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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M et al.. Nature genetics, 2019-02-28
Topic: Amyloid, tau and blood-test diagnosis
Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Key findings
- We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia.
- Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD.
- Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD.
- Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified.
- We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Why it matters
In a genome-wide meta-analysis of 94,437 people with or without clinically diagnosed late-onset Alzheimer's disease, researchers confirmed 20 known genetic risk locations and found five new ones (IQCK, ACE, ADAM10, ADAMTS1 and WWOX). They also confirmed the immune-system variant HLA-DR15 as a risk factor. The genes point to immunity, lipid metabolism, tau-binding proteins and amyloid processing, and the authors say more rare variants remain to be found. These are statistical associations with risk: the study tests no treatment and does not show that any of these genes causes the disease.
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Study details
- Study designmeta-analysis
- Participants94,437
- Evidence strengthHigh
Limitations
This is a genetic association study of diagnosed cases versus controls; it identifies statistical links between DNA locations and Alzheimer's risk but does not by itself establish how these genes cause disease.
How this study scored 85/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for effect reported 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 | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — within 10 year(s) of the newest study here |
| Sample size | 4 / 4 | 94,437 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 | A review of other studies — randomisation is not credited here |
| Times cited | 7 / 7 | Cited 2,955 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 328.3 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 6 / 6 | Cited 54.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 5 / 6 | Cited by 150 other studies in this library |
| Still being cited | 4 / 4 | Cited 1,172 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Thomas Fairchild: h-index 15 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 76 institution(s) in 14 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30820047) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 85 / 100 | — |
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Read the original
- DOI: 10.1038/s41588-019-0358-2
- PubMed: 30820047
- Original source →
- Free full text: Explore Bristol Research →
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
Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature genetics. https://doi.org/10.1038/s41588-019-0358-2
Vancouver
Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature genetics. 2019. doi:10.1038/s41588-019-0358-2. PMID: 30820047.
BibTeX
@article{kunkle2019-30820047,
author = {Kunkle, B. W. and Grenier-Boley, B. and Sims, R. and Bis, J. C. and Damotte, V. and Naj, A. C. and Boland, A. and Vronskaya, M. and others},
title = {{Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing}},
journal = {Nature genetics},
year = {2019},
doi = {10.1038/s41588-019-0358-2},
pmid = {30820047},
url = {https://doi.org/10.1038/s41588-019-0358-2}
}
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