Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles
Bennett DA, De Jager PL, Leurgans SE, Schneider JA.. Neurology, 2009-04-01
Topic: Amyloid, tau and blood-test diagnosis
Objective The identification of susceptibility alleles to risk of Alzheimer disease (AD) is a major public health priority. Using apolipoprotein E genotype (APOE), we examined whether neuropathologic intermediate phenotypes, the pathology underlying clinical AD that presumably lies intermediate in the causal chain, would increase power for genetic associations. Methods More than 700 older persons underwent annual evaluation and organ donation as part of the Religious Orders Study or Rush Memory and Aging Project. A total of 536 autopsied persons with clinical AD or without dementia with APOE genotyping and a quantitative measure of AD pathology were analyzed. Regression analyses were used to examine the relation of APOE to clinical AD, to the level of cognitive function proximate to death, and to measures of AD neuropathology. Results APOE epsilon4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10(-12)). However, the use of quantitative measures of AD pathology markedly enhanced the association (p = 9 x 10(-24)). The APOE epsilon2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82). However, its association with AD pathology (p = 1 x 10(-5)) was sufficiently strong that it would have warranted follow-up if discovered in a genome-wide association study. Power calculations demonstrate that a sample size of 625 subjects with our measure of AD pathology would be required to meet genome-wide significance of p = 5 x 10(-8) for epsilon2. Conclusion Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches.
Key findings
- Results APOE epsilon4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10(-12)).
- The APOE epsilon2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82).
Why it matters
This study found that using measures of Alzheimer brain pathology strengthened the genetic association with APOE, and that APOE epsilon2 was linked to Alzheimer pathology even though it was not linked to clinical Alzheimer disease. It is about improving genetic research methods, not about treating or preventing the disease.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Participants625
- Evidence strengthLow
How this study scored 53/100
Published in a leading specialty journal. Scored zero for study design, effect reported 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 | 2009 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 625 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 94 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.9 citations a year over 19 year(s) since 2009 |
| Impact for its field and year | 3 / 6 | Cited 5.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 8 other studies in this library |
| Still being cited | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Julie A. Schneider: h-index 151 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 19398704) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1212/wnl.0b013e3181a2e87d
- PubMed: 19398704
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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. Check the citation against the original before you use it.
APA 7th
Bennett, D. A., De Jager, P. L., Leurgans, S. E., & Schneider, J. A. (2009). Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles. Neurology. https://doi.org/10.1212/wnl.0b013e3181a2e87d
Vancouver
Bennett DA, De Jager PL, Leurgans SE, Schneider JA. Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles. Neurology. 2009. doi:10.1212/wnl.0b013e3181a2e87d. PMID: 19398704.
BibTeX
@article{bennett2009-19398704,
author = {Bennett, D. A. and De Jager, P. L. and Leurgans, S. E. and Schneider, J. A.},
title = {{Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles}},
journal = {Neurology},
year = {2009},
doi = {10.1212/wnl.0b013e3181a2e87d},
pmid = {19398704},
url = {https://doi.org/10.1212/wnl.0b013e3181a2e87d}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 25.
Later studies that cite this one
8 studies in the alzhub library list this one in their references.
Related studies in Genetics
Also tagged “amyloid-beta”
1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.