Identification of Genes that Modify the Age of Onset in a Large Familial Alzheimer's Disease Kindred
We have identified more than 20 nuclear Alzheimer's disease (AD) families in Colombia that carry a single point mutation, E280A, in the presenilin 1 (PSEN1) gene. Genealogical and genetic studies have demonstrated that these families share a common founder more than 400 years ago. The mean age of onset of AD in these families is 45.2 years but the range is almost 30 years (35–62 years). The wide range in age of onset suggests that genetic and/or environmental risk factors modify the age of onset. We are using two complementary approaches to the identification of genetic modifiers: candidate gene analyses and a whole genome screen analysis.
We have genotyped polymorphisms in each of the known AD genes: ß-amyloid protein precursor gene (APP), presenilin 1 (PSEN1) gene, presenilin 2 (PSEN2) gene and apolipoprotein E gene (APOE). Several polymorphisms in these genes have previously been associated with risk for AD in some but not all studies. To determine whether these polymorphisms modify the age of onset in the Colombian kindreds, we initially used survival curve analysis. The only gene that modified age of onset with this methodology was APOE. The APOE4 allele was associated with an earlier age of onset whereas the presence of the APOE2 allele was associated with later age of onset. This result is consistent with the observations of the effect of APOE alleles on sporadic AD and suggests that genes that influence the risk for late onset AD may also modify age of onset in familial early onset Alzheimer's disease (FAD).
We have also used survival analysis to examine several putative environmental risk factors. These studies demonstrated that both years of education and urban dwelling were associated with an earlier age of onset. Since these two factors were highly correlated in this study, it was not possible to determine which one was primarily the responsible risk factor.
To identify novel genetic risk factors for AD, we have used two complementary approaches: genetic analysis of a large series of late onset AD sibling pairs and a search for genes that modify age of onset in the Colombian families. Our genome screen in AD sibling pairs has provided evidence of AD susceptibility genes on chromosomes 9, 10, and 12 and suggestive evidence of an age of onset modifier gene on chromosome 12.
KeywordsCerebral Amyloid Angiopathy PSEN1 Mutation PSEN2 Gene Colombian Family E280A PSEN1 Mutation
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