AUTHOR'S REPLY

Abstract

<h3>ABSTRACT</h3> The few established causal genes in Alzheimer’s disease (AD), mutations in <i>APP</i> and <i>PSENs,</i> have been functionally characterized using biomarkers, capturing an <i>in vivo</i> profile reflecting the disease’s initial preclinical phase. <i>SORL1</i>, 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 <i>SORL1</i> can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of <i>SORL1</i> haploinsufficiency in Göttingen Minipigs taking advantage of porcine models for biomarker investigations. <i>SORL1</i> haploinsufficiency in young minipigs was found to phenocopy the preclinical <i>in vivo</i> 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 <i>SORL1</i> 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.