24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia

The brain is the most cholesterol-rich organ in the human body. Accumulation of excess cholesterol in hippocampal neurons promotes the cleavage of the amyloid precursor protein (APP) into amyloidogenic components with the consequence of the acceleration of neuronal degeneration. Conversion of cholesterol to 24S-hydroxycholesterol mediated by cholesterol 24S-hydroxylase (CYP46) is the major pathway for the elimination of brain cholesterol and the maintenance of brain cholesterol homeostasis. We examined whether cerebrospinal fluid (CSF) 24S-hydroxycholesterol levels differ between patients with dementia, patients with mild cognitive impairment (MCI), and cognitively intact control subjects. Plasma and CSF concentrations of 24S-hydroxycholesterol and cholesterol in 32 patients with Alzheimer's disease (AD), 11 patients with vascular dementia, seven patients with MCI, and seven cognitively intact control subjects were measured by combined gas-chromatography/mass spectrometry. We show elevated concentrations of 24S-hydroxycholesterol in the CSF of AD patients and we interpret this finding as a consequence of increased cholesterol turnover in the central nervous system during neurodegeneration. The observed influence of the apolipoprotein E epsilon4 (APOE4) allele on CSF 24S-hydroxycholesterol concentrations with a gene-dosage effect suggests the existence of a link between the AD risk factor APOE4 and CNS cholesterol metabolism. The elevation of CSF 24S-hydroxycholesterol appears to occur early in the disease process, since patients with mild cognitive impairment had also increased CSF concentrations of this compound. We believe that the CSF concentration of 24S-hydroxycholesterol is altered in AD-related neurodegeneration and thus, CSF 24S-hydroxycholesterol may be a marker for monitoring the onset and progression of the disease.