These findings reveal that increasing tau can serve as an upstream factor to activate C/EBPβ‐TRPC1‐SOCE‐ER‐kinase/phosphatase axis, leading to a persistent and aggravated tau hyperphosphorylation and eventually neurodegeneration, while targeting TRPC1 or C/EBPβ could be promising to arrest the aggravating tauopathies during AD progression. The gene discussed is MAPT; the disease is Alzheimer disease.