Metformin and cognition from the perspectives of sex, age, and disease

Abstract

Metformin is the safest and the most widely prescribed first-line therapy for managing hyperglycemia due to different underlying causes, primarily type 2 diabetes mellitus. In addition to its euglycemic properties, metformin has stimulated a wave of clinical trials to investigate benefits on aging-related diseases and longevity. Such an impact on the lifespan extension would undoubtedly expand the therapeutic utility of metformin regardless of glycemic status. However, there is a scarcity of studies evaluating whether metformin has differential cognitive effects across age, sex, glycemic status, metformin dose, and duration of metformin treatment and associated pathological conditions. By scrutinizing the available literature on animal and human studies for metformin and brain function, we expect to shed light on the potential impact of metformin on cognition across age, sex, and pathological conditions. This review aims to provide readers with a broader insight of (a) how metformin differentially affects cognition and (b) why there is a need for more translational and clinical studies examining multifactorial interactions. The outcomes of such comprehensive studies will streamline precision medicine practices, avoiding "fit for all" approach, and optimizing metformin use for longevity benefit irrespective of hyperglycemia.

Keywords: Age; Brain function; Cognition; Diabetes; Gender; Metformin; Sex.

Fig. 1

Mechanisms of action of metformin in the neuro-glial environment. Metformin via AMPKα-dependent pathways promote cell survival, neural differentiation, autophagy, neuroprotection, proliferation, and self-renewal. Metformin inhibits amyloid-β-plaque formation via AMPKα. Metformin inhibits inflammation via inhibiting NF-κB. Metformin activates apoptosis via PI3K pathway and inhibits apoptosis via the ERK1/2 pathway. Metformin promotes Tau dephosphorylation via PP2A pathway

Fig. 2

Multifactorial interaction on the effect of metformin on cognition. The effect of metformin on cognition is mediated by a variety of factors, including age, sex, blood sugar levels, and associated disease condition. The color-coding in this predictive model is a summary of existing evidence on known mediators of metformin-induced cognitive changes. A more substantial clinical investigation should aim to extend these data to achieve a more accurate precision medicine approach to metformin pharmacotherapy