Tau reporter compositions, tau reporter cells, and tau reporter animals are provided that comprise a four-repeat (4R) tau isoform linked to a first reporter protein and a three-repeat (3R) tau isoform linked to a second reporter protein that is different from the first reporter protein. Methods are provided for making such tau reporter cells and tau reporter animals and for using such tau reporter cells and tau reporter animals for assessing the activity of tau-targeting reagents.