Existing models of frontotemporal dementia (FTD) may not fully recapitulate the pathophysiology of the disease. To generate more pathophysiologically relevant FTD models, we engineered MAPT knockin mouse lines carrying triple mutations, among which the MAPT(P301S;Int10+3;S320F) line exhibited robust tau pathology starting before 6 months of age. Severe tau accumulation was predominantly observed in the thalamus, hypothalamus, and amygdala with milder involvement of the cortex and hippocampus, leading to synaptic loss, brain atrophy, and FTD-like behavioral abnormalities. Crossbreeding MAPT(P301S;Int10+3;S320F) mice with App knockin, App(NL-G-F), mice markedly enhanced tau pathology in the cortex and hippocampus, highlighting the interplay between β-amyloid and tau. These findings establish the mutant mice as valuable models for investigating the mechanisms underlying FTD and other tauopathies, providing a relevant platform for in vivo drug screening.