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Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease
Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami V. Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo et al.. Molecular Neurodegeneration, 2025-04-28
Topic: Brain proteins, microglia and lab models
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Martiskainen, H., Willman, R.-M., Harju, P., Heikkinen, S. V., Heiskanen, M., Müller, S. A., et al. (2025). Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease. Molecular Neurodegeneration. https://doi.org/10.1186/s13024-025-00830-3
Vancouver
Martiskainen H, Willman R.-M, Harju P, Heikkinen SV, Heiskanen M, Müller SA, et al. Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease. Molecular Neurodegeneration. 2025. doi:10.1186/s13024-025-00830-3. PMID: 40301889.
BibTeX
@article{martiskainen2025-40301889,
author = {Martiskainen, Henna and Willman, Roosa-Maria and Harju, Päivi and Heikkinen, Sami V. and Heiskanen, Mette and Müller, Stephan A. and Sinisalo, Rosa and Takalo, Mari and others},
title = {{Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease}},
journal = {Molecular Neurodegeneration},
year = {2025},
doi = {10.1186/s13024-025-00830-3},
pmid = {40301889},
url = {https://doi.org/10.1186/s13024-025-00830-3}
}
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.
Key findings
- We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers.
- Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP.
- Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.
Why it matters
This study found that carrying a monoallelic TYROBP deletion was associated with an increased risk and earlier onset of Alzheimer's disease and dementia in Finnish biobank participants. The authors also report the first case of a monoallelic carrier with NHD-type bone cysts and show that the deletion leads to decreased DAP12 protein and altered inflammatory and unfolded protein responses in microglia-like cells.
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Study details
- Evidence strengthLow
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 42 of the 96 points we could judge it on, which is 44 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular Neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 10 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 5.5× 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 | 1 / 4 | Cited 10 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 3 / 3 | Broad Institute: institution h-index 2,541 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 25 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40301889) |
| Free to read | 2 / 2 | Free to read |
| Points | 42 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 42 of the 96 points we could judge it on is 44 out of 100. |
| Total | 44 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s13024-025-00830-3
- PubMed: 40301889
- Original source →
- Free full text: Molecular Neurodegeneration →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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