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Cited by 194Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholesterol and Lipid Metabolism

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

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Wood, W. Gibson, Li, Ling, Müller, Walter E., Eckert, Gunter P.·2014·Journal of Neurochemistry
DOI 10.1111/jnc.12637PMC PMC3999290
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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. image 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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  • Lowering cholesterol decreases Aβ levels.

    “HDL reduces cholesterol (159) and lowering cholesterol decreases Aβ levels. (152)”

    From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [152]

    The Animal and Cell Culture AD Models section says reducing cholesterol generally decreases Aβ abundance in animal and cell-culture studies. It cautions that applying those findings to AD patients is challenging, so the unqualified claim is broader than the evidence the paper presents. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • High LDL-C in midlife, but not later life, might be a risk factor for cognitive decline, all-cause dementia and AD, but evidence is inconsistent.

    “Meta-analytic evidence found inconsistent evidence from HICs that high LDL-C in midlife, but not in later life, might be a risk factor for cognitive decline, all cause dementia and AD.”

    From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [152]

    The ‘Serum/Plasma Cholesterol Levels and AD’ section (page not provided) reports mixed findings and says elevated midlife cholesterol may be a risk factor for AD in a small number of individuals, while cholesterol measured at age 65 or older was not associated with later dementia or AD in one study. But those age-related findings concern total or unspecified cholesterol, not specifically LDL-C; the section does not provide meta-analytic evidence for midlife LDL-C as a risk factor for cognitive decline, all-cause dementia and AD, or characterize that evidence by high-income-country setting. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Wood, W. G., Li, L., Müller, W. E., & Eckert, G. P.
Affiliations
  • University of Minnesota (US)
  • Goethe University Frankfurt (DE)
Corresponding author
Wood, W. Gibson
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2014-01-02
Volume
129
Issue
4
Pages
559-572
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.12637
PMC
PMC3999290
OpenAlex
W2036433301
Cited by
194
References
171
Citations by year
2026: 3 · 2025: 9 · 2024: 11 · 2023: 18 · 2022: 10 · 2021: 16 · 2020: 19 · 2019: 27 · 2018: 14 · 2017: 17 · 2016: 14 · 2015: 20 · 2014: 16
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (AG-23524, AG-18357, AG-31846)
  • Hanna-Bragard-Apfel Foundation
  • Alzheimer Forschung Initiative
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
Alzheimer's disease, cholesterol, cholesterol hypothesis, statins, amyloid precursor protein, amyloid-beta, mevalonate pathway, lipids, cholesterol homeostasis, risk factors
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Cell Membrane, Cells, Cultured, Cholesterol, Cholesterol, Dietary, Disease Models, Animal, Humans, Hydroxycholesterols, Hypercholesterolemia, Models, Biological, Neurons, Polyisoprenyl Phosphates, Rabbits, Sesquiterpenes, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mice

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