The Alzheimer disease-associated β-amyloid peptide has been shown to induce apoptotic neuronal death. In the present study, we test the hypothesis that the apoptotic pathway activated by β-amyloid is similar to the pathway activated by the Fas/TNFR family of death receptors, which requires caspase-8 activity and adaptor proteins such as FADD. We demonstrate that the selective caspase-8 inhibitor IETD-fmk blocks neuronal death induced by β-amyloid. Furthermore, using viral-mediated gene delivery, we show that neurons expressing dominant-negative FADD are protected from apoptosis induced by β-amyloid. Together these results indicate that the apoptotic pathway activated by β-amyloid requires both caspase-8 activity and FADD. These findings further support the hypothesis that β-amyloid might initiate apoptosis by cross-linking death receptors of the Fas/TNFR family.