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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

The SorLA protein, encoded by the Sortilin-related receptor 1 ( SORL1 ) gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional studies demonstrated that SorLA deficiency results in increased production of Aβ peptide, and thus a higher risk of AD. SorLA can be subject to proteolytic shedding at the cell surface, leading to the release of the soluble ectodomain of the protein (sSorLA) in the extracellular space. Recently, we demonstrated that a large proportion (~25%) of rare SORL1 missense variants found in AD patients alter SorLA trafficking along the constitutive secretory pathway, resulting in reduced delivery of SorLA to the plasma membrane and thus a loss of function. Here, we aimed to determine if CSF levels of sSORLA in AD patients carrying SORL1 rare variants that impact or not the trafficking of the protein can be used as a novel biomarker to explore disrupted trafficking of SorLA protein in AD. A total of 151 participants were categorized into 5 study groups: controls without any neurodegenerative disease ( n =30), patients suffering from Fronto-Temporal Lobar Degeneration (FTLD, n =34), AD patients not carrying a SORL1 rare variant (AD SORL1 WT , n =40), AD patients carrying SORL1 trafficking-defective variants or a protein-truncating variant (PTV) (AD SORL1 TD , n =16), and AD patients carrying a SORL1 variant with no evidence of trafficking defect (AD SORL1 nTD, n =31). Thirty-three unique rare variants of SORL1 were included for this study: 3 PTVs, 13 missense variants that impact SorLA protein trafficking in in vitro cellular assays, and 17 variants with no detectable effect on SorLA protein trafficking. We measured amounts of cleaved sSorLA by western blot in CSF samples. We found significantly decreased levels of sSorLA in AD SORL1 TD , compared to all other groups. According to ROC curve analysis, levels of sSorLA showed good performances to distinguish AD SORL1 TD patients from other AD patients (AUC=0.89 [95%CI: 0.81-0.97]). Our results suggest that differential levels of sSorLA in CSF could be used as a novel marker to explore disrupted trafficking of SorLA protein in Alzheimer disease. This could help solve some proportion of variants of uncertain significance in SORL1 .

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APA 7th

Castelot, R., Zaréa, A., Wallon, D., Rovelet‐Lecrux, A., Schramm, C., Quillard‐Muraine, M., et al. (2025). Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease. Alzheimer s Research & Therapy. https://doi.org/10.1186/s13195-025-01748-0

Vancouver

Castelot R, Zaréa A, Wallon D, Rovelet‐Lecrux A, Schramm C, Quillard‐Muraine M, et al. Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease. Alzheimer s Research & Therapy. 2025. doi:10.1186/s13195-025-01748-0. PMID: 40336092.

BibTeX

@article{castelot2025-40336092,
  author  = {Castelot, Romain and Zaréa, Aline and Wallon, David and Rovelet‐Lecrux, Anne and Schramm, Catherine and Quillard‐Muraine, Muriel and Beaume, Anne and Blanc, Frédéric and others},
  title   = {{Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease}},
  journal = {Alzheimer s Research \& Therapy},
  year    = {2025},
  doi     = {10.1186/s13195-025-01748-0},
  pmid    = {40336092},
  url     = {https://doi.org/10.1186/s13195-025-01748-0}
}

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Key findings

Functional studies demonstrated that SorLA deficiency results in increased production of Aβ peptide, and thus a higher risk of AD.
Recently, we demonstrated that a large proportion (~25%) of rare SORL1 missense variants found in AD patients alter SorLA trafficking along the constitutive secretory pathway, resulting in reduced delivery of SorLA to the plasma membrane and thus a loss of function.
We found significantly decreased levels of sSorLA in AD SORL1 TD , compared to all other groups.
Our results suggest that differential levels of sSorLA in CSF could be used as a novel marker to explore disrupted trafficking of SorLA protein in Alzheimer disease.

Why it matters

This study found significantly decreased levels of soluble SorLA in cerebrospinal fluid from Alzheimer's patients carrying SORL1 variants that disrupt protein trafficking, compared with other groups. This supports sSorLA as a potential biomarker for disrupted SorLA trafficking, but it is a biomarker study and does not test any treatment, cure or prevention.

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Study details

Participants30
Effect sizeAUC=0.89
Evidence strengthLow

How this study scored 45/100

Published in a peer-reviewed journal. Scored zero for study design 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	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	1 / 4	30 participants
Effect reported	3 / 3	Effect reported with a statistic (interval, p-value, ratio or similar)
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	1 / 7	Cited 2 times (OpenAlex, 2026-10-10)
Citations per year	0 / 5	0.7 citations a year over 3 year(s) since 2025
Impact for its field and year	2 / 6	Cited 1.1× 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 2 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	2 / 4	Last-listed author Magalie Lecourtois: h-index 24 (OpenAlex, whole career)
Institution's track record	3 / 3	Centre National de la Recherche Scientifique: institution h-index 2,511 (OpenAlex)
Multi-centre collaboration	3 / 3	OpenAlex lists 28 institution(s) in 1 country
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 40336092)
Free to read	2 / 2	Free to read
Total	45 / 100	—

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