Association of cumulative exposure to metformin and other T2D medications with cognitive impairment and AD/ADRD biomarkers

The goal of Project 3 is to examine the association of cumulative exposure to type 2 diabetes (T2D) medications, primarily metformin, with cognitive impairment and its underlying neuropathology in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS) cohort. Repurposing of T2D medications, particularly insulin sensitizing medications, has been proposed for the treatment and prevention of Alzheimer’s disease (AD). Metformin is the first line treatment and the most widely used T2D medication, but there are conflicting data on whether metformin is beneficial, harmful, or has no effects on AD and risk of cognitive impairment. The DPP/DPPOS provided randomly assigned metformin and now includes over 20 years of data on cumulative metformin exposure. It provides a unique opportunity to examine the association of metformin with cognitive impairment and related neuropathology. GLP1a, DPP4i, and SGLT2i have been used more recently and less frequently in DPPOS compared with metformin and can be examined on an exploratory basis. We now propose to ascertain dementia and MCI in all DPPOS participants. We will examine amyloid (Aß42/40 ratio), tau (ptau- 181), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (Glial Fibrillary Acidic Protein [GFAP]) in plasma in all participants. In 650 participants we will ascertain brain amyloid with 18F-Florbetaben Positron Emission Tomography (PET); using brain magnetic resonance imaging (MRI), we will ascertain atrophy (cortical thickness), and cerebrovascular disease (CVD), and explore microbleeds, white matter microstructure, and resting functional connectivity. We will classify the cognitive syndromes as AD continuum or non-AD pathology following the National Institute on Aging (NIA)/Alzheimer’s Association (AA) research framework using primarily ptau-181 in all participants. We will explore classification by tau, neurodegeneration, and vascular contributions to cognitive impairment and dementia (VCID). We will use statistical methods to ensure that findings are not confounded by propensity to use T2D medications. We will achieve our goal through the following aims: (1) To examine the association of cumulative metformin exposure with amnestic and non- amnestic cognitive decline, MCI, and dementia; (2) To examine the association of cumulative metformin exposure with brain amyloid, neurodegeneration and CVD in the 650 participants with brain imaging; (3) To examine the association of cumulative metformin exposure with trajectories of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation. We will also explore: other T2D medications as exposures; metformin associated cobalamin deficiency in relation to cognitive impairment; neuronal insulin signaling as an outcome; glycemia, advanced glycation end products, insulinemia, peripheral inflammation, endothelial function, vascular risk factors, and neuroprotective factors as mediators; the aggregate exposure to T2D medications and physical activity; the genomic signatures moderating the associations in aims 1-3; effect modification by sex, ethnic/racial group, cognitive reserve, and APOE-ε4 in all aims.