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.