Age-Related Macular Degeneration-Associated Genes in Alzheimer Disease

Objectives: Given the clinical and pathological similarities between age-related macular degeneration (AMD) and Alzheimer disease (AD), to assess whether AMD-associated single nucleotide polymorphisms (SNPs), including those from complementrelated genes, are associated with AD. Design: A case-control association study-type design. Setting: A UK tertiary care dementia clinic. Participants: 322 cognitively normal participants and 258 cases with a clinical diagnosis of AD. Measurements: Polymorphisms in the following genes were studied: CFH, ARMS2, C2/CFB, C3, CFI/PLA2G12a, SERPING1, TLR3, TLR4, CRP, APOE, and TOMM40. Haplotypes were analysed for CFH, TOMM40, and APOE. Univariate analysis was performed for each genetic change and case-comparator status, and then correction for multiple testing performed. Results: The presence of an epsilon 4 APOE allele was significantly associated with AD. No association was evident between CFH SNPs or haplotypes, or other AMD-associated SNPs tested, and AD. The exceptions were TOMM40 SNPs, which were associated with AD even after correction for multiple comparisons. The associations disappeared, however, when entered into a regression model including APOE genotypes. Conclusions: The results for most SNPs tested, as well as CFH haplotypes, are novel. The functional effects of abnormal complement activity in AD's pathogenesis may be contradictory, but methodological reasons may underlie the lack of association-for example, genetic changes other than SNPs being involved.