Of the 516 participants who received either the placebo or vitamin E, 239 (46.3%) were APOEε4 negative and 277 (53.7%) were APOEε4 positive, with 18% of these participants having two e4 alleles present. 136 (52.5%) of the participants in the placebo arm and 141 (54.9%) in the vitamin E were APOEε4 positive (p = 0.65). There were no significant group differences at baseline in age (p = 0.85), education (p = 0.95) or sex (p = 0.38). APOEε4 carriers were more impaired at baseline on ADAS-Cog 11, ADAS-Cog 13, Delayed Word List Recall, MMSE, CDR-SOB, GDS, Clock Drawing, Category Fluency, NYU Delayed Paragraph Recall Immediate, NYU Delayed Paragraph Recall Delayed, Number Cancellation Target Hits, and Symbol Digit Modalities (all p-values <0.05). Baseline characteristics categorized by APOEε4 status are shown in .
Each cognitive score was compared at each completed visit by APOEε4 status. APOEε4 carriers were more impaired on the ADAS-Cog 11 compared to APOEε4 non-carriers at all visits (all p < 0.001). Similarly, APOEε4 carriers scored worse on ADAS-Cog 13, Delayed Word List Recall, NYU Delayed Paragraph Recall Delayed, NYU Delayed Paragraph Recall Immediate, MMSE, Category Fluency, Number Cancellation Target Hits and Symbol Digit Modalities compared to APOEε4 non-carriers at all visits (all p < 0.05). The Boston Naming and Clock Drawing baseline scores through month 6 were similar by APOEε4 status; however APOEε4 carriers began to score significantly lower at month 12 (all p< 0.05). The Digit Backward baseline scores through month 12 were similar by APOEε4 status (excluding month 6, at which time APOEε4 carriers scored significantly worse); however APOEε4 carriers began to score significantly worse compared to APOEε4 non-carriers from 18–36 months (all p< 0.05). The Maze Tracing baseline scores through month 18 were similar by APOEε4 status; however APOEε4 carriers began to score significantly worse compared to their APOEε4 non-carriers in subsequent visits (all p< 0.05). APOEε4 carriers did not differ from their APOEε4 non-carriers on the Number Cancellation Target Errors at any time point, except at Month 30 (p= 0.03). APOEε4 carriers were more impaired compared to APOEε4 non-carriers on the CDR-SOB, and the GDS at all visits (p < 0.001). Activities of daily living scores were similar by APOEε4 status through month 6; however APOEε4 carriers began to score significantly lower in subsequent visits (all p< 0.05).
The correlation matrices between observed raw scores over time for each cognitive, global and functional score appeared similar by APOEε4 status and supported the use of compound symmetry for the GEE Modeling. Age, education and sex did not meet our pre-specified definition of a confounder; therefore the final GEE model of each of the outcome measures remained unadjusted for these variables. Annualized rates of decline in raw cognitive, global and functional scores are shown in , with p-values representing the significance level of change over time associated with APOEε4 status from the GEE models. GEE models demonstrated that APOEε4 carriers had significantly increased rates of decline, with and without controlling for differences in baseline global cognitive status, on all outcome measures except Number Cancellation Target Errors (p-value 0.33) and Maze tracing (p-value 0.21). This included a statistically significant decline over time, with the APOEε4 carriers declining faster than non-carriers, on the CDR-SOB (p<0.001), MMSE (p<0.001), GDS (p<0.001), ADAS Cog11 (p<0.001), ADAS-Cog13 (p<0.001), ADL (p<0.001), Delayed Word List Recall (p<0.001), Digit Backwards (p<0.001), Boston Naming Test (p<0.001), Clock Drawing (p<0.004), NYU Paragraph Delayed Recall (p<0.001), NYU Paragraph Immediate Recall (p=0.012), Category Fluency (p<0.001), Symbol Digit Modality (p<0.001) and on the Number Cancellation Target Hits (p<0.001). Lastly, the estimate of APOEε4 by time interaction from the mixed-effects regression model evaluating sensitivity was 0.118 (SE 0.009) which was similar to the ones obtained by the GEE model 0.117 (RSE 0.017). Final GEE models of cognitive, global and functional outcome measures by APOEε4 status are shown in .
Annual rates of change in raw scores for continuous outcome measures
Transformation of the raw score outcome measures to standardized Z-scores demonstrated relative differences in rates of decline between outcome measures. Plots of standardized outcome measures over 36 months illustrating comparative trajectories of change over time for APOEε4 carriers versus non-carriers are shown in . shows the rank ordering of relative rates of decline between measures, with the CDR-SOB, MMSE, GDS and ADAS-Cog showing the largest differences in standardized rates of decline between APOEε4 status groups, compared to measures of specific cognitive domains and activities of daily living.
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 (more ...)
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 (more ...)