In vivo evidence that SORL1, encoding the endosomal recycling receptor SORLA, can function as a causal gene in Alzheimer’s Disease

The few established causal genes in Alzheimer’s disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. SORL1 , a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Göttingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in Aβ and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease. ### Competing Interest Statement LB and MD are employees of AbbVie and own AbbVie stock. AbbVie participated in the design, study conduct, and financial support for this research as well as in the interpretation of data, review, and approval of the publication. Ellegaard Goettingen Minipigs A/S is having the commercialization rights to the genetically altered Goettingen Minipigs SORL1 KO model. OMA and SAS has commercial interests in Retromer Therapeutics, but this company was not involved in any aspects of the current study.