Alzheimer’s disease (AD) is an irreversible, progressive brain disorder caused by massive neuronal cell death in the frontal and temporal cortices and the hippocampus. AD is associated with the accumulation of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated MAPT (tau) (NFTs). However, how NFTs contribute to neuronal cell death remains unclear. Recent data from our lab has demonstrated that the histone demethylase KDM1A( LSD1) is mislocalized with NFTs in AD cases. In addition, loss of LSD1 systemically in adult mice is sufficient to recapitulate many aspects of AD. These data raise the possibility that neurofibrillary tangles contribute to neuronal cell death, in AD, by interfering with the continuous requirement for LSD1 to repress inappropriate transcription. Here we further test this model by removing one copy of Kdm1a from Tg(Prnp-MAPT*P301S)PS19Vle (P301S Tau) mice, which contain a human transgene overexpressing an aggregation-prone mutant of tau. Our preliminary results show these mice exhibit a much faster and more severe neurodegeneration phenotype. This suggests that aggregated tau functions genetically through the loss of LSD1. As a result, it may be possible to target this step therapeutically to block the progression of AD.