Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease
Qureshi YH, Guo J, Rinald JH, Li Z, Soni RK, Govindarajan A, Tortora E, Uzunova G et al.. bioRxiv, 2026-10-30
Topic: Disease mechanisms in lab and animal studies
MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. An endosomal recycling pathway regulated by the interaction of SORL1 with retromer is pathogenically disrupted in AD. Here we test the hypothesis, that the pathway might drive the neurodegenerative process, via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling SORL1's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, when taken together with other findings the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.
Key findings
- MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b.
- Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients.
- Besides supporting the hypothesis, when taken together with other findings the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, 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 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| 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 | 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 | Laboratory or animal study (title names “mice”) — scores zero |
| 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 | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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APA 7th
Qureshi, Y. H., Guo, J., Rinald, J. H., Li, Z., Soni, R. K., Govindarajan, A., et al. (2026). Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease. bioRxiv. https://doi.org/10.64898/2026.10.26.761980
Vancouver
Qureshi YH, Guo J, Rinald JH, Li Z, Soni RK, Govindarajan A, et al. Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease. bioRxiv. 2026. doi:10.64898/2026.10.26.761980.
BibTeX
@article{qureshi2026-118c9caa,
author = {Qureshi, Y. H. and Guo, J. and Rinald, J. H. and Li, Z. and Soni, R. K. and Govindarajan, A. and Tortora, E. and Uzunova, G. and others},
title = {{Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.26.761980},
url = {https://doi.org/10.64898/2026.10.26.761980}
}