Deficiency of CARD8 Is Associated with Increased Alzheimer's Disease Risk in Women

NF-kappa B, a major transcription factor controlling inflammation, is activated in Alzheimer's disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-kappa B activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-kappa B and an amplification of the inflammatory process. Apolipoprotein E (ApoE) epsilon 4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-kappa B 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 epsilon 4 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 epsilon 4 allele. Copyright (C) 2008 S. Karger AG, Basel