Cholesterol metabolism and oxysterols in neurodegenerative disorders: Spotlight on Alzheimer's disease

Cholesterol metabolism in the brain is tightly regulated and differs from the periphery due to the blood-brain barrier (BBB). Oxysterols, oxidized cholesterol metabolites, can cross the BBB and play key roles in brain cholesterol homeostasis and neurodegeneration, particularly in Alzheimer’s disease (AD). This review highlights two major oxysterols: brain-derived 24S-hydroxycholesterol (24-OH) and peripherally derived 27-hydroxycholesterol (27-OH). Both have been studied as potential AD biomarkers, with altered levels observed in cerebrospinal fluid and plasma, though findings vary due to sex, age, and comorbidities. Animal studies suggest that CYP46A1 and its product 24-OH support cognitive function, reduce neuroinflammation, and attenuate AD pathology, especially in females. Conversely, increased 27-OH is linked to metabolic dysfunction, synaptic deficits, and memory loss, possibly bridging peripheral hypercholesterolemia and AD risk. This review summarizes recent advances in oxysterol research and their implications for AD, emphasizing sex-specific effects and their potential as biomarkers and therapeutic targets. Keywords : 24(S)-hydroxycholesterol, 27-hydroxycholesterol, cholesterol, oxysterols, Alzheimer’s Disease, Parkinson’s Disease, cognition