Neuron-specific isoforms of Endophilin-B1, also known as Bax-interacting factor-1 (Bif-1), are neuroprotective. Wang et al. reveal reduced expression of these variants in Alzheimer’s disease, and propose the existence of a feed-forward mechanism whereby beta-amyloid suppresses neuron-specific Bif-1, which in turn enhances beta-amyloid accumulation and neuronal vulnerability to stress.