Resource: Guideline to select a mouse genetic background to study Tau. (A) Signatures A–C of this study represent a core response to expressing AAV-hTauP301L (Signature A), wild-derived specific response to AAV-hTauP301L expression (Signature B), and a tau seeding–associated module (Signature C). (B) Given a gene of interest, the resources in this paper can guide genetic background selection for functional studies in mice. For example, Trem2, a gene with strong evidence for a role in tau pathology, is present in Signature A (core Tau response) and Signature C (Tau seed response). Based on this evidence, while Trem2 is differentially expressed in response to tau across all mouse strains, there is a possibility that it is involved in a CAST- or PWK-specific reaction to tau seeds.