Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways
Bradley J, Pottier C, da Fonseca EL, Kurup JT, Western D, Wang C, Neupane A, Ray NR, Jean-Francois M, Ali M, Timsina J, Bergmann K, et al.. Alzheimer's & Dementia, 2025-06
Topic: Amyloid, tau and blood-test diagnosis
Introduction Most genetic studies for Alzheimer's disease (AD) have been focused on late-onset AD (LOAD). There are no large genetic studies on early-onset AD (EOAD). Methods We performed a multi-ancestry (non-Hispanic European, African, and East Asian) genome-wide association study (GWAS) including a total of 7,349 cases and 17,887 control. Cases with age at onset younger than 70 years were included. Sensitivity analysis including cases with onset Results We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and functional annotations, we nominate eight novel genes that are involved in microglia activation, glutamate production, and signaling pathways. Discussion EOAD, although sharing genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification. Highlights We performed the largest and first multi-ethnic genetic screening for early-onset Alzheimer's disease (AD). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. The novel genes are implicated microglia activation, glutamate production, and signaling pathways. EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.
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APA 7th
Bradley, J., Pottier, C., da Fonseca, E. L., Kurup, J. T., Western, D., Wang, C., et al. (2025). Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways. Alzheimer's & Dementia. https://doi.org/10.1002/alz.70377
Vancouver
Bradley J, Pottier C, da Fonseca EL, Kurup JT, Western D, Wang C, et al. Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways. Alzheimer's & Dementia. 2025. doi:10.1002/alz.70377. PMID: 40556318.
BibTeX
@article{bradley2025-40556318,
author = {Bradley, J. and Pottier, C. and da Fonseca, E. L. and Kurup, J. T. and Western, D. and Wang, C. and Neupane, A. and Ray, N. R. and Jean-Francois, M. and Ali, M. and Timsina, J. and Bergmann, K. and others},
title = {{Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways}},
journal = {Alzheimer's \& Dementia},
year = {2025},
doi = {10.1002/alz.70377},
pmid = {40556318},
url = {https://doi.org/10.1002/alz.70377}
}
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Key findings
- Sensitivity analysis including cases with onset Results We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis.
- We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis.
Why it matters
This genetic study found eight new gene regions linked to early-onset Alzheimer's disease, involving microglia activation, glutamate production, and signaling pathways. These findings could help build better prediction models or identify new treatment targets, though they are genetic associations rather than proven treatments.
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Study details
- Study designcase-control
- Participants25,236
- Evidence strengthModerate
Limitations
Gene prioritisation relied on molecular QTL data available only for European-ancestry individuals, so overlaps for non-European and multi-ancestry loci may be missed; the pQTL data did not cover the full genome; several prioritisation categories used in earlier European studies could not be applied.
How this study scored 60/100
Published in a leading specialty journal, and it is a case-control study. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 59 of the 98 points we could judge it on, which is 60 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 | 4 / 4 | 25,236 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 7 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 1 / 4 | Cited 7 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Carlos C Cruchaga: h-index 102 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40556318) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 59 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 59 of the 98 points we could judge it on is 60 out of 100. |
| Total | 60 / 100 | — |
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