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Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and related dementias and Parkinson's disease and related disorders
Le Guen, Y.; Pena-Tauber, A.; Catoia Pulgrossi, R.; Park, J.; Orias, H.; Greicius, M. D.. medRxiv (preprint), 2026-09-18
Topic: Amyloid, tau and blood-test diagnosis
Alzheimers disease and related dementias (ADRD)1 and Parkinsons disease and related disorders (PDRD)2 have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale3-6. We performed gene-burden testing of loss-of-function and deleterious missense variants in biobanks and disease-focused sequencing cohorts, using calibrated proxy-phenotypes and diagnosed-case sensitivity analyses to increase power for late-onset disease7. At study-wide significance, we confirmed rare-variant burden in established ADRD genes (TREM2, ABCA7, SORL1, PSEN1, GRN, ATP8B4, ABCA1, ADAM10) and PDRD genes (GBA1, LRRK2). We also identified a novel ADRD burden association at IMPA2, and novel PDRD associations at ANKRD27, and CCL7. The strongest signal was observed for ANKRD27, where damaging variants clustered within domains mediating interactions with Rab GTPases and retromer components. Our results demonstrate the value of population-scale sequencing to identify rare coding risk genes for neurodegenerative diseases.
Key findings
- Our results demonstrate the value of population-scale sequencing to identify rare coding risk genes for neurodegenerative diseases.
Why it matters
This large genetic study confirmed known risk genes and identified new ones, including IMPA2 for Alzheimer's disease and related dementias. It adds to understanding of the genetic causes of these diseases but does not test any treatment or prevention.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 26 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 24 of the 94 points we could judge it on, which is 26 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 | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 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 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Michael D. Greicius: h-index 65 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Stanford University: institution h-index 2,684 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 24 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 24 of the 94 points we could judge it on is 26 out of 100. |
| Total | 26 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
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. Check the citation against the original before you use it.
APA 7th
Le Guen, Y., Pena-Tauber, A., Catoia Pulgrossi, R., Park, J., Orias, H., & Greicius, M. D. (2026). Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and related dementias and Parkinson's disease and related disorders. medRxiv (preprint). https://doi.org/10.64898/2026.03.03.26347540
Vancouver
Le Guen Y, Pena-Tauber A, Catoia Pulgrossi R, Park J, Orias H, Greicius MD. Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and related dementias and Parkinson's disease and related disorders. medRxiv (preprint). 2026. doi:10.64898/2026.03.03.26347540.
BibTeX
@article{leguen2026-c49638e3,
author = {Le Guen, Y. and Pena-Tauber, A. and Catoia Pulgrossi, R. and Park, J. and Orias, H. and Greicius, M. D.},
title = {{Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and related dementias and Parkinson's disease and related disorders}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.03.03.26347540},
url = {https://doi.org/10.64898/2026.03.03.26347540}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.