To address the unclear mechanism of neuronal loss and the lack of therapeutic targets in Alzheimer’s disease (AD), Western blot, real-time PCR, and immunohistochemistry were used to examine brain tissues from 32 AD patients and 20 controls. MTT assay, PI staining, Morris water maze, and Nissl staining were performed to investigate the effects of phosphorylated tau on HT22 cells and the intervention of Nec-1s in APP/PS1 mice. Results showed that mRNA levels of RIPK1, RIPK3, and MLKL in AD brains were increased by 2.86-, 2.43-, and 2.17-fold, respectively, and p-MLKL was positively correlated with CDR scores. 1.0 μmol/L phosphorylated tau reduced cell viability to 52.3%, while Nec‑1 increased viability by 56.0%. Nec‑1s shortened the escape latency by 28.5% and increased CA1 neurons by 42.6% in model mice. These findings suggest that RIPK1‑RIPK3‑MLKL axis‑mediated necroptosis is involved in AD pathogenesis, and targeting RIPK1 can alleviate pathological damage in AD.