Alpha-2 macroglobulin is genetically associated with Alzheimer disease
Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, Perry R, Watson B et al.. Nature genetics, 1998-08-01
Topic: Amyloid, tau and blood-test diagnosis
Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C., et al. (1998). Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature genetics. https://doi.org/10.1038/1243
Vancouver
Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature genetics. 1998. doi:10.1038/1243. PMID: 9697696.
BibTeX
@article{blacker1998-9697696,
author = {Blacker, D. and Wilcox, M. A. and Laird, N. M. and Rodes, L. and Horvath, S. M. and Go, R. C. and Perry, R. and Watson, B. and others},
title = {{Alpha-2 macroglobulin is genetically associated with Alzheimer disease}},
journal = {Nature genetics},
year = {1998},
doi = {10.1038/1243},
pmid = {9697696},
url = {https://doi.org/10.1038/1243}
}
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.
Key findings
- Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001).
- The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009).
- A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.
Why it matters
This genetic study found that inheriting a deletion in the A2M gene was associated with an increased risk of Alzheimer's disease, but unlike the APOE-epsilon4 allele, it did not affect the age when symptoms began. The authors suggest A2M, LRP1, APOE and APP may act in a common pathway leading to the disease.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 56/100
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 (Nature genetics) |
| Journal's citation record | 4 / 4 | Nature Genetics: journal h-index 776 (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 | 1998 — 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 644 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 21.5 citations a year over 30 year(s) since 1998 |
| Impact for its field and year | 6 / 6 | Cited 55.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 15 other studies in this library |
| Still being cited | 1 / 4 | Cited 10 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Rudolph E. Tanzi: h-index 145 (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 9697696) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 56 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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.
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
15 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Genetics
Also tagged “precursor”
1,339 studies in the library carry the topic tag “precursor”; 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.