Project: Identifying and treating SORL1-associated Alzheimer’s disease

Acronym SORLA-FIX (Reference Number: JPND2019-466-197)
Project Topic In the past two-three years it has become clear that alterations in the genetic sequence of the SORL1 gene are associated with and possibly causative for Alzheimer’s Disease (AD). We have previously shown that as many as 2% of all AD patients carry a pathogenic or a strong risk-increasing variant in the SORL1 gene, while an even larger fraction of AD patients carries a SORL1 variant with an uncertain effect on AD risk. Compromised SORLA function increases Amyloid-ß levels, which likely explains the robust association of damaging SORL1 variants with Alzheimer’s disease. However, it is currently unclear which SORL1 variants are causative for disease, which variants are risk-increasing, and which variants are benign. The strong association of pathogenic SORL1 genetic variants with AD calls for a robust variant pathogenicity screen, enabling the accurate diagnosis of patients with SORL1-associated AD. Furthermore, the abundance of AD-patients with SORL1 genetic variants makes a promising case for the design of a selective treatment of affected individuals. Therefore, we, four young international investigators, all experts in our fields, will join forces to (1) generate a working-pipeline to evaluate SORL1 variant pathogenicity, and (2) to identify small molecules that selectively enhance SORLA activity, applicable to individuals who are genetically predisposed to compromised to SORL1-associated AD. Together, we anticipate that our research will unravel the effect of individual SORL1 variants on AD risk, allowing the clinical diagnosis of SORL1-associated AD patients. We further anticipate that our aim to restore SORLA function in SORL1-variant carriers will be an essential first step towards developing precision medication for SORL1-associated AD-patients and to prevent the development of AD for their (presymptomatic) family members who carry the same SORL1 variant. ***Please note that SORLA is the protein product encoded by the SORL1 gene.***

Project partner

Number Name Role Country
1 Stichting VUmc (VU University Medical Center) Coordinator Netherlands
2 Aarhus University Partner Denmark
3 Masaryk University Brno Partner Czech Republic
4 Max-Planck-Institute für Biophysik Partner Germany
5 Institute of Experimental Medicine Partner Hungary