The Crosstalk Between Diabetes and Alzheimer's Disease: A Molecular Perspective

The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3β (GSK-3β) activity, promoting tau hyperphosphorylation and amyloid-β (Aβ) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways.