Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis

Authors

  • W. Gibson Wood,

    Corresponding author
    1. Geriatric Research, Education and Clinical Center, VAMC, Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
    • Address correspondence and reprint requests to W. Gibson Wood, Department of Pharmacology, University of Minnesota School of Medicine, Jackson Hall 6-120, 321 Church St., Minneapolis, MN 55455, USA. E-mail: woodx002@umn.edu

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  • Ling Li,

    1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA
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  • Walter E. Müller,

    1. Department of Pharmacology, Biocenter Niederursel, Goethe University, Frankfurt, Germany
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  • Gunter P. Eckert

    1. Department of Pharmacology, Biocenter Niederursel, Goethe University, Frankfurt, Germany
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Abstract

High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Aβ) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD. Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only amyloid precursor protein and Aβ. The purpose of this review, therefore, was to examine the above-mentioned issues, discuss the pros and cons of the cholesterol-AD hypothesis, involvement of other lipids in the mevalonate pathway, and consider that AD may impact cholesterol homeostasis.

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High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). This Review addresses the Pro's and Con's of whether cholesterol is a causative factor in AD, covering articles ranging from human to cell culture studies, both in vitro and in vivo. Among others, we review models of how abeta could act on a membrane and of how abeta might be perturbing cholesterol in a cell.

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