. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.

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  1. The two new Alzheimer's GWAS reports from the NIA-ADGC (Naj et al., 2011) and European consortium (Hollingworth et al., 2011) provide further support for roles of the innate immune system, cholesterol metabolism, and protein trafficking in the etiology and pathogenesis of Alzheimer's disease (Bertram et al., 2010).

    With regard to innate immunity, CD33 is a particularly compelling AD candidate gene, both genetically and biologically. In 2008, we reported CD33 to show genomewide significant association with AD in a large family-based GWAS: genomewide significance for association in the NIMH family sample, and replication in two other large AD family samples from the NIA AD family collection. This study (Bertram et al., 2008), was part of the Cure Alzheimer's Fund Alzheimer's Genome Project. Thus, CD33 now exhibits genomewide significant association in both family-based and case-control GWAS study designs, albeit with different SNPs. The AD-associated SNP that we had reported in CD33 increases risk for AD (Bertram et al., 2008). However, the neighboring SNP in CD33 reported by the ADGC in the case-control study confers protection against AD (Naj et al., 2011).

    CD33 controls the initiation of the innate immune system. Thus, it will be important to determine whether the problem in AD is that CD33 does not sufficiently trigger innate immunity and, for example, microglial degradation of β amyloid. Or, perhaps, in AD, CD33 triggers innate immunity too robustly, leading to excessive inflammation and secondary neurodegeneration. In any event, the combined genetic findings from the new case-control GWAS (Naj et al., 2011, Hollingworth et al., 2011) and the previous family-based GWAS (Bertram et al., 2008) clearly warrant further study of the genetics and role of CD33 (and innate immunity) in AD.

    References:

    . Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011 May;43(5):436-41. Epub 2011 Apr 3 PubMed.

    . Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.

    . The genetics of Alzheimer disease: back to the future. Neuron. 2010 Oct 21;68(2):270-81. PubMed.

    . Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008 Nov;83(5):623-32. PubMed.

    View all comments by Rudy Tanzi

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