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Using a Genetic Approach to Understand the Vascular Basis of Alzheimer Disease

By Lindsey Farrer

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Background: There is a growing body of evidence from pathological and epidemiological studies that risk factors for vascular disease also enhance risk of AD. Objectives: To evaluate the association between genes involved in vascular function and susceptibility to AD in Caucasian and African American families in the MIRAGE Study and in Wadi Ara, an inbred Israeli-Arab community with a high prevalence of AD. Methods: In the Wadi Ara sample, we profiled a subset of more than 90 AD cases and 160 elderly non-demented controls for the well-studied insertion/deletion polymorphism of the ACE gene as well as 17 ACE SNPs including 13 within the coding region, 2 within the promoter region, and two in the flanking regions whose sequence, location, and polymorphism information were obtained from the NCBI data base. Results: Significant associations were found with two intronic ACE SNPs which are less than 5 kb apart. The rs4343 G allele was present on 42% of AD subject chromosomes but on less than 18% of normal subject chromosomes (p = 0.000017). The rs4353 A allele was present on 62% of AD subject chromosomes but on 42% of normal subject chromosomes (p = 0.007). The distribution of rs4343/rs4353 haplotypes was significantly different between cases and controls (p = 0.0003). Sequencing the 10 kb region including rs4343 and rs4353 did not reveal additional polymorphic sites in this population. Analysis of these SNPs in the MIRAGE cohort is currently in progress. Conclusions: Confirmation studies in independent samples and functional data are needed to prove the contribution of ACE to AD susceptibility. These results encourage studies of other genes related to vascular function.

Citation: Lindsey Farrer, R.P. Friedland, A. Bowirrat, R.C. Green, A. Yip1, R. Inzelberg, C. Baldwin. Using a Genetic Approach to Understand the Vascular Basis of Alzheimer Disease. NeuroBiology of Aging, Volume 25, Number S2 , July 2004, Page 25

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