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Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias
Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, Corneveaux JJ, Hardy J et al.. PLoS genetics, 2014-09-04
Topic: Amyloid, tau and blood-test diagnosis
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Key findings
- GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS.
- Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Why it matters
Using autopsy findings from 4,914 brains rather than clinical diagnoses, this genetic study linked APOE variants to plaques, tangles, amyloid in blood vessels and Lewy body disease, and found new associations for plaque burden (GALNT7, ABCG1, a chromosome 9 region) and hippocampal sclerosis (KCNMB2). It confirmed 12 of 21 known non-APOE Alzheimer's risk genes, 9 of them with larger odds ratios than in clinically diagnosed samples. These are statistical associations that point to biology worth studying; they do not test any treatment or predict an individual's risk.
Study details
- Evidence strengthLow
How this study scored 64/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (PLoS genetics) |
| Journal's citation record | 3 / 4 | PLoS Genetics: journal h-index 341 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies (from PubMed type “Meta-Analysis”) |
| 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 | 2014 — within 20 year(s) of the newest study here |
| 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 | A review of other studies — randomisation is not credited here |
| Times cited | 6 / 7 | Cited 348 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 24.9 citations a year over 14 year(s) since 2014 |
| Impact for its field and year | 3 / 6 | Cited 3.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 23 other studies in this library |
| Still being cited | 2 / 4 | Cited 49 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Thomas J. Montine: h-index 48 (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 25 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25188341) |
| Free to read | 2 / 2 | Free to read |
| Total | 64 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1371/journal.pgen.1004606
- PubMed: 25188341
- Original source →
- Free full text: PLoS Genetics →
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
Beecham, G. W., Hamilton, K., Naj, A. C., Martin, E. R., Huentelman, M., Myers, A. J., et al. (2014). Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLoS genetics. https://doi.org/10.1371/journal.pgen.1004606
Vancouver
Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLoS genetics. 2014. doi:10.1371/journal.pgen.1004606. PMID: 25188341.
BibTeX
@article{beecham2014-25188341,
author = {Beecham, G. W. and Hamilton, K. and Naj, A. C. and Martin, E. R. and Huentelman, M. and Myers, A. J. and Corneveaux, J. J. and Hardy, J. and others},
title = {{Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias}},
journal = {PLoS genetics},
year = {2014},
doi = {10.1371/journal.pgen.1004606},
pmid = {25188341},
url = {https://doi.org/10.1371/journal.pgen.1004606}
}
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