Genetic susceptibility for Alzheimer disease neuritic plaque pathology
Shulman JM, Chen K, Keenan BT, Chibnik LB, Fleisher A, Thiyyagura P, Roontiva A, McCabe C et al.. JAMA neurology, 2013-09-01
Topic: Amyloid, tau and blood-test diagnosis
Importance While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. Objectives To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Design, setting, and participants Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. Main outcomes and measures A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Results Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. Conclusions and relevance These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
Key findings
- Results Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden.
- In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6).
- This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition.
- Conclusions and relevance These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
Why it matters
In brain tissue from 725 deceased subjects, this study found that the ABCA7 and CD2AP risk loci are associated with neuritic plaque burden, and it identified a novel variant near the APP gene linked to plaques. These findings connect known Alzheimer's risk genes to the actual plaque pathology in the brain.
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Study details
- Participants114
- Evidence strengthModerate
How this study scored 57/100
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 (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (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 | 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 | 2013 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 114 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 | 5 / 7 | Cited 162 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 10.8 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 4 / 6 | Cited 10.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 11 other studies in this library |
| Still being cited | 2 / 4 | Cited 22 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author David Bennett: h-index 45 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 11 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23836404) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 57 / 100 | — |
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Read the original
- DOI: 10.1001/jamaneurol.2013.2815
- PubMed: 23836404
- 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. 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
Shulman, J. M., Chen, K., Keenan, B. T., Chibnik, L. B., Fleisher, A., Thiyyagura, P., et al. (2013). Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA neurology. https://doi.org/10.1001/jamaneurol.2013.2815
Vancouver
Shulman JM, Chen K, Keenan BT, Chibnik LB, Fleisher A, Thiyyagura P, et al. Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA neurology. 2013. doi:10.1001/jamaneurol.2013.2815. PMID: 23836404.
BibTeX
@article{shulman2013-23836404,
author = {Shulman, J. M. and Chen, K. and Keenan, B. T. and Chibnik, L. B. and Fleisher, A. and Thiyyagura, P. and Roontiva, A. and McCabe, C. and others},
title = {{Genetic susceptibility for Alzheimer disease neuritic plaque pathology}},
journal = {JAMA neurology},
year = {2013},
doi = {10.1001/jamaneurol.2013.2815},
pmid = {23836404},
url = {https://doi.org/10.1001/jamaneurol.2013.2815}
}
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