Interaction of Cellular and Molecular Mechanisms in Diabetes-Associated Neurodegeneration and Alzheimer’s Disease

Diabetes, inflammation, and neurodegeneration, particularly Alzheimer’s disease (AD), are deeply interconnected (brain diabetes). Type 2 diabetes mellitus (T2DM) acts as a significant risk factor for neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s (PD) by inducing chronic inflammation, oxidative stress, and metabolic dysfunction. Hyperglycemia drives neuroinflammation and damages the blood-brain barrier (BBB), exacerbating cognitive decline and neuronal loss. Chronic inflammation acts as a central bridge, linking high blood sugar, insulin resistance, and metabolic dysfunction in the brain to the buildup of amyloid plaques, tau tangles, and neuronal damage due to shared insulin signaling issues in the brain. Diabetes accelerate AD risk through inflammation-driven mitochondrial damage and impaired insulin pathways, which hinder amyloid clearance and disrupt normal brain function. Insulin resistance and impaired glucose metabolism accelerate brain aging and neurodegeneration. This narrative review aims to summarize the underlying molecular and cellular mechanisms in the pathophysiology of hyperglycemia-associated neurodegeneration with a focus on Alzheimer’s disease as a manifestation of type 3 diabetes mellitus (type 2 diabetes in the brain).