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

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

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.