Protocol for a Randomized Phase II/III Double-Blind Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Extended-Release Metformin in Amnestic Mild Cognitive Impairment: Metformin in Alzheimer Dementia Prevention (MAP).

Background: Metformin has been suggested as a possible strategy for the prevention of Alzheimer disease (AD) and AD related dementias. An early phase II clinical trial of short acting metformin versus placebo showed preliminary evidence of efficacy and safety in slowing cognitive decline among persons with amnestic mild cognitive impairment (aMCI) without diabetes.

Objective: To conduct a phase II/III randomized clinical of extended-release metformin versus placebo in participants with aMCI without diabetes.

Methods: Ratio of 1:1 randomized placebo-controlled trial of extended-release metformin in 326 persons with aMCI without diabetes, aged 55 to 90 years, lasting 18 months, with 4 visits every 6 months including baseline. The primary outcome is changes in total recall in the Free and Cued Selective Reminding Test. Secondary outcomes include (1) changes in global cognitive performance, measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC); (2) changes in neurodegeneration, ascertained as cortical thickness in areas affected by AD on brain MRI; (3) changes in cerebrovascular disease, ascertained as white matter hyperintensities (WMH) volume on brain MRI; (4) changes in whole brain amyloid ß (Aß) SUVR and in incident amyloid positivity; (5) changes in tau SUVR in a composite brain region comprising medial and inferolateral temporal cortex; (6) changes in plasma AD biomarkers.

Conclusion: Observational studies and pilot trials suggest that metformin may help prevent cognitive decline in neurodegenerative disorders. This clinical trial aims to assess metformin's potential in preventing cognitive decline in at-risk individuals and its impact on biomarkers indicative of disease modification.