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APOEε4 attenuates early TREM2-mediated microglial responses and influences disease trajectories in dementia with Lewy bodies
Rodríguez EM, Zaragoza-Ballester P, Alcolea D, Esteller-Gauxax D, Nuscher B, Chacón S, Fernández-León Á, Rodríguez-Baz Í et al.. Research Square, 2026-07-31
Topic: Inflammation, microglia and astrocytes
Dementia with Lewy bodies (DLB) is characterized by marked biological heterogeneity, only partly explained by the frequent presence of Alzheimer’s disease (AD) copathology. Whether microglial responses contribute to this heterogeneity and how they are modulated by APOE genotype remain poorly understood. Using a specific immunoassay targeting cleaved soluble TREM2 (sTREM2), we investigated TREM2-dependent microglial responses across two independent DLB cohorts (n = 129) with molecular biomarker profiling and longitudinal follow-up. sTREM2 showed stage-dependent associations with AD-related biomarkers, being associated with amyloid-related changes during prodromal DLB and predominantly to tau-related markers at dementia stage. APOEε4 carriers exhibited approximately two-fold lower sTREM2 levels than non-carriers specifically during prodromal DLB, independently of AD copathology, with more pronounced effects observed in women. Longitudinal analyses showed that higher baseline sTREM2 levels during prodromal DLB were associated with slower cognitive decline independently of AD-related biomarkers. These findings suggest that APOEε4 attenuates early TREM2-mediated microglial responses in DLB through mechanisms beyond AD copathology. Together, our results identify the APOE–TREM2 axis as a potential contributor to disease heterogeneity and support stage-specific, biomarker-guided therapeutic strategies targeting TREM2 signaling in Lewy body disorders.
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APA 7th
Rodríguez, E. M., Zaragoza-Ballester, P., Alcolea, D., Esteller-Gauxax, D., Nuscher, B., Chacón, S., et al. (2026). APOEε4 attenuates early TREM2-mediated microglial responses and influences disease trajectories in dementia with Lewy bodies. Research Square. https://doi.org/10.21203/rs.3.rs-10429506/v1
Vancouver
Rodríguez EM, Zaragoza-Ballester P, Alcolea D, Esteller-Gauxax D, Nuscher B, Chacón S, et al. APOEε4 attenuates early TREM2-mediated microglial responses and influences disease trajectories in dementia with Lewy bodies. Research Square. 2026. doi:10.21203/rs.3.rs-10429506/v1.
BibTeX
@article{rodriguez2026-ef1dd141,
author = {Rodríguez, E. M. and Zaragoza-Ballester, P. and Alcolea, D. and Esteller-Gauxax, D. and Nuscher, B. and Chacón, S. and Á, Fernández-León and Í, Rodríguez-Baz and others},
title = {{APOEε4 attenuates early TREM2-mediated microglial responses and influences disease trajectories in dementia with Lewy bodies}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10429506/v1},
url = {https://doi.org/10.21203/rs.3.rs-10429506/v1}
}
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Key findings
- Using a specific immunoassay targeting cleaved soluble TREM2 (sTREM2), we investigated TREM2-dependent microglial responses across two independent DLB cohorts (n = 129) with molecular biomarker profiling and longitudinal follow-up. sTREM2 showed stage-dependent associations with AD-related biomarkers, being associated with amyloid-related changes during prodromal DLB and predominantly to tau-related markers at dementia stage.
- Longitudinal analyses showed that higher baseline sTREM2 levels during prodromal DLB were associated with slower cognitive decline independently of AD-related biomarkers.
- These findings suggest that APOEε4 attenuates early TREM2-mediated microglial responses in DLB through mechanisms beyond AD copathology.
- Together, our results identify the APOE–TREM2 axis as a potential contributor to disease heterogeneity and support stage-specific, biomarker-guided therapeutic strategies targeting TREM2 signaling in Lewy body disorders.
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Study details
- Study designlongitudinal study
- Participants129
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 44 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for effect reported 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 27 of the 62 points we could judge it on, which is 44 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 | 2 / 4 | 129 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 | — / 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 | 27 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 27 of the 62 points we could judge it on is 44 out of 100. |
| Total | 44 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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