Emily Sears and Dr. John Kauwe, Biology
Introduction
Vascular dementia (VaD) is a neurodegenerative disease caused by atherosclerosis, or inadequate blood flow to the brain as a result of the build-up of fat deposits, dead cells, or other cell debris on the inside of arteries. It shortens the lifespan of those affected, and severely impairs their quality of life. VaD is the second most common form of dementia, after Alzheimer’s disease, accounting for 20-30% of dementia cases. Thus far the risk factors that have been determined are non-specific to the brain: high blood pressure, high cholesterol, and high blood sugar (Roman et. al 2003). There has not been much success targeting genetic variants that increase risk.
Recently, a rare genetic variant, rs75932628 (R47H), located on the gene TREM2 has been identified as a risk factor for Alzheimer’s disease, as well as other central nervous system disorders, such as Parkinson’s disease and frontotemporal dementia (Guerreiro et al. 2013, Jonsson et al. 2013, Rayaprolu et al. 2013). TREM2 is expressed on microglia, the immune response cells in the brain, and is involved in both phagocytosis of cell debris and plaques, and in suppressing inflammation. R47H is an amino acid substitution that compromises the function of TREM2, decreasing the activity of microglia. Inflammation and an increase of cell debris in the brain, as a result of R47H, could increase risk for vascular dementia by promoting atherosclerosis. The results from the analysis of the correlation of R47H with increased risk of vascular dementia within the data set (Cache County Study) used were not statistically significant.
Methods
Subjects
We used data from the Cache County Study on Memory, Health, and Aging (Breitner et al. 1999). The Cache County Study began in 1994 and involved a cohort of 5,092 individuals from Cache County, Utah, representing 89.7% of permanent residents over the age of 65. These individuals were screened with a cognitive assessment test every three years in four examination waves. Vascular dementia diagnoses in the Cache County study follow NINDS-AIREN criteria (Roman et al. 1993). Cases used in this study were those diagnosed with vascular dementia that includes those with comorbid types of dementia (including Alzheimer’s disease). The controls used in this study were those who had negative test results on all examinations and showed no signs of dementia.
Genotyping
SNP Genotyping was performed prior to this study for the 2694 DNA samples from the participants in the Cache County Study for rs75932628 (R47H) using a custom Taqman Assay. Included in the 2694 samples were 217 vascular dementia cases and 2477 cognitively normal control participants.
Analysis
Association between R47H and case control status was tested using logistic regression models with adjustment for age at onset, education, and number of APOE ε4 alleles. Data were analyzed using the statistical software R, version 3.1.3.
Results
Our analysis did not find a significant association between R47H and VaD (p=0.2818). We observed 2 heterozygous cases and 12 heterozygous controls in the 2694 individuals from the Cache County Study genotyped for the R47H polymorphism whose vascular dementia status was known. The mutant allele frequency was 0.461% in VaD patients and 0.242% in controls.
Discussion
Several studies have tested the association of R47H to neurodegenerative disorders, including Alzheimer’s disease, Nasu-Hakola Disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis (Guerreiro et al. 2013, Rayaprolu et al. 2013, Yaghmoor et al. 2014). Interestingly, although VaD is more likely to result from brain inflammation than other dementias, no studies have yet been published testing its association with R47H. Since R47H causes an increase in brain inflammation and buildup of cell debris, we expected that R47H would increase risk for VaD. Unfortunately, the data set we used in this study did not yield statistically significant results for this association.
The genetic cause of VaD is not well understood, and has not been studied as thoroughly as Alzheimer’s disease. There are currently no drugs approved that specifically treat symptoms of VaD. Identifying a genetic variant that increases risk for VaD would increase understanding of the role of genetics in the disease, and also could have great clinical significance in leading to treatments in the future.
Conclusion
In this study, we tested whether the R47H variant was associated with increased risk for VaD but did not find a significant association in individuals from the Cache County Study (p=0.2818). While the association was not significant in the population we studied, the mutant allele frequency in VaD patients (0.461%) was higher than that in controls (0.242%), indicating that the association is in the direction we predicted. The number of cases heterozygous for the SNP was very low, so it is of interest to repeat this study using a larger population.
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