Metformin in Alzheimer's dementia Prevention (MAP)

The goal of this competitive revision application to grant R01AG062624 entitled ?Metformin in Alzheimer?s dementia Prevention (MAP)?, submitted in response to PAR-18-878 (Late Stage Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline), is to add biomarkers of Alzheimer?s disease (AD) to a randomized placebo controlled clinical trial of metformin in amnestic mild cognitive impairment (aMCI) funded on 08/15/2019, and expected to begin enrolling participants in August of 2020. MAP is a multisite 1:1 randomized placebo controlled clinical trial of long acting metformin (2,000 mg a day) vs. placebo among 370 persons with aMCI aged 55 to 90 years (ClinicalTrials.gov identifier NCT04098666 ). The duration of MAP is 24 months with 5 visits (baseline, 6 months, 12 months, 18 months, 24 months); 186 study participants will get brain MRI at baseline and 24 months. We propose to examine the effect of metformin on AD neuropathology in-vivo through brain imaging and plasma biomarkers of AD. The only imaging modality already funded in MAP is MRI. None of the PET studies or plasma biomarkers are funded. We propose to conduct amyloid PET twice (baseline and 24 months) using 11C-PIB or 18F-Florbetaben, and tau PET twice (baseline and 24 months) with the ligand 18F-MK- 6240, among the 186 MAP participants undergoing brain MRI. We also propose to measure plasma Ab42 and Ab40, plasma tau, and neurofilament light (NFL), using Single Molecule Array (Simoaä) assays, at all 5 scheduled visits in all 370 MAP participants. Our overall hypothesis is that, compared with placebo, the metformin arm will be related to less brain Ab and tau accumulation, less brain atrophy in areas affected by AD (addressed in the parent grant), less decline in plasma Ab 42/40 ratio, and less increase in plasma tau and NFL. The following are our specific aims:(1)To compare changes in whole brain Ab standardized uptake value ratio (SUVR) and in incident amyloid positivity from baseline to 24 months between the metformin and placebo arms; (2) To compare changes in tau SUVR in a composite brain region comprising medial and inferolateral temporal cortex from baseline to 24 months between the metformin and placebo arms; (3) To compare changes in plasma Ab 42/40 ratio, plasma tau, and plasma NFL between metformin and placebo. Our secondary aim is to examine the cross- sectional and longitudinal correlations of plasma AD biomarkers with brain AD biomarkers. Our exploratory aims are (a) to explore if amyloid, tau, or neurodegeneration mediate the effect of metformin on MAP?s clinical outcomes, changes in the free and cued selective reminding test (FC-SRT) and the Preclinical Alzheimer Cognitive Composite from the Alzheimer?s Disease Cooperative Study and ADCS-PACC; and (b) to explore whether baseline status for amyloid, tau, and neurodegeneration biomarkers (A/T/N) predict response to metformin treatment.