Examining the impact of a rare protein‐truncating SORL1 variant on AD pathology

Recent analyses of rare variants using whole exome sequencing have found an enrichment of SORL1 loss‐of‐function (LoF) variants in early onset Alzheimer’s disease (EOAD). This makes SORL1 one of the highest risk factors for AD, along with other candidate EOAD genes such as APP, PS1, and PS2. SORL1 encodes an endocytic receptor involved in the trafficking of amyloid‐β precursor protein (APP) and the secretion of amyloid‐β. We identified a family with multiple individuals affected with EOAD carrying a single base pair deletion (c.4293del) in SORL1, resulting in a frameshift and premature termination of the protein (p.Cys1431fs; Kunkle et al. JAMA Neurol. 2017). Several recent studies have demonstrated that haploinsufficiency of SORL1 can induce AD‐related phenotypes in cultured neurons. However, the functional consequences of specific variants remain largely undefined. In this study, we used patient‐specific induced pluripotent stem cell (iPSC)‐derived neurons to evaluate the effect of a rare LoF SORL1 variant on AD‐related pathology.