Targeting Brain Cholesterol Homeostasis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.

Cholesterol is a fundamental component of the central nervous system, supporting myelin integrity, synaptic structure, membrane organization, and neuronal signaling. Because the brain is largely isolated from peripheral cholesterol pools, tight regulation of brain cholesterol homeostasis is required to sustain neuronal and glial function across the lifespan. Growing evidence indicates that disruption of this balance is not merely a downstream consequence of neurodegeneration, but an upstream contributor to Alzheimer's disease (AD) pathogenesis. Altered brain cholesterol homeostasis has been linked to amyloidogenic processing, tau pathology, neuroinflammation, synaptic dysfunction, and cerebrovascular injury. This review synthesizes current evidence showing how multiple converging stressors, including peripheral hypercholesterolemia, neurodegeneration, oxidative stress, and inflammatory signaling, perturb brain cholesterol regulation. These drivers disrupt the coordinated processes of cholesterol synthesis, metabolism, and transport, shifting the system from tightly regulated sterol flux toward impaired clearance, abnormal lipid distribution, and membrane instability. Such disturbances remodel membrane lipid composition, alter lipid raft organization, and impair glial-neuronal lipid coupling, thereby accelerating amyloid-β production, tau-related vulnerability, innate immune activation, and neurovascular dysfunction. Finally, we provide an overview of therapeutic strategies aimed at restoring cholesterol balance, and highlight the potential of integrated, multi-target strategies to complement amyloid- and tau-directed therapies. By clarifying how disruptions in brain cholesterol homeostasis link systemic and central stressors to AD pathology, this review identifies cholesterol regulation as a critical, upstream axis for therapeutic intervention and disease prevention.