Alzheimer's disease: Donepezil effects on cholesterol and oxysterol plasma levels

Background Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer's disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)‐hydroxycholesterol (24OHC) which can be driven through the blood‐brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)‐hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short‐ and long‐term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. Method The sample comprised 30 patients with mild or moderate AD and 33 physically and cognitively healthy elderly controls. In the last 6 months prior to enrolment in the study, patients and the control group did not use AChEi or other drugs. After the completion of baseline assessments, all patients were started on donepezil treatment (5 mg/day). Doses were administered orally and increased to 10 mg/day after 1 month. Patients were monitored monthly, the MMSE was evaluated after 3 and 6 months, and CAMCOG was evaluated 6 months after donepezil treatment. Plasma cholesterol concentrations were measured using commercially available enzymatic–colorimetric methods. Measurements of oxysterols (24‐hydroxycholesterol and 27‐hydroxycholesterol) were performed by gas chromatography–mass spectrometry. Result At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. Conclusion These results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer's disease.