Caitlin Munger and Dr. John Kauwe, Biology
Introduction
Late-onset Alzheimer’s disease (LOAD) is a fatal neurodegenerative disease and is the sixth leading cause of death in the US. There are currently no successful therapies to prevent or treat LOAD, and predicting disease status remains a challenge1. Apolipoprotein E (APOE)—a gene involved in cholesterol regulation—is the strongest genetic predictor for LOAD. Because of the association between APOE and LOAD, cholesterol levels were suspected and have since been shown to increase LOAD risk2. Similar to APOE, the Cholesteryl Ester Transfer Protein (CETP) gene facilitates cholesteryl ester and triglyceride exchange between lipoproteins3 and is found in the same pathway as APOE, making CETP a gene of interest in LOAD etiology.
Several studies have investigated associations between CETP and LOAD as well as cognitive function, but results conflict. Accordingly, we chose to further investigate the association between CETP I405V and LOAD and cognitive function in the Cache County study—a large population-based sample of European descent.
Methodologies
For this study, DNA samples were available for 4486 subjects from the Cache County Study on Memory, and Aging, a cohort comprising 5,092 Cache County, Utah residents constituting 90% of individuals aged 65+ was followed continually for over fifteen years, completing four triennial waves of data collection with additional clinical assessments for those at high risk for dementia. DNA genotyping was performed at Brigham Young University using the c_790057_10 TaqMan Assay according to the manufacturer’s recommendation on the ViiA 7 apparatus using the ViiA 7 software (Applied Biosystems). Alleles were determined using the default calling criteria.
Mixed linear regression models were used to determine the association between cognitive decline over time while correcting for the APOE ε4 allele, age, education, and gender. Appropriate interaction terms were added to these regression models to assess the modifying effects of APOE genotype on the association between CETP and 3MS (the cognitive test used to measure cognitive decline). Cox Proportional Hazard models were also used to test association between genotype and LOAD-free survival. All analyses were performed using SAS version 9.3.
Results
Analyses revealed an association between CETP I405V and slower 3MS decline. This decline occurred at a rate of 0.6 points less per year than average for each additional valine (p < 0.011). We failed to detect association between CETP I405V and LOAD status (p < 0.28).
Our analysis further suggests a mitigating effect of APOE genotype on the association between CETP and progression (p = 0.097 for an interaction between APOE, CETP, and time). Specifically, individuals with additional APOE ε4 alleles experienced less rapid cognitive decline relative to each additional CETP I405V valine replacement. For example, among those with no APOE ε4 alleles, each additional CETP valine slowed 3MS decline by 0.4 points per year, on average. However, among those with a single APOE ε4, each additional valine slowed the annual average decline by 1.1 points.
Discussion
Previous studies on this topic have produced widely varied findings. Some suggest that CETP I405V is involved in increased cognitive function and slower rate of decline while others find the opposite. This variation also exists in the debate around CETP I405V’s involvement in Alzheimer’s disease. Our results combined with the findings of Reynolds et al.4 suggest that CETP I405V is not a LOAD risk factor. It is difficult to determine with presently available data whether this is indicative of a different relationship between the disease and the protein itself, or if there are other untested variants. These results reinforce the unique role of APOE in the development of Alzheimer’s.
Conclusion
In conclusion, we found a decrease in the rate of cognitive decline by 0.6 points less per year for each additional valine. These findings reaffirm the role of CETP I405V in cognitive decline. We did not observe any association between CETP I405V and LOAD status. The connection between CETP I405V and cognitive decline but not AD could shed light on differences between normal cognitive decline and dementia. Additionally, the possible interaction between APOE and CETP could prove fruitful in understanding the contradictory effects of CETP on AD and cognitive decline.
References
- Ebbert, M. T. W., Ridge, P. G., Wilson, A. R., Sharp, A., Bailey, M., Norton, M. C., … Kauwe, J. S. K. (2013). Population-‐based analysis of Alzheimer’s disease risk alleles implicates genetic interactions. Biological Psychiatry, Submitted.
- Hartmann, T. (2001). Cholesterol, Aβ and Alzheimer’s disease. Trends in Neurosciences, 24(11), S45–S48. doi:10.1016/S0166-‐2236(00)01990-‐1
- Plump, A. S., & Breslow, J. L. (1995). Apolipoprotein E and the apolipoprotein E-‐deficient mouse. Annual Review of Nutrition, 15(1), 495–518.
- Reynolds, C. A., Gatz, M., Pedersen, N. L., & Prince, J. A. (2011). An assessment of CETP sequence variation in relation to cognitive decline and dementia risk. International journal of molecular epidemiology and genetics, 2(2), 122–129.