Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize G_M2 ganglioside by β-hexos-aminidase A (Hex A) due to mutations of the α subunit (Tay-Sachs disease) or β subunit (Sandhoff disease) of Hex A. Hex B ( ββ homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hexa^-−/− (Tay-Sachs) mice remain asymptomatic to at least 1 year of age while Hexb^−/− (Sandhoff) mice succumb to a profound neurodegenerative disease by 4–6 months of age. Here we find that neuron death in Hexb^−/− mice is associated with apoptosis occurring throughout the CNS, while Hexa^−/−mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated G_M2 ganglioside or a derivative in triggering of the apoptotic cascade.