Interaction between Apolipoprotein e and Butyrylcholinesterase Genes on Risk of Alzheimer's Disease in a Prospective Cohort Study

Background: An epistatic interaction between the ϵ4 allele of apolipoprotein E (APOE ϵ4) gene and the K-variant of butyrylcholinesterase (BCHE-K) 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. Objective: To examine the interaction between APOE ϵ4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study. Methods: The study sample for survival analysis included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits. Results: A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOE ϵ4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95% CI=1.99-6.89, p<0.001) compared to non-carriers of both genes (APOE ϵ4 x BCHE-K interaction p=0.025). There was no APOE ϵ4-BCHE-K interaction effect on rate of cognitive decline and brain atrophy. Conclusion: The APOE and BCHE genes interact to influence risk of incident AD/MCI but not rates of brain atrophy and decline in cognitive performance before onset of cognitive impairment. This may suggest the epistatic interaction between APOE ϵ4 and BCHE-K on AD risk is disease stage-dependent.