providing a rare opportunity to quantify timing of exposure and reactivation of latent infections in relation to cognitive and functional decline and Alzheimer’s disease biomarkers and potential pathways. The MPIs of the proposed study are currently completing Wave 5 of data collection in the ECA, including measures of cognitive and functional decline, adjudicated MCI and dementia diagnoses, cellular aging and genome-wide genetic and epigenetics assays. Our preliminary data in the ECA link common pathogens of interest with lower cognitive performance and suggest effect modification by apolipoprotein E genotype. Our team consists of experts in cognitive aging and Alzheimer’s disease, neurovirology, neuropsychology, Alzheimer’s disease biomarkers, genetics and epigenetics, and the biology of aging. Results will clarify the extent to which common infections increase the risk for Alzheimer’s disease and related dementias, and because this work is performed in a longitudinal cohort, it will elucidate mechanisms, identify moderators and candidate pathways which precede decline, thus informing future preventive, and perhaps therapeutic, efforts.

阿尔茨海默病是对公众健康的重大威胁。因为阿尔茨海默病无法治愈，所以至关重要的是