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45/100

✓ Peer-reviewed alzhub usefulness score 45 out of 100. Risk genes beyond APOE

Topic: Brain proteins, microglia and lab models

Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged TREM2 knockout human induced pluripotent stem cell–derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.

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APA 7th

Albanus, R. D., Finan, G. M., Brase, L., Sweeney, N., Kim, T. Y., Chen, S., et al. (2025). Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.adx0027

Vancouver

Albanus RD, Finan GM, Brase L, Sweeney N, Kim TY, Chen S, et al. Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease. Science Translational Medicine. 2025. doi:10.1126/scitranslmed.adx0027. PMID: 40737431.

BibTeX

@article{albanus2025-40737431,
  author  = {Albanus, Ricardo D’Oliveira and Finan, Gina M. and Brase, Logan and Sweeney, Nicholas and Kim, Tae Yeon and Chen, Shuo and Ryoo, Yeonsu and others},
  title   = {{Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease}},
  journal = {Science Translational Medicine},
  year    = {2025},
  doi     = {10.1126/scitranslmed.adx0027},
  pmid    = {40737431},
  url     = {https://doi.org/10.1126/scitranslmed.adx0027}
}

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Key findings

Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells.
Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia.
In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques.
These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance.

Why it matters

This laboratory study using human brain tissue and cells found that a gene network involving SEMA6D and TREM2 is active near amyloid plaques and appears disrupted in later Alzheimer's stages. The findings suggest that loss of SEMA6D signaling may impair microglial activation and Aβ clearance, but this is early mechanistic work and no treatment was tested in patients.

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Study details

Evidence strengthLow

How this study scored 45/100

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. We have no data on senior author's track record, so that was left out: it earned 43 of the 96 points we could judge it on, which is 45 out of 100.

Component	Points	Why
Journal tier	7 / 10	Tier 3 — peer-reviewed journal (Science Translational Medicine)
Journal's citation record	3 / 4	Science Translational Medicine: journal h-index 365 (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)
Randomised / blinded	0 / 2	No randomisation or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	2 / 7	Cited 12 times (OpenAlex, 2026-10-10)
Citations per year	2 / 5	4.0 citations a year over 3 year(s) since 2025
Impact for its field and year	3 / 6	Cited 3.6× 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 12 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	— / 4	OpenAlex's profile for last-listed author Tae-Wan Kim holds only 6 work(s), too few to judge a track record — left out of this score
Institution's track record	3 / 3	Harvard University: institution h-index 3,235 (OpenAlex)
Multi-centre collaboration	3 / 3	OpenAlex lists 13 institution(s) in 3 countries
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 40737431)
Free to read	2 / 2	Free to read
Points	43 / 96	Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 43 of the 96 points we could judge it on is 45 out of 100.
Total	45 / 100	—

What each of these 20 components measures, and what this score is not →

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