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

J Neurochem. 2014 May;129(4):559-72. doi: 10.1111/jnc.12637. Epub 2014 Jan 2.


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 (Ab) 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 Ab. 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.

Keywords: Alzheimer's disease; amyloid beta-protein; apolipoprotein E; cholesterol; isoprenoids; statins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / etiology*
  • Alzheimer Disease / prevention & control
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Apolipoproteins E / metabolism
  • Astrocytes / metabolism
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cholesterol / adverse effects*
  • Cholesterol / biosynthesis
  • Cholesterol / blood
  • Cholesterol, Dietary / adverse effects
  • Disease Models, Animal
  • Humans
  • Hydroxycholesterols / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hypercholesterolemia / complications*
  • Hypercholesterolemia / drug therapy
  • Mice
  • Models, Biological*
  • Neurons / metabolism
  • Polyisoprenyl Phosphates / metabolism
  • Rabbits
  • Sesquiterpenes / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Apolipoproteins E
  • Cholesterol, Dietary
  • Hydroxycholesterols
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Polyisoprenyl Phosphates
  • Sesquiterpenes
  • 24-hydroxycholesterol
  • farnesyl pyrophosphate
  • Cholesterol
  • geranylgeranyl pyrophosphate