Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer's disease

The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood.The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans.We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEɛ4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group.The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau.

Biosynthesis of cholesterol: from lanosterol to cholesterol, and the conversion to 24S- and 27-hydroxycholesterol 24 DHCR = 24-dehydrocholesterol reductase; Cyp 46A1 = cytochrome P-450 46A1; and Cyp 27A1 = cytochrome P-450 27A1.