Neuronal loss is a hallmark of Alzheimer disease (AD), but the mechanisms through which the neurons die are unclear. Here, the authors described evidence for the activation of necroptosis — a programmed form of necrosis that has been implicated in multiple sclerosis and amyotrophic lateral sclerosis — both in the post-mortem human AD brain and in a mouse model of AD that features neuronal loss. Inhibiting necroptosis in neurons from AD mice in vitro or in vivo reduced neuronal death, suggesting that inhibition of necroptosis could be examined as a possible future therapeutic strategy for AD.