Genetic studies conducted over the past four decades have provided investigators 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, they have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Dr. Koob's group is playing a central role in the NIH efforts to directly address this problem by developing the first sets of AD/ADRD mouse lines that model the genetics of AD as closely as possible. To do this, Koob devised Gene Replacement (GR) technologies that allow investigators for the first time to generate mouse lines in which genes-of-interest are precisely and completely replaced by their human orthologs. Each set of models Koob's laboratory makes consists of a control line with a wt human allele, and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation that are specifically introduced.