Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.

de Waal, M. W. J.; van der Lee, S. J.; Lunding, M.; Boonkamp, L.; Barrett, N.; Monti, G.; Jensen, A. M. G.; Vaegter, C. B.; Raska, J.; Cesnarikova, S.; Sedmik, J.; Trieu, C.; Weiss, M. M.; van Spaendonk, R.; Vermunt, L.; Ozhegov, G.; Tesi, N.; Hulsman, M.; Januliene, D.; Möller, A.; Bohaciakova, D.; van der Flier, W. M.; Andersen, O. M.; Teunissen, C.; Holstege, H.

doi:10.1101/2025.08.05.668459

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bioRxiv · 10.1101/2025.08.05.668459

Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.

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Abstract

BackgroundAs part of the retromer, sortilin-related receptor (SORL1) sorts cargo proteins away from the endosome to the trans-Golgi network or to the cell surface, where SORL1 is cleaved into sSORL1 and shed into the interstitial fluid and CSF. SORL1s cargo includes APP and A{beta}, which may explain why protein-truncating genetic variants (PTVs) in SORL1 are observed almost exclusively in Alzheimers Disease (AD) patients, and that rare, predicted pathogenic missense variants have been associated with a 10-fold increased risk of AD. However, functional evidence supporting variant pathogenicity is warranted. Here we investigated whether soluble SORL1 (sSORL1) concentrations in cerebrospinal fluid (CSF) offer a potential in vivo biomarker to support impaired SORL1 function in variant carriers. MethodsUsing an ELISA assay for SORL1 (ABCAM), we determined sSORL1 concentrations in CSF from 218 participants of the Alzheimer Dementia Cohort (ADC) (54% females). We compared sSORL1 in CSF derived from 90 carriers of diverse SORL1 variants with concentrations observed in 78 SORL1-WT AD patients, and 50 SORL1-WT controls for whom CSF-pTau-181, CSF-tTau, CSF-A{beta}42 concentrations were available. In a subset of 36 individuals, we used Western blotting (WB) to validate sSORL1 concentrations as determined by ELISA. ResultsCSF-sSORL1 concentrations did not differ between SORL1-WT AD patients and controls. While CSF-sSORL1 did not correlate with CSF-A{beta}42 concentrations in SORL1-WT AD patients (p=0.62), it correlated with sCSF-ptau-181 (p=9.7x10-6). The mean CSF-sSORL1 concentration in the SORL1 WT AD cases and controls was 466 pg/ml, with wide variance (SD = 133). Comparatively, concentrations were significantly lower in PTV carriers (260 pg/ml, p=3.2x10-7) and in carriers of predicted damaging SORL1 missense variants (323 pg/ml, p=2.4x10-7). CSF-sSORL1 concentrations measured by ELISA correlated strongly with concentrations estimated by WB ({rho}=0.552; p=5.0x10-4). ConclusionCSF-sSORL1 increases with CSF-ptau, suggesting that increased SORL1-retromer activity may serve to rescue cellular stress associated with AD-related processes. However, impairing SORL1 genetic variants may preclude SORL1 trafficking to the cell surface, as supported by lower CSF-sSORL1 protein concentrations in carriers. While further refinements are necessary, we present first evidence for the applicability of ELISA-based quantification of sSORL1 in CSF to evaluate the functional impact of rare SORL1 variants.

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de Waal, M. W. J., van der Lee, S. J., Lunding, M., Boonkamp, L., Barrett, N., Monti, G., Jensen, A. M. G., Vaegter, C. B., Raska, J., Cesnarikova, S., Sedmik, J., Trieu, C., Weiss, M. M., van Spaendonk, R., Vermunt, L., Ozhegov, G., Tesi, N., Hulsman, M., Januliene, D., Möller, A., Bohaciakova, D., van der Flier, W. M., Andersen, O. M., Teunissen, C., Holstege, H.. 2025-08-07. Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.. https://doi.org/10.1101/2025.08.05.668459

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