Alzheimer’s disease (AD) remains the most common cause of dementia worldwide and one of the greatest health challenges of the twenty-first century. Traditionally viewed as a neurodegenerative disorder defined by amyloid-β plaques and tau tangles, recent evidence implicates systemic metabolic dysfunction and endothelial injury as key drivers of the disease progression. Insulin resistance, dyslipidemia, and chronic hyperglycemia impair neuronal glucose utilization and insulin signaling, leading to mitochondrial dysfunction, oxidative stress, and tau hyperphosphorylation. Concurrently, abnormal lipid metabolism and the presence of the apolipoprotein E4 allele accelerate amyloidogenic processing, while advanced glycation end-products (AGEs) formed during hyperglycemia activate RAGE-mediated inflammatory pathways that amplify neuronal injury. Endothelial dysfunction further compounds these effects by reducing nitric oxide (NO) bioavailability, disrupting the blood–brain barrier, and diminishing cerebral perfusion inhibiting amyloid clearance and intensifying neuroinflammation. These interconnected metabolic and vascular abnormalities establish a “metabolic–vascular–neurodegenerative axis” that links systemic disease to progressive neuronal degeneration. Understanding this integrative framework shifts the perspective of AD from a purely brain-centered disorder to a systemic, multi-organ pathology. Emerging therapeutic strategies that combine metabolic regulation, endothelial protection, and anti-inflammatory approaches offer a more comprehensive path toward prevention and disease modification. future research and clinical interventions can achieve a sustained neuroprotection by addressing the metabolic and vascular roots of AD.
Sunday et al. (2025) studied this question.