Identification of pathogenic SORL1 genetic variants in Alzheimer’s disease patients

Abstract

AbstractBackgroundAn estimated ∼2‐3% of early‐onset Alzheimer’s disease (AD) patients carry a predicted rare damaging variant in the SORL1 gene, which encodes the SORLA receptor protein. While protein‐truncating variants (loss‐of‐function, LOF) occur almost exclusively in AD patients, the large majority of damaging variants are missense variants. However, the effect of individual missense variants on AD risk varies widely, warranting a variant pathogenicity screen.MethodsWe prioritized genetic variants in SORL1 by investigating to what extent they lead to familial disease when they occur in protein homologs. We used a sample of 18,959 non‐related AD cases from the ADES/ADSP studies to investigate the age‐at‐onset in carriers of a prioritized SORL1 variant relative to WT SORL1 in context of APOE genotype. Second, since functional SORLA is cleaved at the neuronal membrane into soluble SORLA (sSORLA) we used Western Blot and proteomics to test whether SORL1 variants affected the level of sSORLA in CSF.ResultsCompared to SORL1 wild type AD patients, carriers of prioritized SORL1 variants had an expedited age at onset similar to carriers of LoF variants: of those homozygous for APOE‐ε4 who carried a prioritized SORL1 variant, 80% had AD by age 61 (95%CI 60‐NA, n = 6) compared to 73 for WT‐SORL1 carriers (95%CI 72‐73, n = 1091). Of those heterozygous for APOE‐ε4 who carried a prioritized SORL1 variant, 80% had AD by age 71 (95%CI 68‐76, n = 62) compared to age 78 WT‐SORL1 carriers (95%CI 78‐78, n = 4816). Of those negative for the APOE‐ε4 allele with a SORL1 variant, 80% had AD by 83 years (95%CI 78‐90, n = 54) compared to 85 years for WT‐SORL1 carriers (95%CI 85‐85, n = 5773). These effects were absent for non‐prioritized missense variants. Second, using WB we found that sSORLA levels in carriers of pathogenic missense variants were reduced to ∼50% relative to carriers of benign SORL1 variants, while levels of truncating SORL1 variants were reduced to ∼65%.DiscussionPrioritizing SORL1 missense variants according to variant‐effects in protein homologs leads to variants that expedite the age‐at‐onset independent of APOE background. Carriers of pathogenic missense or truncating variants have low CSF‐sSORLA levels, which may serve as a biomarker for impaired SORL1.