The factors which determine rate of progression in Alzheimer’s disease remain incompletely understood. It has been proposed that carriers of the ε4 allele may demonstrate accelerated cognitive decline (3
) due to the allele’s cumulative impact on beta amyloid and neurofibrillary tangle biochemical pathways (20
). However, studies directly examining decline as a function of APOE genotype have produced markedly inconsistent findings (4
). In the current study, we had a unique opportunity to examine the influence of APOE- ε4 on cognitive decline in both population- and clinic-based samples of participants with AD.
The population-based samples were primarily Hispanic and African American, and were on average older and less educated than the predominantly Caucasian participants in the clinic-based sample. There was also a lower proportion of ε4 carriers in the population-based samples than in the clinic sample, consistent with the older age of the population samples (37
), and the fact that participants in the population samples were primarily Hispanic and African American, ethnic groups in which there may be a weaker association between ε4 and AD onset leading to an under-representation of the ε4 allele in demented participants (38
). Overall, however, rates of ε4 in all samples were comparable to other studies of AD and higher than rates in the general population (38
The influence of ε4 on rate of cognitive decline varied across samples. In the incident sample, we were able to examine rate of change from the earliest stages of clinically observable AD. In this sample, the presence of the ε4 allele was associated with more rapid cognitive decline, even after adjustment for potential demographic contributors to disease course, suggesting a robust relationship between the ε4 allele and faster cognitive decline in incident AD. In contrast, ε4 was not associated with rate of change in either of the prevalent AD samples (population or clinic-based). As a possible explanation for this inconsistency, we hypothesized that more advanced illness among prevalent cases may have limited our ability to detect ε4-associated decline. In fact, when we accounted for disease severity by adjusting for disease duration or by restricting analyses to those with better cognitive function at baseline we were able to demonstrate faster decline in ε4 carriers in both prevalent samples.
Our interpretation of the overall pattern of results is that ε4 influences cognitive decline most clearly in the earliest stages of disease and less so, or not at all, in the moderate to severe stages. There may be several explanations for this. First, to the extent that our cognitive batteries are less sensitive to change as the disease progresses, we may be unable to detect a differential role for ε4 on rate of change in the later stages. It is possible that a different cognitive assessment tool or a functional measure would better capture differential rates of decline further into the disease. A second possibility is that the influence of the ε4 allele may be time limited, until some neurobiological threshold is crossed and after which medical, social, or disease related variables other than ε4 become more prominent in determining rate of decline.
Investigations documenting faster rates of decline in ε4 carriers (8
) included two of the largest studies to date. Convincingly, a recent study detected faster rates of decline using both a linear and non-linear mixed-effect statistical model (8
). Faster rates of cognitive decline in ε4 carriers is consistent with the well established role of APOE ε4 as a risk factor for developing AD (35
), and parallels findings from imaging studies suggesting accelerated rates of neurodegenerative change in ε4 carriers (40
Three studies, including an early study from our group, found slower
decline among ε4 carriers than non-carriers. However, the earliest study retrospectively estimated baseline MMSE score based on age and education predicted values (4
), and is thus less compelling than the remaining studies which used growth curve analysis (GCA) to determine rate of progression (5
). The GCA study from our group likely suffered from selective attrition as APOE genotyping was done 6 years after the study began. It is thus possible that ε4 carriers progressed more quickly in the early years of the study, and were more likely to have been lost to follow up by the time ε4 data was collected. Additionally, as genotyping was completed on 42% of participants in the first cohort compared with 71% in the second (current) cohort, the current study better represents the population of ε4 carriers. In fact, re-examination of the Predictors I data with additional follow-up data using the GEE model described in the current paper found no relationship between ε4 status and rate of decline in that cohort (data not shown).
In the current study, stratified analyses revealed that ε4 influenced rate of change differentially across a number of demographic subgroups. Specifically, ε4 appears to influence rate of decline primarily in Caucasians rather than Hispanics and African Americans. This pattern of results is largely consistent with the literature examining the risk for developing AD (38
) although there is some evidence for ε4 as a factor in Hispanic (42
) and African American populations as well (44
APOE status may also interact with educational level; results offered marginal support for the ε4 allele predicting faster decline in those with higher education (greater than six years) only. The relevance of this finding is unclear, and further work is needed to more thoroughly investigate this potential interaction. One possibility is that ε4 exacerbates the increased rate of decline previously observed in individuals with higher education (25
Although initial stratified analyses revealed a differential effect of ε4 by sex, follow-up GEE analyses did not support this finding. A sex-specific role of ε4 has been noted in previous studies reporting increased 4-related entorhinal atrophy in early AD most prominently in women (45
), and increased risk for age-related cognitive decline in women carrying the ε4 allele (46
). Studies examining the development of late-onset familial AD have also revealed a sex-associated role of APOE genotype with the ε4 allele conferring greater risk in women (47
). In contrast, a recent study linked ε4 to mortality rate in men only (48
); however, the processes contributing to disease development and rate of decline early in the disease course may differ from those contributing to mortality at a later stage. Future work is needed to directly examine this potential discrepancy.
The current study was limited by the fact that ε4 genotyping was not available for 100% of individuals, introducing the possibility that participants do not accurately represent the distribution of ε4 in the population. Individuals excluded from the study were largely similar to the analysis sample with regard to basic demographic and clinical variables, except that excluded individuals were generally older and more highly educated than participants in each of the final samples. A third limitation to the current study may be the use of a linear rather than non-linear approach to model cognitive decline, a technique that may have restricted our ability to observe differential rates of decline in the more impaired participants.