Project 3: Precision biomarkers of Brain Health, Age-related Cognitive Impairment and AD

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SUMMARY/ABSTRACT: Project 3 Precision Biomarkers of Brain Health Project 3 entitled “Precision biomarkers of brain health, age-related cognitive impairment and AD” will evaluate novel CSF biomarkers of brain pathways that impact human cognitive health across lifespan. We have selected three biochemical and cellular pathways that have strong rationale from fundamental neuroscience research and recent deep-proteomic analyses to play a role in resilience, organismal longevity, and redox homeostasis. These pathways also have a strong link to fundamental mechanisms of cognition and are disrupted in aging and AD brain. Pathways are designated based on key molecules that center each of three Aims. Aim 1 focuses on NPTX2 (Neuronal Pentraxin 2), which plays an essential role in adaptive inhibitory circuit function in neocortex and hippocampus to maintain homeostasis of excitation/inhibition. NPTX2 is down regulated with age-related cognitive impairment (ARCI) and disrupted in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Aim 2 focuses on mTORC1 (mammalian/mechanistic target of rapamycin complex 1), which mediates metabolic homeostasis in neurons, is implicated in aging and longevity, and is upregulated in AD brain where it is thought to inhibit autophagy and contribute to aberrant accumulation of proteins. Aim 3 focuses on GDE2 (Glycerophosphodiester phosphodiesterase 2), which regulates extracellular proteases that control -secretase (ADAM10) processing of APP as well as a host of proteins that are tethered to the plasma membrane by GPI linkage. GDE2 enzymatic function requires dynamic control of redox. Cleaved substrates accumulate in CSF and provide an indication of GDE2 function and redox homeostasis. We have developed parallel reaction monitoring mass spectroscopy (PRM-MS) to quantitate proteins linked to each of these pathways. These proteins constitute mechanism-based biomarkers that will be assayed in CSF from the cohort of subject samples from Project 2. We estimate this will include ~800 samples from approximately equal numbers of Hispanic/Latino, Non-Hispanic White, and non-Hispanic Black individuals in the age range of 50-79. Clinical data from Project 2 examining cognitive function and brain structure/functional connectivity, together with determinants of risk factors including cardiovascular insufficiency, glucose dysregulation, inflammation and immune dysfunction will be evaluated in Project 4 together with blood and sweat biomarkers. Studies will identify cross-sectional and longitudinal correlations that will provide insight into the aging process and provide a rational basis for precision medicine of aging.