Re-assessing the relationship between cholesterol, statins and Alzheimer's disease

Abstract

This communication integrates the purported role of cholesterol and statins in Alzheimer's disease (AD) with recent data. Meta-analysis of association studies relevant to AD indicates that apolipoprotein (apo)E4 is the only cholesterol-related polymorphism that shows clear association with AD. This suggests that the effect of apoE4 on the pathophysiology of AD occurs via a mechanism that is not directly related to cholesterol, such as fibrillization of Abeta. Despite the lack of genetic association, cholesterol and statins clearly modulate amyloid precursor protein (APP) processing in cell culture and animal models. Statins appear to act by a pleiotropic mechanism, involving both cholesterol (via lipid rafts) and isoprenylation. The pleiotropic mechanism of statin action clarifies conflicting data from clinical studies, where statins exert an action on Abeta and AD that might be dose dependent because of actions on both cholesterol and isoprenylation. Reduced isoprenylation can also inhibit inflammation. Our own studies of brains from Alzheimer subjects +/- statins indicate that statins inhibit inflammation in humans but might not reduce cerebral Abeta load. These results suggest that the primary action of statins in humans with AD might be to reduce inflammation rather than decrease Abeta load.

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

“…Statin treatment significantly reduces serum cholesterol but it is not clear whether statins have a direct influence on cholesterol in the central nervous system (CNS). It was reported that treatment of human subjects for 3 months with lovastatin resulted in a decrease of Aβ peptides in serum [46], whereas most clinical studies have not confirmed the effect of statins on Aβ levels in the brain [47,48]. Activation of the α-secretase and inhibition of the β-secretase require strong reduction of cellular cholesterol, therefore it is unlikely that physiological statin concentrations can influence the production of Aβ peptides in the brain.…”

Enrichment of cholesterol in microdissected Alzheimer’s disease senile plaques as assessed by mass spectrometry

“…In order to quantify cholesterol in the samples, an internal standard made of 20 ng (51.5 pmol) of [3,[4][5][6][7][8][9][10][11][12][13] C]cholesterol was added to the collected material. For each cap, four successive extractions were carried out with 200 l of hexane.…”

“…We were able to visualize the SPs using a rapid immunohistochemistry technique without pretreatment. The frozen brain sections were thawed for a few minutes at room temperature and incubated for 30 min at room temperature in a 200 l solution containing 5 g/ml of monoclonal 6F/3D antibody (specifi c for the A ␤ peptide epitope amino acids [8][9][10][11][12][13][14][15][16][17]. The samples were then washed three times for 5 min with TBS.…”

Semisynthesis of novel monacolin J derivatives: hypocholesterolemic and neuroprotective activities

“…19,20 Very recently, results in experimental animal models showed that lower cholesterol levels slow the expression of Alzheimer's pathology, 21 and it has been reported that the intake of statins is associated with a decreased incidence of AD. 22 Furthermore, it has been shown that hypercholesterolemia accelerated AD pathology in transgenic animal models, 23 being also an early risk factor for AD in epidemiology studies. 24,25 These data point out the possibility that treating human patients with these cholesterol-lowering drugs might either reduce the risk of developing AD or help to treat it.…”