Fine-mapping reveals four TMEM106B haplotypes associated with neurodegenerative risk and preserved cognition at extreme age
Salazar, A.; Tesi, N.; Knoop, L.; van Schoor, N. M.; Huisman, M.; Tijms, B.; Vijverberg, E. G. B.; van der Lee et al.. medRxiv (preprint), 2026-08-17
Topic: Brain proteins, microglia and lab models
Genetic variation at the TMEM106B locus has been associated with Alzheimers disease (AD) and related neurodegenerative phenotypes, yet its haplotypic architecture remains incompletely resolved. We refined the genetic landscape of TMEM106B by integrating AD-GWAS summary statistics ([~]978K individuals) with haplotype analyses in 5,873 Dutch genomes including AD-cases, age-matched controls, and cognitively healthy centenarians. In addition to the known linkage disequilibrium (LD) block defining risk and protective haplotypes characterized by the amino acid substitution at residue 185 (Threonine/Serine), we identify a second conditionally independent LD block. Together these form four haplotypes (T1-T4), with T3 strongly enriched in centenarians. Long-read whole-genome sequencing in 493 individuals reveals haplotype-linked structural variation and methylation patterns, including a [~]19 Kbp genomic rearrangement carried by T3. These findings indicate that the TMEM106B locus comprises multiple haplotypes defined by methylation patterns and structural variants, offering insights into GWAS associations with AD risk and preserved cognition at extreme age.
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APA 7th
Salazar, A., Tesi, N., Knoop, L., van Schoor, N. M., Huisman, M., Tijms, B., et al. (2026). Fine-mapping reveals four TMEM106B haplotypes associated with neurodegenerative risk and preserved cognition at extreme age. medRxiv (preprint). https://doi.org/10.1101/2025.02.02.25321330
Vancouver
Salazar A, Tesi N, Knoop L, van Schoor NM, Huisman M, Tijms B, et al. Fine-mapping reveals four TMEM106B haplotypes associated with neurodegenerative risk and preserved cognition at extreme age. medRxiv (preprint). 2026. doi:10.1101/2025.02.02.25321330.
BibTeX
@article{salazar2026-28f7dc41,
author = {Salazar, A. and Tesi, N. and Knoop, L. and van Schoor, N. M. and Huisman, M. and Tijms, B. and Vijverberg, E. G. B. and der Lee, van and others},
title = {{Fine-mapping reveals four TMEM106B haplotypes associated with neurodegenerative risk and preserved cognition at extreme age}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.1101/2025.02.02.25321330},
url = {https://doi.org/10.1101/2025.02.02.25321330}
}
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Key findings
- Genetic variation at the TMEM106B locus has been associated with Alzheimers disease (AD) and related neurodegenerative phenotypes, yet its haplotypic architecture remains incompletely resolved.
- These findings indicate that the TMEM106B locus comprises multiple haplotypes defined by methylation patterns and structural variants, offering insights into GWAS associations with AD risk and preserved cognition at extreme age.
Why it matters
Fine-mapping of the TMEM106B locus identified four haplotypes, one of which was strongly enriched in cognitively healthy centenarians. This describes genetic architecture linked to Alzheimer's risk and preserved cognition at extreme age, not a treatment or cure.
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Study details
- Participants493
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 29 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 27 of the 94 points we could judge it on, which is 29 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| 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 | 2 / 4 | 493 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| 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 | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Henne H. Holstege: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 15 institution(s) in 5 countries |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 27 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 27 of the 94 points we could judge it on is 29 out of 100. |
| Total | 29 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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