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Re‐assessing the relationship between cholesterol, statins and Alzheimer's disease
Author(s) -
Wolozin B.,
Manger J.,
Bryant R.,
Cordy J.,
Green R. C.,
McKee A.
Publication year - 2006
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/j.1600-0404.2006.00687.x
Subject(s) - cholesterol , apolipoprotein e , inflammation , mechanism (biology) , prenylation , mechanism of action , alzheimer's disease , statin , lipid raft , disease , medicine , neuroscience , pharmacology , biology , biochemistry , philosophy , epistemology , in vitro , enzyme
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 A β . 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 A β 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 A β load. These results suggest that the primary action of statins in humans with AD might be to reduce inflammation rather than decrease A β load.