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A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer’s disease
Lin D, Atkinson JR, Wu W, Chen M, Jayasekara S, Segal BM, Ma A, Gao J.. bioRxiv, 2026-09-20
Topic: Inflammation, microglia and astrocytes
Microglia are key drivers of Alzheimer’s disease (AD), and TREM2, one of the strongest genetic risk factors, enables the disease-associated microglia (DAM) state required for plaque engagement. How TREM2 sustains this protection, and why it falters as disease advances, remain unclear. Using proteomics, single-cell transcriptomics, and in vivo metabolic labeling, we show that plaque-associated microglia mount a TREM2-dependent anabolic program coupling nascent protein synthesis to mitochondrial biogenesis. This program, not the DAM signature, marks phagocytically competent microglia; its loss is associated with proteostatic overload and mitochondrial dysfunction. Unexpectedly, this anabolic program is self-limiting, peaking at low amyloid burden and declining as burden rises. This decline is conserved in humans: across 523 donors, anabolic capacity tracks TREM2 but falls at advanced Braak stage even as DAM signature keeps rising. Thus, anabolic capacity, rather than activation state, marks microglial resilience in AD, and sustained stimulation of phagocytosis by anti-amyloid antibodies risks biosynthetic exhaustion and self-limiting efficacy.
Key findings
- This program, not the DAM signature, marks phagocytically competent microglia; its loss is associated with proteostatic overload and mitochondrial dysfunction.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 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 times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| 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 | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 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 →
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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. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Lin, D., Atkinson, JR., Wu, W., Chen, M., Jayasekara, S., Segal, B. M., et al. (2026). A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer’s disease. bioRxiv. https://doi.org/10.64898/2026.09.16.752098
Vancouver
Lin D, Atkinson JR, Wu W, Chen M, Jayasekara S, Segal BM, et al. A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer’s disease. bioRxiv. 2026. doi:10.64898/2026.09.16.752098.
BibTeX
@article{lin2026-703e2eb0,
author = {Lin, D. and Atkinson, JR. and Wu, W. and Chen, M. and Jayasekara, S. and Segal, B. M. and Ma, A. and Gao, J.},
title = {{A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer’s disease}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.16.752098},
url = {https://doi.org/10.64898/2026.09.16.752098}
}