Influence of apolipoprotein e ε4 on rates of cognitive and functional decline in mild cognitive impairment

Background: Apolipoprotein E ε4 (APOE ε4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE ε4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE ε4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI). Methods: A total of 516 aMCI participants aged 55-90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE ε4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period. Results: APOE ε4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE ε4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Conclusions: These findings demonstrate that APOE ε4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE ε4 status needs to be accounted for in treatment trials of MCI.