Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience
Ashley Lu, Wei-Ting Chen, Maria Dalby, Diego Sainz Garcia, Marisa Vanheusden, Luuk E de Vries, Veerle van Lieshout, Araks Martirosyan et al.. Nature medicine, 2026-06-04
Topic: Inflammation, microglia and astrocytes
Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.
Key findings
- Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.
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Study details
- Evidence strengthLow
How this study scored 50/100
Published in a top-tier 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 journal's citation record, 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, multi-centre collaboration and free to read, so those were left out: it earned 28 of the 56 points we could judge it on, which is 50 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature medicine) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 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 | 2 / 2 | Indexed in PubMed (PMID 42243549) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 28 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 28 of the 56 points we could judge it on is 50 out of 100. |
| Total | 50 / 100 | — |
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APA 7th
Lu, A., Chen, W.-T., Dalby, M., Garcia, D. S., Vanheusden, M., de Vries, L. E., et al. (2026). Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience. Nature medicine. https://doi.org/10.1038/s41591-026-04393-8
Vancouver
Lu A, Chen W.-T, Dalby M, Garcia DS, Vanheusden M, de Vries LE, et al. Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience. Nature medicine. 2026. doi:10.1038/s41591-026-04393-8. PMID: 42243549.
BibTeX
@article{lu2026-42243549,
author = {Lu, Ashley and Chen, Wei-Ting and Dalby, Maria and Garcia, Diego Sainz and Vanheusden, Marisa and de Vries, Luuk E and van Lieshout, Veerle and Martirosyan, Araks and others},
title = {{Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience}},
journal = {Nature medicine},
year = {2026},
doi = {10.1038/s41591-026-04393-8},
pmid = {42243549},
url = {https://doi.org/10.1038/s41591-026-04393-8}
}
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