Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice.

1. Alzheimers Dement. 2024 Apr;20(4):3080-3087. doi: 10.1002/alz.13730. Epub 2024 Feb 11. Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice. Benzow K(1), Karanjeet K(1), Oblak AL(2), Carter GW(3), Sasner M(3), Koob MD(1). Author information: (1)Laboratory Medicine and Pathology, and Institute for Translational Neuroscience University of Minnesota, Minneapolis, Minnesota, USA. (2)Indiana University School of Medicine, Indianapolis, Indiana, USA. (3)The Jackson Laboratory, Bar Harbor, Maine, USA. INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible. METHODS: To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs. RESULTS: Each model set consists of a control line with a wild-type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation or risk variant. © 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. DOI: 10.1002/alz.13730 PMCID: PMC11032548 PMID: 38343132 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no conflicts of interest. Author disclosures are available in the supporting information.