Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology
Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL et al.. Neurology, 2003-07-01
Topic: Amyloid, tau and blood-test diagnosis
Background Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. Objective To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. Methods The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Results Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Conclusions Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.
Key findings
- Background Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD.
- Results Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects).
- A logistic regression model showed consistent results (McFadden rho2 = 0.445).
Why it matters
In this autopsy study, higher cholesterol was linked to amyloid deposition in the youngest subjects aged 40 to 55, but this difference disappeared in older subjects. It suggests cholesterol may matter early, but it does not show that lowering cholesterol prevents Alzheimer disease.
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Study details
- Evidence strengthLow
How this study scored 51/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2003 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 313 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 12.5 citations a year over 25 year(s) since 2003 |
| Impact for its field and year | 4 / 6 | Cited 8.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 16 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 | 2 / 4 | Last-listed author Lorenzo M. Refolo: h-index 25 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California San Diego: institution h-index 1,852 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 12874399) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 51 / 100 | — |
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May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.
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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
Pappolla, M. A., Bryant-Thomas, T. K., Herbert, D., Pacheco, J., Fabra Garcia, M., Manjon, M., et al. (2003). Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. https://doi.org/10.1212/01.wnl.0000070182.02537.84
Vancouver
Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. 2003. doi:10.1212/01.wnl.0000070182.02537.84. PMID: 12874399.
BibTeX
@article{pappolla2003-12874399,
author = {Pappolla, M. A. and Bryant-Thomas, T. K. and Herbert, D. and Pacheco, J. and Fabra Garcia, M. and Manjon, M. and Girones, X. and Henry, T. L. and others},
title = {{Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology}},
journal = {Neurology},
year = {2003},
doi = {10.1212/01.wnl.0000070182.02537.84},
pmid = {12874399},
url = {https://doi.org/10.1212/01.wnl.0000070182.02537.84}
}
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