P2–153: Alterations of brain cholesterol metabolism: Relevance of desmosterol in Alzheimer's disease and vascular dementia

Cholesterol metabolism is altered in Alzheimer's disease (AD) and vascular dementia (VD). It has been shown that seladin–1, the enzyme catalyzing the reaction from cholesterol precursor desmosterol into cholesterol, is reduced in AD brains. To determine if alterations of brain cholesterol metabolism in AD and/or VD may cause changes in the levels of cholesterol precursors (lathosterol and desmosterol) as well as of cholesterol elimination products (i.e. 24S–hydroxycholesterol). CSF and plasma levels of cholesterol, the cholesterol precursors lathosterol and desmosterol and of the major brain cholesterol elimination product, 24S–hydroxycholesterol, in AD, VD and mild cognitive impaired (MCI) patients and in non–demented subjects were measured by a modified highly sensitive method using combined gas chromatography–mass spectrometry (GC–MS). Plasma cholesterol levels were comparable in all groups (p=0.22), however, we found concentrations of CSF cholesterol to be reduced in AD, VD and MCI patients compared to non–demented subjects (p=0.004). CSF levels of desmosterol were increased in each patient group (p<0.001), we found also increased levels of desmosterol in plasma of AD and VD patients (p<0.001). CSF and plasma levels of lathosterol were not significantly altered (CSF: p=0.54; plasma: p=0.21). As also reported earlier, we found plasma levels of 24S–hydroxycholesterol to be decreased in patient groups (p=0.001) whereas, CSF 24S–hydroxycholesterol levels were not influenced (p=0.96). Our results support, that cholesterol metabolism is altered in dementing disorders. Increased levels of cholesterol precursor desmosterol and decreased levels of CSF cholesterol might indicate either a reduced seladin–1 activity or the activation of a compensatory mechanism in cholesterol de novo synthesis in patients. Since alterations in the levels of 24S–hydroxycholesterol were only detected in plasma but not in CSF of patients, further investigation on the cholesterol elimination processes in brain is needed. The biochemical and functional consequences of altered cholesterol CSF levels and especially on increased desmosterol in CSF and plasma in dementing disorders will have to be explored in further studies.