Midcareer Award for Research in Dementia Risk Factors and Prevention

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This is a competitive renewal application for grant K24AG045334 (Midcareer Award for Research in Dementia Risk Factors and Prevention). Consistent with PA-20-186 (Midcareer Investigator Award in Patient Oriented Research [POR]), I propose to continue protecting 25% of my time to augment my capabilities in POR, and provide mentoring to junior clinical investigators in the conduct of POR. The current K24 supported scientific project and its related mentoring and training activities has leveraged grant R01AG050440 (Diabetes Status and Brain Amyloid in Middle Aged Hispanics; PI: Luchsinger). The current K24 award proposed the examination of plasma biomarkers of Alzheimer’s disease (AD), metabolomics, and a pilot study of tau Positron Emission Tomography (PET), which were successfully achieved while providing mentoring and resources to several early investigators, who have successfully obtained K and R funding. R01AG050440 will be renewed for another 5 years on 08/01/21 for another 5 years of funding, and will be leveraged again for the scientific, training, and mentoring goals of this proposal. The new funding period will extend the ascertainment of amyloid, tau, and neurodegeneration with brain imaging (18F-Florbetaben PET, 18F-MK6240 PET, 3T magnetic resonance imaging [MRI]) and plasma biomarkers (Aß42/40 ratio, neurofilament light, ptau-181) for two more waves, in addition to comprehensive cognitive testing and ascertainment of cerebrovascular disease (CVD). Preliminary data shows that microgliosis (neuroinflammation) accompanies neurodegeneration and cognitive impairment in diabetic (db/db) mice. Thus, I propose to train in neuroinflammation and its measurement in humans, including plasma Glial Fibrillary Acidic Protein (GFAP) and, brain imaging (11C-ER176 PET), and apply them to the parent study during the proposed period. The overarching hypothesis of this application is that diabetes causes neuroinflammation that leads to neurodegeneration and associated cognitive deficits, independent of amyloid, tau, and CVD. My primary scientific aim is to examine the association of neuroinflammation, ascertained with plasma GFAP, with neurodegeneration, ascertained as cortical thickness on brain MRI, and memory impairment, ascertained as total recall in the Buschke Selective Reminding Test. My first training aim 1: to train in the role of neuroinflammation in neurodegenerative diseases and in diabetes, its measurement in plasma, and its interpretation. My first mentoring aim is to train mentees in the primary (amyloid, tau, neurodegeneration) and secondary constructs (cognition, CVD) of the NIA/AA research framework, and their potential relation to diabetes and other cardiometabolic risk factors for AD/ADRD. My secondary scientific aim is to conduct a pilot study of brain imaging with the 18kDA translocator protein (TSPO) ligand 11C-ER-176 in 20 participants in the parent study. My second training aim is to train in the application of imaging of microglial activity and its interpretation. My second mentoring aim is to train mentees in the importance of neuroinflammation in neurodegenerative diseases with the assistance of the neuroinflammation experts collaborating in this proposal.