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.

Background
Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear.

Methods
To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls.

Results
In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects.

Conclusion
Our results justify a debate on whether HPV carriers should be considered for clinical counseling.