Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants
Matthijs W.J. de Waal (Amsterdam UMC, Vrije Universiteit Amsterdam)
Sven J. van der Lee (TU Delft - Pattern Recognition and Bioinformatics, Vrije Universiteit Amsterdam, Amsterdam UMC, Alzheimer Center Amsterdam)
Melanie Lunding (Aarhus University)
Lynn Boonkamp (Amsterdam UMC, Vrije Universiteit Amsterdam)
Nolan Barrett (Vrije Universiteit Amsterdam, Amsterdam UMC)
Jan Raska (St. Anne's Faculty Hospital, Masaryk University)
Niccolo Tesi (Amsterdam UMC, TU Delft - Pattern Recognition and Bioinformatics, Vrije Universiteit Amsterdam)
Marc Hulsman (Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics, Amsterdam UMC)
Henne Holstege (VIB, TU Delft - Intelligent Systems, Vrije Universiteit Amsterdam, Katholieke Universiteit Leuven, Amsterdam UMC, Alzheimer Center Amsterdam)
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Abstract
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.
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