In tauopathies such as Alzheimer disease, accumulation of hyperphosphorylated tau (p-tau) can appear decades before neurodegeneration occurs, suggesting that other factors might be involved in the shift from a latent to an active disease state. One contender is glucose hypometabolism, which is frequently observed in individuals with mild cognitive impairment (MCI) who later progress to dementia. How the mechanisms triggered by glucose hypometabolism might intersect with those associated with p-tau accumulation and lead to neurodegeneration is unknown. Now, Chen et al. show that these two pathological features of Alzheimer disease combine to drive necroptosis, thereby leading to neuronal loss.

Necroptosis is a type of programmed cell death that results in membrane rupture and activation of inflammatory pathways. It depends on the formation of a protein signalling complex containing the kinase RIPK1 and is kept in check by the ubiquitin-editing enzyme A20.