Role of Cholesterol Metabolism in the Link Between Diabetes and Alzheimer's Disease

Type 2 Diabetes Mellitus (T2DM) and Alzheimer's Disease (AD) share complex metabolic disturbances, with cholesterol dysregulation emerging as a central mechanistic link. Although brain cholesterol metabolism operates largely independently of peripheral lipid pools, it is highly susceptible to disruption, particularly in the insulin-resistant ApoE4 genotype.

This review follows a structured literature approach using PubMed, Scopus, and Web of Science (2000-2025) to critically evaluate mechanistic and translational evidence on cholesterol- T2DM-AD interplay. It critically evaluates current evidence on cholesterol production, transport, and elimination in the Central Nervous System (CNS), focusing on the roles of astrocytes, neurons, and transporters such as ATP-binding cassette transporter A1 (ABCA1). It also explores how peripheral metabolic stress in T2DM affects central cholesterol homeostasis and contributes to amyloid- beta (Aβ) accumulation and neurodegeneration. Pharmacological approaches targeting cholesterol regulation, including statins, liver X receptor (LXR) modulators, and glucagon-like peptide-1 (GLP-1) receptor agonists, are discussed.

Findings indicate that impaired cholesterol regulation disrupts neuron-astrocyte interactions, enhances Aβ deposition, and accelerates neurodegeneration. Controversies remain regarding the relative impact of peripheral vs. central cholesterol imbalance and Blood-Brain Barrier (BBB) permeability in therapy. In T2DM, peripheral insulin resistance and hypercholesterolemia exacerbate central cholesterol imbalance, thereby intensifying AD pathology. Emerging therapeutic studies suggest that modulation of cholesterol pathways may reduce neuroinflammation, promote Aβ clearance, and slow cognitive decline.

The overlap between T2DM and AD highlights cholesterol metabolism as a pivotal pathogenic axis. While peripheral factors worsen central dysregulation, CNS-specific disturbances independently drive disease progression. Targeted modulation of cholesterol pathways, through statins, LXR modulators, and GLP-1 agonists, shows promise but demands precision approaches tailored to genotype and BBB permeability.

The cholesterol-AD-T2DM axis represents a promising therapeutic target. Addressing cholesterol dysregulation could enable novel, personalized strategies to mitigate neurodegeneration and cognitive decline.