Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores
Nicholas K. O’Neill, Nuzulul Kurniansyah, Congcong Zhu, Oluwatosin A Olayinka, Richard P Mayeux, Jonathan L. Haines, Margaret Ann Pericak‐Vance, Li-San Wang et al.. Neurobiology of Aging, 2025-07-16
Topic: Amyloid, tau and blood-test diagnosis
Alzheimer disease (AD) polygenic risk scores (ADPRS) built from cell-type (ct) specific genetic variants can be used to infer cell-type contributions to AD. We derived two ct-ADPRSs using variants near single-nuclei RNA-seq (snRNA) derived cell-type specific genes or on single-nuclei ATAC-seq (snATAC) derived cell-type specific accessible chromatin regions. We generated a multi-omic ct-ADPRS for eight neuron subtypes using both single-nuclei datasets. SnATAC-derived ct-ADPRSs demonstrated considerably lower correlations among cell types (average r=0.071) than snRNA-derived ct-ADPRSs (average r=0.19), indicating their heightened cell-type specificity. The association of these ct-ADPRSs with AD endophenotypes was evaluated using logistic and linear regression models. Tau tangle burden was associated with astrocyte (AST) ct-ADPRS derived from snATAC (β=0.82, FDR=0.0013) and snRNA (β=0.60, FDR=0.045) as well as microglia (MIC) ct-ADPRS from both (snATAC: β=0.75, FDR=0.0047) (snRNA: β=0.63, FDR=0.028). AST ct-ADPRS was significantly associated with Mini-Mental State Examination score only when derived from snATAC data (β=-0.82, FDR=0.011). SST expressing GABAergic neuron ADPRS was strongly associated ct-ADPRS with neuritic plaque burden (β=0.087, FDR=0.0014) and the only neuron subtype ct-ADPRS significantly associated with AD endophenotypes. We investigated 1,954 SNPs contributing to this ct-ADPRS and found the strongest association with variants upstream of the neuropeptide Y gene, NPY , particularly rs3940268 (β=-0.13, P=8.2x10 -5 ). This association is significant even after adjusting for diffuse plaque (β=-0.12, P=1.5x10 -4 ) or neurofibrillary tangle burden (β=-0.08, P=3.9x10 -3 ). NPY was expressed in a small subset of neurons, and these findings suggest its strong impact on the association of SST+ GABAergic neurons with early AD pathology.
Key findings
- SnATAC-derived ct-ADPRSs demonstrated considerably lower correlations among cell types (average r=0.071) than snRNA-derived ct-ADPRSs (average r=0.19), indicating their heightened cell-type specificity.
- Tau tangle burden was associated with astrocyte (AST) ct-ADPRS derived from snATAC (β=0.82, FDR=0.0013) and snRNA (β=0.60, FDR=0.045) as well as microglia (MIC) ct-ADPRS from both (snATAC: β=0.75, FDR=0.0047) (snRNA: β=0.63, FDR=0.028).
- AST ct-ADPRS was significantly associated with Mini-Mental State Examination score only when derived from snATAC data (β=-0.82, FDR=0.011).
- SST expressing GABAergic neuron ADPRS was strongly associated ct-ADPRS with neuritic plaque burden (β=0.087, FDR=0.0014) and the only neuron subtype ct-ADPRS significantly associated with AD endophenotypes.
- This association is significant even after adjusting for diffuse plaque (β=-0.12, P=1.5x10 -4 ) or neurofibrillary tangle burden (β=-0.08, P=3.9x10 -3 ).
Why it matters
Cell-type-specific Alzheimer's disease polygenic risk scores derived from single-nuclei data were associated with tau tangle burden, neuritic plaque burden, and MMSE score. This is a genetic and molecular analysis and does not test any treatment, cure, or prevention.
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Study details
- Evidence strengthLow
How this study scored 37/100
Published in a peer-reviewed 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 | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of Aging) |
| Journal's citation record | 3 / 4 | Neurobiology of Aging: journal h-index 263 (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 | 4 / 5 | 2025 — within 3 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 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 1 / 6 | Cited 0.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Xiaoling Zhang: h-index 35 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Pennsylvania: institution h-index 1,859 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40706314) |
| Free to read | 2 / 2 | Free to read |
| Total | 37 / 100 | — |
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Read the original
- DOI: 10.1016/j.neurobiolaging.2025.07.009
- PubMed: 40706314
- Original source →
- Free full text: Neurobiology of Aging →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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APA 7th
O’Neill, N. K., Kurniansyah, N., Zhu, C., Olayinka, O. A., Mayeux, R. P., Haines, J. L., et al. (2025). Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2025.07.009
Vancouver
O’Neill NK, Kurniansyah N, Zhu C, Olayinka OA, Mayeux RP, Haines JL, et al. Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores. Neurobiology of Aging. 2025. doi:10.1016/j.neurobiolaging.2025.07.009. PMID: 40706314.
BibTeX
@article{oneill2025-40706314,
author = {O’Neill, Nicholas K. and Kurniansyah, Nuzulul and Zhu, Congcong and Olayinka, Oluwatosin A and Mayeux, Richard P and Haines, Jonathan L. and Pericak‐Vance, Margaret Ann and Wang, Li-San and others},
title = {{Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores}},
journal = {Neurobiology of Aging},
year = {2025},
doi = {10.1016/j.neurobiolaging.2025.07.009},
pmid = {40706314},
url = {https://doi.org/10.1016/j.neurobiolaging.2025.07.009}
}
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