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BackgroundMetformin has been proposed to have neuroprotective benefits, but its effects on AD-related brain changes remain unclear and may be influenced by apolipoprotein E ε4 (APOE4) genotype, a major genetic risk factor for AD.ObjectiveTo examine the association between metformin use and in vivo AD pathologies and to evaluate whether APOE4 status moderates these associations in older adults with type 2 diabetes mellitus (T2DM).MethodsThis cross-sectional study used baseline data from 76 non-demented older adults with T2DM (aged 55-90 years), who were enrolled in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment and multimodal neuroimaging, including global amyloid- β (Aβ) retention ([¹¹C] PiB-PET), inferior temporal tau deposition ([¹⁸F] AV-1451 PET), AD-signature cortical thickness (AD-CT), and white matter hyperintensity (WMH) volume. Global cognition was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery.ResultsAmong 76 participants, 55 (72%) were metformin users and 21 (28%) were non-users. Metformin use was significantly associated with greater AD-CT, but not with Aβ, tau, or WMH volume. A significant interaction between metformin use and APOE4 status was observed with respect to AD-CT. In APOE4-stratified analyses, metformin use was significantly associated with greater AD-CT and better global cognition among APOE4 non-carriers, but not among carriers.ConclusionsOur findings indicate that metformin use is associated with greater AD-CT-independently of amyloid or tau pathology-particularly among APOE4 non-carriers, and this structural preservation is accompanied by better cognitive outcomes.