Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology
Sierksma A, Lu A, Mancuso R, Fattorelli N, Thrupp N, Salta E, Zoco J, Blum D et al.. EMBO molecular medicine, 2020-01-17
Topic: Amyloid, tau and blood-test diagnosis
Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1 L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Sierksma, A., Lu, A., Mancuso, R., Fattorelli, N., Thrupp, N., Salta, E., et al. (2020). Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology. EMBO molecular medicine. https://doi.org/10.15252/emmm.201910606
Vancouver
Sierksma A, Lu A, Mancuso R, Fattorelli N, Thrupp N, Salta E, et al. Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology. EMBO molecular medicine. 2020. doi:10.15252/emmm.201910606. PMID: 31951107.
BibTeX
@article{sierksma2020-31951107,
author = {Sierksma, A. and Lu, A. and Mancuso, R. and Fattorelli, N. and Thrupp, N. and Salta, E. and Zoco, J. and Blum, D. and others},
title = {{Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology}},
journal = {EMBO molecular medicine},
year = {2020},
doi = {10.15252/emmm.201910606},
pmid = {31951107},
url = {https://doi.org/10.15252/emmm.201910606}
}
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 identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ.
- We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
Why it matters
In mice with amyloid-β pathology, but not in mice with tau pathology, a group of genes rich in Alzheimer risk genes switched on in microglia, the brain's immune cells. The group included 7 well-known risk genes such as APOE, CD33 and PLCG2, plus 11 genes that genetic studies had flagged only weakly. The authors conclude that genetic risk acts through the microglial response to amyloid, before tau, but this is gene-activity data from two mouse models, not a test of any treatment or of risk in people.
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Study details
- Evidence strengthLow
How this study scored 52/100
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 (EMBO molecular medicine) |
| Journal's citation record | 2 / 4 | EMBO Molecular Medicine: journal h-index 186 (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 | 2 / 5 | 2020 — within 10 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 | 5 / 7 | Cited 291 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 36.4 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 5 / 6 | Cited 24.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 19 other studies in this library |
| Still being cited | 3 / 4 | Cited 99 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Mark W. E. J. Fiers: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 31951107) |
| Free to read | 2 / 2 | Free to read |
| Total | 52 / 100 | — |
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Read the original
- DOI: 10.15252/emmm.201910606
- PubMed: 31951107
- Original source →
- Free full text: EMBO Molecular Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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