Alzheimer-type (AD) and non-AD dementias and neurocognitive impairment have origins in dysregulated me- tabolism, leading to consideration of dementia as a ?type 3 diabetes? phenotype. A wide array of basic labora- tory, model systems-based, and human investigations around identifying precise metabolic defects as the core of AD/non-AD dementias have emerged. A critical feature of studies attempting to identify a metabolic basis of neurocognitive dysfunction is the application of a broad assessment of metabolism to a well phenotyped hu- man cohort with dementia and related outcomes. As part of R01AG059729, Drs. Shah, Newman, Murthy and Clish have been performing metabolite profiling in a biracial subsample of the Healthy Aging and Body Com- position Study (Health ABC) to identify metabolic pathways relevant to healthy aging. While the parent study includes some neurocognitive measures, it only assays a subsample within Health ABC for lipid and lipid me- diators, the key metabolites felt to be relevant to AD and related dementias. Based on data suggesting the emerging importance of inflammation and lipid abnormalities in AD, the study team is requesting supplemental funds as part of this application to complete lipid and lipid intermediate metabolite profiling to facilitate (1) wider scientific discovery in AD and AD-related phenotypes and (2) integration with other metabolite modes already completed in Health ABC to provide a wider description of the metabolic abnormalities important in the life- course of neurocognitive dysfunction and AD. We hypothesize that lipid and lipid mediators will be associated with phenotypes and phenotypic groups central to AD and may facilitate discovery of potentially intervenable pathways at the heart of AD and AD-related neurocognitive dysfunction. To address this hypothesis, we will perform metabolite profiling in a wider sample size in Health ABC for lipid (C8 positive) and lipid mediators (C18 negative) to identify metabolites and encoded pathways associated with clinical and imaging-based de- mentia endpoints.
In Aim 1, we will identify lipid and lipid mediator metabolite signatures associated with sub- sequent cognitive decline, preclinical AD phenotypes, and dementia.
In Aim 2, we will identify association of lipid and lipid mediators with selected MRI markers of dementia previously reported.
In Aim 3, we will test how metabolic pathways linked to dementia differ by race and sex and how these metabolite signatures are related to diet, fitness, activity, and adiposity, key modifiable lifestyle features linked to improved neurocognitive func- tion. This supplement is unique in that it has been conceived and constructed in full collaboration with the Na- tional Institutes of Aging (Dr. Luigi Ferrucci and Qu Tian), experts in aging and AD and substantially augments the sample size for metabolite profiling covered by the parent R01 grant, while leveraging its substantial re- sources. Completion would afford the scientific community a wider array of quantitative metabolic phenotyping to address AD and AD-related phenotypes, directly addressing NOT-AG-20-008 by integrating efforts in ongo- ing studies of aging to address neurocognitive endpoints relevant to AD.
Nearly 100 million Americans will be >65 years by 2060. Dementia and neurocognitive decline represent a major source of morbidity in older Americans. Recent studies suggest that these conditions may have a basis in altered metabolism. Here, we will perform metabolite profiling in the Health ABC study to identify metabolic pathways related to dementia and its clinical manifestations across race and sex to identify precise metabolic pathways underlying age-related neurocognitive decline and dementia in Caucasian and African-Americans.
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