Abstract
BackgroundAlzheimer's disease is the leading cause of dementia in the elderly and the third most common cause of death in the United States. A vast number of genes regulate Alzheimer’s disease, including Presenilin 1 (PSEN1). Multiple studies have attempted to locate novel variants in the PSEN1 gene that affect Alzheimer's disease status. A recent study suggested that one of these variants, PSEN1 E318G (rs17125721), significantly affects Alzheimer's disease status in a large case–control dataset, particularly in connection with the APOEε4 allele.MethodsOur study looks at the same variant in the Cache County Study on Memory and Aging, a large population-based dataset. We tested for association between E318G genotype and Alzheimer’s disease status by running a series of Fisher’s exact tests. We also performed logistic regression to test for an additive effect of E318G genotype on Alzheimer’s disease status and for the existence of an interaction between E318G and APOEε4.ResultsIn our Fisher’s exact test, it appeared that APOEε4 carriers with an E318G allele have slightly higher risk for AD than those without the allele (3.3 vs. 3.8); however, the 95 % confidence intervals of those estimates overlapped completely, indicating non-significance. Our logistic regression model found a positive but non-significant main effect for E318G (p = 0.895). The interaction term between E318G and APOEε4 was also non-significant (p = 0.689).ConclusionsOur findings do not provide significant support for E318G as a risk factor for AD in APOEε4 carriers. Our calculations indicated that the overall sample used in the logistic regression models was adequately powered to detect the sort of effect sizes observed previously. However, the power analyses of our Fisher’s exact tests indicate that our partitioned data was underpowered, particularly in regards to the low number of E318G carriers, both AD cases and controls, in the Cache county dataset. Thus, the differences in types of datasets used may help to explain the difference in effect magnitudes seen. Analyses in additional case–control datasets will be required to understand fully the effect of E318G on Alzheimer's disease status.
Highlights
Alzheimer's disease is the leading cause of dementia in the elderly and the third most common cause of death in the United States
It would appear that APOEε4 carriers with an E318G allele have slightly higher risk for Alzheimer’s disease (AD) than those without the allele (3.3 vs. 3.8); the 95 % confidence intervals of these two estimates overlap completely (Table 1)
Comparisons of odds ratios for AD risk based on E318G and number of APOEε4 alleles revealed that E318G carriers with one APOEε4 allele were at a higher—but nonsignificant—risk for AD (OR = 3.5, CI = 1.0-12.7, p = 0.043) compared to APOEε4 heterozygotes who did not carry the E318G allele (OR = 3.0, CI = 2.4 - 3.7, p < 2.2 × 10−16)
Summary
Alzheimer's disease is the leading cause of dementia in the elderly and the third most common cause of death in the United States. A vast number of genes regulate Alzheimer’s disease, including Presenilin 1 (PSEN1). Multiple studies have attempted to locate novel variants in the PSEN1 gene that affect Alzheimer's disease status. A recent study suggested that one of these variants, PSEN1 E318G (rs17125721), significantly affects Alzheimer's disease status in a large case–control dataset, in connection with the APOEε4 allele. Alzheimer’s disease (AD) is the most common type of dementia in the elderly and the third most common cause of death in the United States [1]. The Presenilin 1 gene (PSEN1) is one of the genes known to affect Alzheimer’s disease risk [7]; it codes for a transmembrane protein that forms the core of the gamma secretase complex, an enzyme
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