Pathogenic SORL1 variants in Alzheimer’s disease (SORLA - FIX)
The SORLA protein is a neuronal sorting receptor encoded by the SORL1 gene. Functional SORLA keeps the levels of Amyloid-β in the brain in a healthy balance regulating APP processing into Amyloid-β, and by binding excess Amyloid-β to target it for lysosomal degradation. In the past two-three years it has become clear that heterozygous, damaging variants in the SORL1 gene are associated with and possibly causative for AD. Furthermore, the load of pathogenic and risk-increasing SORL1 variants in AD patients is large, which suggests that it is imperative to invest in the identification of those at risk to become affected with SORL1-associated AD, and the selective treatment of affected individuals. In this proposal we have created a collaboration of international investigators who are highly capable of answering the open questions regarding SORL1 variant pathogenicity and protein functions. Within this synergy of expertise, we will generate a working-pipeline to assess SORL1 variant pathogenicity, allowing the accurate diagnosis of patients with SORL1-associated AD and we will invest in the identification of selective SORL1-boosting or SORL1-fixing treatments applicable to individuals affected by compromised SORLA function.