The potential effects of alternative splicing of death-domain expressing genes and neuronal death have not been determined in Alzheimer's disease (AD). We analyzed DENN/MADD/IG20 (DMI), the complex of four splice variants. IG20 is known to be involved in cell death and the DENN/MADD splice variant (DM-SV) in cell survival in non-neural systems. DENN/MADD (DM) and DENN/MADD splice variant 2 were also included. Using SH-SY5Y human neuroblastoma cultures exposed to high concentrations of oligomeric Aβ peptides (oAβ) as a model for neuronal death, there was initially an increased ratio of DM-SV to IG20 (DM-SV/IG20) and knockdown of DMI SVs including DM-SV with antisense DNA then increased cell death. Cultures transfected with small interfering RNAs (siRNAs) specific to subsets of DMI SVs but sparing DM-SV increased the DM-SV/IG20 ratio resulting in a reduction of cell death in the presence of oAβ. Effects on cell survival of DM and DM SV2, the other two SVs expressed in the CNS, are less clear. Compared to normal controls, alternative splicing changes in the CNS of AD patients during disease progression resulted in altered ratios of all of the SVs in a pattern over an extended time that mirrored that of the cultures, and coincided with the accumulation of endogenous, dimeric Aβ (dAβ). Thus, DM-SV may be required for neuronal survival by protecting against oAβ neurotoxicity, and IG20 may contribute to selective neuronal vulnerability in AD.