Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis
Proitsi P, Lupton MK, Velayudhan L, Newhouse S, Fogh I, Tsolaki M, Daniilidou M, Pritchard M et al.. PLoS medicine, 2014-09-16
Topic: Amyloid, tau and blood-test diagnosis
Background Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD. Methods and findings We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p Conclusions Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors' Summary.
Key findings
- Background Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported.
- Both full GRSs using all SNPs associated with each trait at p Conclusions Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk.
- The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD.
Why it matters
This mendelian randomization analysis found that genetic predisposition to increased blood cholesterol and triglyceride levels was not associated with elevated late-onset Alzheimer disease risk. The authors suggest the observed epidemiological associations could be due to other factors.
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Study details
- Study designcase-control study
- Participants10,578
- Evidence strengthModerate
How this study scored 62/100
Published in a peer-reviewed journal, and it is a case-control study. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (PLoS medicine) |
| Journal's citation record | 3 / 4 | PLoS Medicine: journal h-index 350 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2014 — within 20 year(s) of the newest study here |
| Sample size | 4 / 4 | 10,578 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 91 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.5 citations a year over 14 year(s) since 2014 |
| Impact for its field and year | 3 / 6 | Cited 4.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 18 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author John F. Powell: h-index 98 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Oxford: institution h-index 2,205 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 13 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25226301) |
| Free to read | 2 / 2 | Free to read |
| Total | 62 / 100 | — |
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Read the original
- DOI: 10.1371/journal.pmed.1001713
- PubMed: 25226301
- Original source →
- Free full text: PLoS Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Proitsi, P., Lupton, M. K., Velayudhan, L., Newhouse, S., Fogh, I., Tsolaki, M., et al. (2014). Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis. PLoS medicine. https://doi.org/10.1371/journal.pmed.1001713
Vancouver
Proitsi P, Lupton MK, Velayudhan L, Newhouse S, Fogh I, Tsolaki M, et al. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis. PLoS medicine. 2014. doi:10.1371/journal.pmed.1001713. PMID: 25226301.
BibTeX
@article{proitsi2014-25226301,
author = {Proitsi, P. and Lupton, M. K. and Velayudhan, L. and Newhouse, S. and Fogh, I. and Tsolaki, M. and Daniilidou, M. and Pritchard, M. and others},
title = {{Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis}},
journal = {PLoS medicine},
year = {2014},
doi = {10.1371/journal.pmed.1001713},
pmid = {25226301},
url = {https://doi.org/10.1371/journal.pmed.1001713}
}
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