Effect of Metformin on Plasma and Cerebrospinal Fluid Biomarkers in Non-Diabetic Older Adults with Mild Cognitive Impairment Related to Alzheimer’s Disease

Issue title: Omics Approaches in Alzheimer’s Disease Research

Guest editors: Sudeshna Das

Article type: Research Article

Authors: Weinberg, Marc S.^{a; b; c; *} | He, Yingnan^b | Kivisäkk, Pia^{b; c} | Arnold, Steven E.^{b; c; 1} | Das, Sudeshna^{b; c; 1}

Affiliations: [a] Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA | [b] Department of Neurology, Massachusetts General Hospital, Boston, MA, USA | [c] Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Marc S. Weinberg, MD, PhD, Department of Neurology, Massachusetts General Hospital, 149 13th Street, Suite 10-136, Charlestown, MA 02129, USA. E-mail: [email protected].

Note: [1] Joint senior authors.

Abstract: Background: Alzheimer’s disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Objective: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. Methods: We analyzed plasma and CSF proteomics data collected previously (ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. Results: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Conclusions: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies.

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, clinical trial, metformin, plasma

DOI: 10.3233/JAD-230899

Journal: Journal of Alzheimer's Disease, vol. 99, no. s2, pp. S355-S365, 2024