Metformin and Cognitive Decline: Mechanisms and Therapeutic Potential in Alzheimer's Disease and Mild Cognitive Impairment

Objectives Metformin, a widely used antidiabetic drug, has gained attention for its potential neuroprotective effects beyond glucose regulation. This review explores metformin's role in modulating cognitive decline in mild cognitive impairment (MCI) and Alzheimer's disease (AD) through mechanisms such as AMP-activated protein kinase (AMPK) activation, neuroinflammation reduction, and enhancement of neurogenesis and synaptic plasticity. Keyword: Metformin, AMPK activation, Brain-derived neurotrophic factor, Alzheimer's disease, Mild cognitive impairment, Neuroinflammation Evidence Acquisition A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify relevant studies published from ۲۰۲۰ onward. Clinical and preclinical studies focusing on metformin's impact on cognitive function and neurodegeneration were included. The selection process followed predefined inclusion and exclusion criteria. Results Metformin exerts its neuroprotective effects by activating AMPK inhibiting oxidative stress, modulating neuroinflammation via nuclear factor kappa B (NF-kB) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways, and enhancing hippocampal neurogenesis and synaptic plasticity. Clinical studies suggest that metformin may slow cognitive decline in MCI and AD patients. However, some findings indicate neutral or adverse effects, potentially due to vitamin B۱۲ deficiency, genetic variability, or metabolic factors. Compared to glucagon-like peptide-۱ (GLP-۱) receptor agonists and Sodium-glucose co-transporter ۲ (SGLT۲) inhibitors, metformin exhibits promising but potentially less potent neuroprotective effects, warranting further investigation. Conclusion Metformin shows therapeutic potential in neurodegenerative diseases, but its long-term cognitive effects remain inconclusive. Further research is necessary to determine optimal dosing, blood-brain barrier (BBB) transport efficiency, and combination therapies with other neuroprotective agents. Large-scale, randomized controlled trials are essential to establish metformin's role in cognitive health.

کلیدواژه ها:

Metformin ، AMPK activation ، Brain-derived neurotrophic factor ، Alzheimer's disease ، Mild cognitive impairment ، Neuroinflammation