Influence of apolipoprotein E varepsilon4 on rates of cognitive and functional decline in mild cognitive impairment

Abstract

Background: Apolipoprotein E varepsilon4 (APOE varepsilon4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE varepsilon4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE varepsilon4 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 varepsilon4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.

Results: APOE varepsilon4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE varepsilon4 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 varepsilon4 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 varepsilon4 status needs to be accounted for in treatment trials of MCI.

Figure 1

Thirty-six month plots of outcome measure scores converted to standardized Z-scores, illustrating differences in slopes of change between APOEε4 carriers and non-carries. Relative influences of the APOEε4 gene on each outcome measure are demonstrated.

Figure 2

Plot demonstrating Z-score differences in standardized mean rates of change between APOEε4 carriers and non-carriers. It can be seen that APOEε4 carriers had more rapid rates of decline on most measures, with global cognitive and dementia status scores demonstrating the widest separation in APOEε4 groups. Note that scores marked with “+” indicate that higher scores are worse, and those with “−” indicate that lower scores are worse for specific measures.