Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent age-related disorders that share striking pathophysiological similarities, leading to the conceptualization of AD as a metabolic disorder often termed "type 3 diabetes." While numerous reviews have documented the epidemiological association between these diseases, a critical synthesis of the underlying molecular convergence-and its implications for therapeutic repurposing-remains fragmented. This review provides a comprehensive and critical analysis of the shared signaling pathways that underpin both AD and T2DM, including insulin resistance, oxidative stress, the AGE-RAGE axis, amyloidogenic protein misfolding (Aβ in AD and IAPP in T2DM), endoplasmic reticulum stress, and vasculopathy. By systematically examining each pathway, we highlight not only their disease-specific manifestations but also their intricate interconnections and the critical unresolved questions that hinder translational progress. We then critically evaluate the current evidence for repurposing major antidiabetic drug classes-insulin and its analogues, metformin, sulfonylureas, thiazolidinediones, incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors), and amylin receptor modulators-for AD treatment. Through this analysis, we identify key sources of clinical inconsistency, including patient heterogeneity (particularly APOE ε4 genotype), disease stage dependency, blood-brain barrier integrity, and off-target safety concerns. By integrating mechanistic insights with a rigorous assessment of clinical evidence, this review advances the understanding of AD as a metabolic disorder and provides a framework for future precision medicine approaches in cross-disease intervention. The synthesis presented here underscores that realizing the therapeutic potential of antidiabetic drugs in AD will require mechanism-guided patient stratification, early-stage intervention, and the development of brain-selective agents with improved efficacy and safety profiles.
