NF-ĸB, a major transcription factor controlling inflammation, is activated in Alzheimer’s disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-ĸB activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-ĸB and an amplification of the inflammatory process. Apolipoprotein E (ApoE) Ε4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-ĸB and enhanced brain inflammation. In a case-control study in 300 AD patients and 300 healthy controls, we examined whether the CARD8 (p.C10X) polymorphism, independently or in concert with the ApoE Ε4 allele, might predispose to AD. Women, but not men, carrying the CARD8 AA genotype (truncated protein) had a 2.39-fold higher risk of developing AD than subjects with the CARD8 TT genotype (full-length protein). This association with susceptibility to AD was independent of the ApoE Ε4 allele.