We evaluated the associations between FhxAD, APOE ε4, and their combination on cognitive change over time as compared with participants with neither risk factor. The cumulative decline over 7 years in the group with both risk factors roughly approximates the sum of the declines for the groups with FhxAD alone and APOE ε4 alone, suggesting that the two factors are additive. A formal test for a multiplicative interaction between FhxAD and APOE ε4 revealed none. After removing incident cases of dementia and prodromal AD, trajectories of the groups became more similar, but a significant effect remained for the FhxAD plus APOE ε4 group. These findings imply that the greater cognitive decline found in those with APOE ε4 reflects the known relation of APOE ε4 to AD, and not to another, independent phenotype of poor cognition.
These analyses may help explain the lack of consensus in the literature on the effects of APOE
ε4 on cognitive change over time. Sources of variation in results have been attributed to different study designs, study populations, follow-up periods, and age distributions of the samples under study. In some instances, prior research did not take future dementia diagnoses into account. For example in the MacArthur Study of Successful Aging, a population based multi-cite study of 965 individuals over 7 years, incident dementia cases were not removed from the sample and the authors concluded that ε4 was related to cognitive decline.19
In studies where incident cases are removed from the sample 27, 30
or groups are analyzed separately according to cognitive status, 28, 29
no decline has been found in cognitively normal individuals with APOE
ε4. However, a careful study by Christensen et al, 20
found that individuals with APOE
ε4 had poorer scores on the MMSE and the Symbol Digit Modalities test after controlling for other risk factors. When mild cases of cognitive disorder were set aside, the results were unchanged. Similarly, Hofer et al found a significant effect of APOE
ε4 on cognitive decline over 7 years using latent growth curve modeling.21
In this study, dementia cases were identified only at the first two evaluations and not the third. Cases of mild impairment or family history of AD were not considered. Indeed, most studies of APOE
ε4 and cognitive decline do not consider family history in their analyses.
In our study, the difference between groups was attenuated with the removal of prodromal AD and incident dementia cases suggesting that much of the decline was due to incipient disease. Nonetheless, a clinically small but statistically significant difference remained. There are several possible explanations for this phenomenon. It may be that we did not identify all incident cases in the sample and the resulting decline is due to unidentified cases. We doubt this is the case, because the CCMS protocol called for close scrutiny of those with APOEε4. A more likely explanation is that much of the residual decline represents early change that has not yet revealed itself as a recognizable cognitive syndrome. Yet another explanation, suggested by others, is that individuals with APOE ε4 decline at a faster rate in a way that is unrelated to development of symptomatic conditions. In our sample, once incident dementia and prodromal AD cases were removed, the group with APOE ε4 and no family history did not show significantly greater decline over time than the reference group. Finally, we note the effects of the combination of family history and APOE ε4, suggesting that the former may act independently, possibly reflecting other genetic influences or shared environment, and these influences may result in cognitive decline that does not reflect incipient AD.
Very few studies have evaluated the combined effects of APOE
ε4 and family history. In a six year follow-up of the Kungsholmen Project cohort, Huang et al,46
concluded that a family history of dementia was only associated with an increased risk of dementia among APOE
ε4 carriers. Duara et al,47
evaluated the combined effects of family history and APOE
ε4 on time to AD onset in a sample of 197 individuals and concluded that APOE
ε4 and family history of disease are independent risk factors that operate in an additive manner. Our results extend these findings and suggest a similar additive effect of APOE
ε4 and FhxAD on cognitive decline.
This study has several strengths and limitations. Our determination of FhxAD was based on self-reported data. We acknowledge that with the advent of widespread genetic testing, self-reported family history information may soon become obsolete. However, the method of data collection applied here was a structured detailed interview similar to those commonly used in genetic studies. This method has been successfully used in numerous studies and found to be reasonably reliable40
albeit with some measurement error. In the current study, measurement error may bias our results in favor of those who have APOE
ε4 as it is associated with earlier disease onset. Individuals with APOE
ε4 and FhxAD were younger than those with FhxAD only (p<0.01). Information about FhxAD the present analysis was updated through the second data point but was not available for the full cohort at the third evaluation. Therefore, it is possible that some individuals with FhxAD were misclassified, however, the effect of such a misclassification would tend to make our results more conservative. Our measure of cognitive performance, the 3MS, mainly reflects global cognition rather than specific cognitive domains. For this reason it is possible that we were unable to detect subtle changes that may be specific to a particular cognitive domains. The strengths of the study include the large sample size and long-term follow-up. We implemented a comprehensive evaluation of cognitive status at all three time points although it is possible that some incident cases of cognitive decline may have been misclassified. This may explain the remaining observed decline among those with FhxAD and APOE
ε4 when incident cases were removed. While this finding was statistically significant, the decline itself was not clinically significant.48
There may appear to be some tautology inherent in this study in that the removal of individuals with cognitive impairment from the analysis yields a sample of individuals with little or no cognitive decline. While this is true, the objective of the study was to evaluate the performance of individuals with FhxAD and APOE ε4 compared with individuals with neither risk factor to see if decline could be observed prior to any clinical manifestation of disease. We have shown that both FhxAD and APOE ε4 have deleterious effects on cognition over time. This effect is significant for those who have both risk factors and suggests, as we know, that genes beyond APOE have influences on AD risk and expression. When prodromal AD and incident dementia cases are removed from the sample, the effects of genes on cognitive decline is mitigated implying that much of the decline can be attributed to early expression of disease. Observable decline in cognitive screening scores over time (among individuals classified as normal) may be a useful indicator for subgroups at risk for AD or already expressing mild symptomatic disease. Further work is needed to elucidate more fully the cognitive patterns that precede and predict cognitive decline for each of these groups.