THE APOE AND BCHE GENES INTERACT TO INCREASE RISK OF INCIDENT ALZHEIMER’S DISEASE IN THE BALTIMORE LONGITUDINAL STUDY OF AGING

Abstract

An epistatic interaction between the ApolipoproteinE (APOE) and Butyrylcholinesterase (BCHE) genes has been previously reported to increase risk of Alzheimer's disease (AD). However, these observations were largely from case-control studies with small sample sizes and have not been consistently replicated, Few studies have examined the role of APOE X BCHE interactions on risk of incident AD/mild cognitive impairment (MCI) prospectively. The Baltimore Longitudinal Study of Aging (BLSA) is a prospective cohort study of community-dwelling participants since1958. Six hundred and ninety-one cognitively normal participants (age at baseline, 58.4 ± 9.9 years) with available APOE and BCHE (rs1803274) genotype data were included in this study. The rs1803274(A) allele encodes a version of the butyrylcholinesterase enzyme known as the K variant (BCHE-K) that produces a 30% reduction in serum butyrylcholinesterase activity and has been previously associated with AD risk. The mean follow-up time was 16.9 ± 9.7 years. Participants who developed AD or mild cognitive impairment (MCI) were captured as having an event at the estimated age of onset. Cox proportional hazards models were used to examine the association between APOE4, BCHE-K and their interaction on the risk of incident AD or MCI controlling for gender, years of education and birth year. A total of 122 participants were diagnosed as MCI (n=43) or AD (n=79) during follow-up. In two separate models, APOE4 was significantly associated with increased risk of AD (adjusted hazard ratio [aHR]=1.77; 95% confidence interval [CI]=1.19- 2.63; p=0.005) whereas BCHE-K did not show a significant association (aHR=1.20; 95%CI=0.82–1.76; p=0.339). The model including both APOE4 and BCHE-K showed a strong and significant effect of APOE4xBCHE-K interaction on the risk of AD (t=2.24, p=0.025). Compared to APOE4 and BCHE-K non-carriers, participants with both APOE4 and BCHE-K variants had a 3.36 fold greater risk of AD (95%CI=1.94–6.77, p < 0.001) (Fig 1).