Association of Apolipoprotein E Genotype With Activities of Daily Living After Subarachnoid Hemorrhage

Background and purpose - Aneurysmal subarachnoid hemorrhage (aSAH) affects approximately 30,000 individuals in the United States each year. Although diagnostic and intervention techniques have improved, there is still an extremely high mortality rate (up to 50%) and it is estimated that only 60% return to a functional, independent state post-stroke. Known risk factors for poor outcomes post-aSAH include severity of initial bleed, age, and location of aneurysm rupture. We hypothesized that genetic variability may be a factor contributing to differences in functional outcomes. Apolipoprotein E (apoE) is a protein known to facilitate lipid transport and aid in neuronal repair within the central nervous system, making it a likely candidate biomarker to predict functional outcome post-aSAH. This protein, coded for by the apolipoprotein gene (APOE) on chromosome 19, has three known alleles (E2, E3, and E4), which can be combined to form six different genotypes (APOE 2/2, APOE 2/3, APOE 2/4, APOE 3/3, APOE 3/4, and APOE 4/4). The relationship between APOE genotype and functional outcomes post-aSAH is poorly understood. APOE allele E4 has been shown to be significantly associated with worse functional outcomes in intracranial hemorrhage and traumatic brain injury populations, but has shown no significant association to functional outcome in an ischemic stroke population. Ability to perform activities of daily living (ADLs) is a significant indicator of independence and quality of life. The relationship between the presence of APOE E4 allele and ability to perform ADLs post-aSAH has not been explored in previous literature. In a study of a combined population of ischemic and hemorrhagic stroke victims, researchers found no significant relationship between APOE and ability to perform ADLs post-stroke. However, other studies have found a significant association between APOE genotype and decreased ability to perform ADLs in other populations, including mild-cognitive impairment patients. The purpose of this study was to examine the relationship between APOE genotype and functional outcomes in persons with aSAH.

Population – Subjects were prospectively recruited as part of an ongoing NIH-funded study approved by the Institutional Review Board (R01NR004339). Patients were included in the study if they were 1) between the age of 18 and 75 years old, 2) diagnosed with aSAH verified with cerebral angiogram, 3) able to read/speak English and 4) had no previous history of neurological disorders.  This project included 382 participants; the majority was female (69.9%, n=267) and white (89%, n=340), with a mean Hunt and Hess (HH) score (measure of clinical severity) of 2.65.

Methods - APOE genotyping was performed using DNA extracted from either cerebrospinal fluid (CSF) or from whole blood samples. Genotypes were determined using Polymerase Chain Reaction followed by restriction digestion and gel electrophoresis. Genotypes were classified based on the presence or absence of at least one APOE E4 allele, using comparisons to a genomic ladder and samples of known (sequenced) genotype. Ability to perform ADLs was evaluated via home visit 3 and 12 months post-aSAH using Barthel Index (BI) score. BI score is a tool used to calculate a composite measure of ability to perform ADLs including functions such as toileting, grooming, dressing, mobility, and transfer, among others. The BI score has demonstrated high inter-rater reliability and test-retest validity, as well as high internal consistency. Multivariate linear regression was performed to determine the relationship between APOE genotype and outcome variability in BI scores controlling for age, sex, and severity of clinical condition (HH Score).

Results – No significant association was found between APOE genotype and BI score at 3 and 12 months post-aSAH (adjusted p values p=0.88 and p=0.95 respectively). Of note, a significant association was found between HH score and BI score at 3 months (p<0.01), which neared significance at 12 months (p=0.05).

Conclusions and discussion – APOE genotype does not appear to have a significant impact on ability to perform ADLs post-aSAH. The findings from this study support findings from Wagle et al. (2010) who found no significant relationship between APOE genotype and ability to perform ADLs as measured by the BI score after ischemic and hemorrhagic stroke. However, HH score does appear to have an association with ability to perform ADLs, supporting existing literature that initial clinical condition is a significant predictor of functional outcome. Although no correlation was found between APOE genotype and ability to perform ADLs, we are in the process of adding more subjects to the analysis. The results from this study adds to the mixed evidence regarding the relationship between APOE and functional status post-aSAH, warranting a need for further exploration of genotype as a predictor of outcome variability.