Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk
Ward, E. L.; Nelson, P. T.; Katsumata, Y.; Fardo, D. W.; Jicha, G. A.; Alzheimer's Disease Neuroimaging Initiative, ; Miller, J. B.. medRxiv (preprint), 2026-09-09
Topic: Amyloid, tau and blood-test diagnosis
BackgroundAlzheimers disease (AD) pathology often accumulates years before memory loss, creating a need to identify high-risk individuals presymptomatically. Polygenic risk scores (PRS) stratify AD risk, but individual-level predictions remain uncertain. Extreme PRS may identify high-risk individuals independent of APOE. MethodsUsing GenoPred, extreme tails of 1,752 PRS methods were evaluated across four genetic ancestries using 11,200 autopsy- or clinically-defined AD cases and 19,321 controls (age [≥]65) from the AD Sequencing Project (ADSP) Release 5. ResultsIndividuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American (Padj=0.02727), African (Padj=0.004827), East Asian (Padj=0.02824), and European (Padj=2.3068x10-13). No controls were observed among the 42 European- and 12 African-ancestry individuals with extreme PRS. Extreme PRS spanned APOE diplotypes; 38% occurred in non-APOE {varepsilon}4 carriers. ConclusionsRare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes. Data AvailabilityAll data are available through the ADSP, which is managed by The National Institute on Aging Genetics of Alzheimers Disease Data Storage Site (NIAGADS).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Ward, E. L., Nelson, P. T., Katsumata, Y., Fardo, D. W., Jicha, G. A., Alzheimer's Disease Neuroimaging Initiative,, et al. (2026). Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk. medRxiv (preprint). https://doi.org/10.64898/2026.09.08.26362504
Vancouver
Ward EL, Nelson PT, Katsumata Y, Fardo DW, Jicha GA, Alzheimer's Disease Neuroimaging Initiative,, et al. Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk. medRxiv (preprint). 2026. doi:10.64898/2026.09.08.26362504.
BibTeX
@article{ward2026-c1a7a162,
author = {Ward, E. L. and Nelson, P. T. and Katsumata, Y. and Fardo, D. W. and Jicha, G. A. and {Alzheimer's Disease Neuroimaging Initiative,} and Miller, J. B.},
title = {{Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.08.26362504},
url = {https://doi.org/10.64898/2026.09.08.26362504}
}
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 names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- ResultsIndividuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American (Padj=0.02727), African (Padj=0.004827), East Asian (Padj=0.02824), and European (Padj=2.3068x10-13).
Why it matters
This study found that people with extreme high polygenic risk scores were more likely to have Alzheimer's disease across ancestries, including some without the APOE ε4 variant. It is about identifying high-risk individuals, not about treating, curing, or preventing the disease.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 18 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 17 of the 94 points we could judge it on, which is 18 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Justin B. Miller: h-index 16 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Kentucky: institution h-index 824 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 17 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 17 of the 94 points we could judge it on is 18 out of 100. |
| Total | 18 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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