The metabolic roots of memory loss: interlinking the Diabetes-Alzheimer's hypothesis.

Diabetes mellitus (DM) and Alzheimer’s disease (AD) are two of the most widely recognized as prevalent conditions affecting the global elderly population. AD is primarily characterized by the accumulation of misfolded proteins, including amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles that lead to progressive neuronal dysfunction in the brain. Conversely, DM is marked by impaired insulin signaling, resulting in reduced glucose uptake, disrupted energy metabolism, and altered hepatic glucose-to-lipid conversion. Despite their distinct clinical manifestations, growing evidence suggests that DM and AD share multiple overlapping molecular and cellular mechanisms. These include impaired glucose and lipid metabolism, mitochondrial dysfunction, oxidative stress, chronic inflammation, and excessive production of Aβ, all of which contribute to neurodegeneration and cognitive decline. Epidemiological studies further indicate that individuals with Type 2 DM are at a markedly higher risk of developing AD, highlighting the significance of metabolic dysfunction in neurodegenerative processes. Environmental and lifestyle factors such as diet, physical inactivity, and exposure to metabolic stressors may further amplify this bidirectional association. This review comprehensively explores the shared pathological mechanisms linking DM and AD, integrating insights from epidemiological data, mechanistic research, and experimental animal studies to elucidate how metabolic dysregulation underpins neurodegeneration, thereby offering a framework for identifying potential therapeutic strategies targeting both disorders.