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Connecting HTT intermediate alleles and microRNA dysregulation to enhanced tauopathy in late-onset Alzheimer’s disease
Juan Castilla‐Silgado, Sergio Pérez‐Oliveira, Paola Pinto-Hernández, Manuel Fernández‐Sanjurjo, María Daniela Corte-Torres, Olaya Fernandez-Alvarez, Eduardo Iglesias‐Gutiérrez, Manuel Menéndez‐González et al.. Alzheimer s Research & Therapy, 2026-04-20
Topic: Brain proteins, microglia and lab models
HTT IAs carriers patients exhibited decreased survival after disease onset compared to non-carriers. Histopathologically, while LOAD patients showed increased soluble HTT levels and altered tau pathology compared to controls, these changes were consistently and markedly exacerbated in HTT IA carriers. This phenotype was characterized by heightened diffuse HTT immunoreactivity and an advanced maturation of tau pathology, specifically a pronounced increase in neuronal tau 3R burden and 3R tau-enriched ghost tangles. Interestingly, this pathological state was associated with alterations in key splicing factors, including decreased SRSF6 levels and increased nuclear FUS-SFPQ complex assembly. Analysis of microRNA (miRNA) profiling in the caudate nucleus revealed that the LOAD-associated miRNA dysregulation was significantly amplified in HTT IA carriers, identifying a signature of five miRNAs (miR-100-5p, miR-218-5p, miR-27b-3p, miR-487-3p, and miR-9-3p). In silico modeling based on high-confidence sequence homology demonstrated that these miRNAs are predicted to target components of the nuclear spliceosome machinery, such as SRSF family, along with MAPT and HTT genes, suggesting a direct link to the observed tauopathy. Our findings underscore that HTT IAs as critical modifiers in LOAD progression through an miRNA-mediated dysregulation of splicing and proteostasis. Thus, identifying HTT IAs through routine blood genetic screening offers a practical, non-invasive biomarker for patient stratification, taking a step forward to personalized therapeutic strategies in LOAD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Castilla‐Silgado, J., Pérez‐Oliveira, S., Pinto-Hernández, P., Fernández‐Sanjurjo, M., Corte-Torres, M. D., Fernandez-Alvarez, O., et al. (2026). Connecting HTT intermediate alleles and microRNA dysregulation to enhanced tauopathy in late-onset Alzheimer’s disease. Alzheimer s Research & Therapy. https://doi.org/10.1186/s13195-026-02039-y
Vancouver
Castilla‐Silgado J, Pérez‐Oliveira S, Pinto-Hernández P, Fernández‐Sanjurjo M, Corte-Torres MD, Fernandez-Alvarez O, et al. Connecting HTT intermediate alleles and microRNA dysregulation to enhanced tauopathy in late-onset Alzheimer’s disease. Alzheimer s Research & Therapy. 2026. doi:10.1186/s13195-026-02039-y. PMID: 42010634.
BibTeX
@article{castillasilgado2026-42010634,
author = {Castilla‐Silgado, Juan and Pérez‐Oliveira, Sergio and Pinto-Hernández, Paola and Fernández‐Sanjurjo, Manuel and Corte-Torres, María Daniela and Fernandez-Alvarez, Olaya and Iglesias‐Gutiérrez, Eduardo and Menéndez‐González, Manuel and others},
title = {{Connecting HTT intermediate alleles and microRNA dysregulation to enhanced tauopathy in late-onset Alzheimer’s disease}},
journal = {Alzheimer s Research \& Therapy},
year = {2026},
doi = {10.1186/s13195-026-02039-y},
pmid = {42010634},
url = {https://doi.org/10.1186/s13195-026-02039-y}
}
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- HTT IAs carriers patients exhibited decreased survival after disease onset compared to non-carriers.
- Histopathologically, while LOAD patients showed increased soluble HTT levels and altered tau pathology compared to controls, these changes were consistently and markedly exacerbated in HTT IA carriers.
- This phenotype was characterized by heightened diffuse HTT immunoreactivity and an advanced maturation of tau pathology, specifically a pronounced increase in neuronal tau 3R burden and 3R tau-enriched ghost tangles.
- Interestingly, this pathological state was associated with alterations in key splicing factors, including decreased SRSF6 levels and increased nuclear FUS-SFPQ complex assembly.
- Analysis of microRNA (miRNA) profiling in the caudate nucleus revealed that the LOAD-associated miRNA dysregulation was significantly amplified in HTT IA carriers, identifying a signature of five miRNAs (miR-100-5p, miR-218-5p, miR-27b-3p, miR-487-3p, and miR-9-3p).
Why it matters
In people with late-onset Alzheimer's disease, carriers of intermediate HTT alleles had decreased survival after disease onset and more severe tau pathology and microRNA dysregulation than non-carriers. This is observational human tissue research that identifies a possible modifier of disease progression but does not test a treatment.
Study details
- Evidence strengthModerate
How this study scored 34/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s Research & Therapy) |
| Journal's citation record | 1 / 4 | Alzheimer s Research & Therapy: journal h-index 146 (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 | 3 / 5 | Rated “moderate” 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 | 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 | 0 / 6 | Cited 0.0× 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 | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Cristina Tomás‐Zapico: h-index 28 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Universidad de Oviedo: institution h-index 510 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42010634) |
| Free to read | 2 / 2 | Free to read |
| Total | 34 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s13195-026-02039-y
- PubMed: 42010634
- Original source →
- Free full text: Alzheimer s Research & Therapy →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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