Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.
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de Waal Matthijs W J, van der Lee Sven J, Lunding Melanie, Boonkamp Lynn, Barrett Nolan, Monti Giulia, Jensen Anne Mette G, Vaegter Christian B, Raska Jan, Cesnarikova Sona, Sedmik Jiri, Trieu Calvin, Weiss Marjan M, van Spaendonk Rosalina, Vermunt Lisa, Ozhegov Georgii, Tesi Niccolo, Hulsman Marc, Januliene Dovile, Moller Arne, Bohaciakova Dasa, van der Flier Wiesje M, Andersen Olav M, Teunissen Charlotte E, Holstege Henne
Аннотация
INTRODUCTION: The sortilin-related receptor (SORL1) directs APP and Aβ trafficking within the retromer pathway. Cleavage at the cell surface releases soluble SORL1 (sSORL1) into cerebrospinal fluid (CSF). We examined whether CSF-sSORL1 can serve as an in vivo marker of genetically impaired SORL1.
METHODS: CSF-sSORL1 was quantified by enzyme-linked immunosorbent assay (ELISA) in 218 participants: 90 carriers of SORL1 variants, 78 SORL1-wildtype (WT) AD patients, and 50 SORL1-WT controls.
RESULTS: sSORL1 concentrations were significantly lower in carriers of protein-truncating and damaging missense variants. In SORL1-WT patients, CSF-sSORL1 correlated with pTau181 but not with Aβ42 among AD patients, and did not differ between patients and controls.
DISCUSSION: These findings suggest that impaired SORL1 trafficking reduces receptor delivery to the cell surface and thereby decreases sSORL1 shedding, supporting its potential use as a pathway-specific biomarker.
HIGHLIGHTS: Enzyme-linked immunosorbent assay (ELISA) enables quantitative measurement of soluble sortilin-related receptor (sSORL1) in cerebrospinal fluid (CSF). sSORL1 levels are reduced in CSF from carriers of a pathogenic SORL1 variant. CSF-sSORL1 levels correlate with tau pathology in Alzheimer's disease. sSORL1 levels represent an in vivo biomarker of SORL1 function.
METHODS: CSF-sSORL1 was quantified by enzyme-linked immunosorbent assay (ELISA) in 218 participants: 90 carriers of SORL1 variants, 78 SORL1-wildtype (WT) AD patients, and 50 SORL1-WT controls.
RESULTS: sSORL1 concentrations were significantly lower in carriers of protein-truncating and damaging missense variants. In SORL1-WT patients, CSF-sSORL1 correlated with pTau181 but not with Aβ42 among AD patients, and did not differ between patients and controls.
DISCUSSION: These findings suggest that impaired SORL1 trafficking reduces receptor delivery to the cell surface and thereby decreases sSORL1 shedding, supporting its potential use as a pathway-specific biomarker.
HIGHLIGHTS: Enzyme-linked immunosorbent assay (ELISA) enables quantitative measurement of soluble sortilin-related receptor (sSORL1) in cerebrospinal fluid (CSF). sSORL1 levels are reduced in CSF from carriers of a pathogenic SORL1 variant. CSF-sSORL1 levels correlate with tau pathology in Alzheimer's disease. sSORL1 levels represent an in vivo biomarker of SORL1 function.