SORL1 and its involvement in Alzheimer's disease pathogenesis and pathophysiology - Genetics Core

Columbia University Health Sciences, New York NY

Investigators

Abstract

CORE B SUMMARY The overarching hypothesis of this PPG is that insights into SORL1-Retromer biology can be used to investigate pathogenicity of specific SORL1 variants. Genetic variants in SORL1 that are predicted risk- increasing or even causative for Alzheimer Disease (AD) are observed in ~2.75% of all unrelated early onset AD cases and 1.5% of unrelated late onset AD cases. In comparison, pathogenic variants in PSEN1, PSEN2 and APP combined explain <<1% of all AD cases. Truncating genetic variants in SORL1 are observed almost exclusively in AD cases. However, the large majority of SORL1 variants are missense variants, which have varying effects: some variants may be causative for AD, others associate with a strongly increased risk, yet others are associated with only moderately increased risk and many are benign. In medical genetics, estimating the penetrance of each variant is vital for the correct interpretation of genetic test results. However, the estimation of SORL1-variant penetrance using classical segregation analysis is complicated because pedigrees of variant carriers are unavailable or too small. Moreover, approaching members of affected families is difficult due to privacy regulations, and since SORL1 is not (yet) identified as an autosomal dominant AD gene, (unaffected) family members are not eligible for clinical counseling, which further impedes segregation analysis. Given the abundance of SORL1 variant carriers in AD patients, it is the goal of Core-B, to overcome this hurdle, and to propose implementation strategies for SORL1-variant screening and counseling into the clinic. For this, it is necessary that the field becomes acquainted with the pathogenicity of specific SORL1 variants such that patient- carriers and their (presymptomatic) family members can be identified and counseled appropriately. Previous evidence suggests that specific variants have diverse effects on AD risk, which may be explained by the nature of their impairing effects on SORL1 biochemical and cell-biological functions. We hypothesize that these effects are observable in readouts of CSF- or blood-based biomarkers and MRI/PET imaging from patient- carriers. To investigate this in the human context, Core B will generate the “SADIE cohort” the (SORL1- associated AD InitiativE) of SORL1 variant carriers. We will collect biospecimens, molecular read-outs imaging and phenotypic data from participants, which will be relayed throughout the consortium for comparison with in mouse models and cell lines, in order to gain mechanistic support for variant effects. Furthermore, we will use a large, existing sample of SORL1 variant-carriers to model variant-specific penetrance (SORL1-PEN). We will test the accuracy of the SORL1-PEN model by applying it to SADIE participants, and we will explore the added value of including patient-specific biomarker read-outs and AD-polygenic risk scores. Lastly, we will design strategies for clinical counseling of SORL1 variant-carriers, using the SORL1-PEN algorithm, taking into account its inherent uncertainties.