Metformin's Effects on Cognitive Function from a Biovariance Perspective: A Narrative Review

Abstract

This study examines the effects of metformin on brain functions focusing on the variability of the results reported in the literature. While some studies suggest that metformin may have neuroprotective effects in diabetic patients, others report an insignificant impact of metformin on cognitive function, or even a negative effect. We propose that this inconsistency may be due to intrinsic cellular-level variability among individuals, which we term "biovariance". Biovariance persists even in demographically homogeneous samples due to complex and stochastic biological processes. Additionally, the complex metabolic actions of metformin, including its influence on neuroenergetics and neuronal survival, may produce different effects depending on individual metabolic characteristics.

Keywords: biovariance; cognition; diabetes; metformin; neuroprotection.

Figure 1

This diagram illustrates the selection and analysis process of the studies.

Figure 2

The red line (corresponding to the function f(x)) represents a bimodal distribution, suggesting two subgroups within the population, each with a different response profile or characteristic. In contrast, the black line, denoted as f₁(x), illustrates a unimodal, normal (Gaussian) distribution. This distribution reflects a homogeneous response pattern with values clustering symmetrically around the mean. The blue vertical line marks the shared mean of the two functions, underscoring a key limitation: while mean is common to both distributions, it fails to capture the unique characteristics of each distribution.

Figure 3

This diagram illustrates how individual metabolic variations, represented by their metabolic products (the primary metabolites Y and Z) resulting from the administration of Drug X, could predict a patient’s response to the subsequent administration of another drug. Consequently, the administration of Drug A may lead to different effects, either favorable or unfavorable, depending on the predominant metabolite.