Abstract
This study explores the potential impact of metformin on the development of severe dementia in individuals with Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). With an emerging interest in the role of the APOE genotype in mediating metformin's effects on cognitive decline in AD patients, we sought to investigate whether metformin usage is associated with a reduced risk of severe dementia. Using data from the National Alzheimer's Coordinating Center (NACC) database (2005-2021), we identified 1306 participants with both AD and T2DM on diabetes medications. These individuals were categorized based on metformin usage, and a propensity score-matched cohort of 1042 participants was analyzed. Over an average follow-up of 3.6 years, 93 cases of severe dementia were observed. A Kaplan-Meier analysis revealed that metformin users and non-users had similar probabilities of remaining severe dementia-free (log-rank p = 0.56). Cox proportional hazards models adjusted for covariates showed no significant association between metformin usage and a lower risk of severe dementia (HR, 0.96; 95% CI, 0.63-1.46; p = 0.85). A subgroup analysis based on APOE ε4 carrier status demonstrated consistent results, with metformin use not correlating with a reduced severe dementia risk. In conclusion, our findings from a substantial cohort of AD and T2DM patients suggest that metformin usage is not significantly associated with a decreased risk of severe dementia. This observation persists across APOE ε4 carriers and non-carriers, indicating a lack of genotype-mediated effect.