Cognitive impairment in the DPPOS cohort and its neuropathologic, neurophysiologic, sociodemographic, and behavioral correlates

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The goal of this project is to characterize the presence and correlates of cognitive decline, mild cognitive impairment [MCI] and dementia in the Diabetes Prevention Program Outcomes Study (DPPOS) cohort. Numerous epidemiologic studies have shown that pre-diabetes (PreD) and type 2 diabetes (T2D) are associated with higher risk of cognitive impairment. However, gaps in knowledge remain about cognitive impairment in preD and T2D: (a) What is the neuropathology other than vascular contributions to cognitive impairment and dementia (VCID)? (b) Is neuronal insulin dysregulation present, and is it related to peripheral insulin resistance characteristic of preD and T2D? (c) Do the associations differ by pertinent sociodemographics, including sex, race/ethnicity, educational attainment, and literacy? (d) Are the associations related to behavioral correlates (sleep disturbances and depressive symptoms), also common in preD and T2D? We will characterize amnestic and non-amnestic cognitive decline, MCI, and dementia, in all participants (n =1979). We will measure plasma biomarkers of amyloid (Aβ42/40 ratio), tau (ptau-181), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in all participants, and brain imaging markers of amyloid, neurodegeneration (cortical thickness), cerebrovascular disease (white matter hyperintensities [WMH] and infarcts), white matter microstructure, and functional connectivity, in a subsample of 650 participants. We will characterize the AD continuum and non-AD pathologic change using plasma ptau-181 and Amyloid Positron Emission Tomography (PET), following the National Institute on Aging (NIA)/Alzheimer’s Association (AA) research framework, and will explore characterization by tau, neurodegeneration, neuroinflammation, and VCID. We will isolate total circulating extracellular vesicles (EVs) and neuronal origin-enriched EVs (nEVs) in all participants once to examine systemic and neuronal insulin signaling. We will achieve our goal through the following specific aims: (1) To examine the prevalence and incidence of amnestic and non-amnestic cognitive decline, MCI and dementia, and examine their association with biomarkers of amyloid, tau, neurodegeneration, neuroinflammation, and with VCID; (2) To examine the association of cognitive syndromes with systemic and neuronal insulin signaling measured using nEVs. (3) To examine the association of sociodemographic factors including sex, race/ethnicity, education, and literacy, with cognitive decline, MCI, and dementia, and neuropathology biomarkers; (4) To explore the association of depressive symptoms, sleep quality, and obstructive sleep apnea with cognitive decline, MCI, and dementia. We will also explore their association with biomarkers of neuropathology. We will also explore (a) whether neuronal insulin signaling is related to peripheral metabolic measures collaborating with Project 2; (b) whether findings in aims 1 and 2 vary by use of T2D medications collaborating with Project 3; (c) the physical correlates of cognitive syndromes collaborating with Project 4.