Using TBM, the results from the present longitudinal study demonstrate that cognitively intact adults with the ApoE ε4 allele showed significantly increased rate of temporal lobe and hippocampal atrophy than those with the ε2 genotype. Furthermore, the rate of volume loss in the right hippocampus was significantly greater than the left hippocampus. While not statistically significant, greater percent volume loss was observed in the frontal, parietal, and occipital lobes of the ε4 group, indicating that ongoing atrophy is widely distributed but significantly greater in areas that are among the first to be involved with AD pathology.
Longitudinal neuroimaging studies of the effects of ApoE ε4 genotype on brain structural changes typically combine individuals with the ε3ε3 and ε2ε3 genotypes into a single “non-carrier” group with inter-scan intervals ranging from 17 months to 3.5 years [15
]. The present study focused on the comparison between ApoE ε2 and ε4 carriers due to the contrasting effects of these two genotypes on the age of onset for AD. The extended time interval of approximately 5 years between MRI examinations also allows for brain structural volume differences to emerge in cognitively intact, high functioning “younger-elderly” individuals. Present findings confirm and extend existing literature reporting accelerated hippocampal atrophy in ε4 carriers [15
] as well as contribute to the mounting evidence of decreased brain atrophy in ε2 carriers. While these results may be suggestive of a protective role of the ε2 genotype against the development of AD [2
], this cannot be conclusively demonstrated without the inclusion of an ε3ε3 group, since it is possible that individuals with the ε3ε3 genotype may show the same attenuated atrophy rate as the ε2 group or they may atrophy at a rate that is intermediate to that of ε2 and ε4 carriers. Future studies that include ε3ε3 subjects can better elucidate the effects of each specific genotype on hippocampal volume and allow more definitive conclusions regarding the potential protective effect of the ε2 allele.
The asymmetric finding of more severe right hippocampal atrophy in association with the ε4 allele has been repeatedly demonstrated in non-demented subjects [11
] and patients with AD [48
]. However, some studies have reported the absence of hemispheric differences in hippocampal volume in relation to ApoE genotype [20
]. The observation of a “normal” asymmetry favoring the right hippocampus has been reported in several MRI studies, and a recent meta-analysis confirmed that the right hippocampal volume is reliably larger than the left in normal adults [52
]. Therefore, the absence or reversal of such a discrepancy was postulated to be a possible indicator of existing or impending pathology [45
] although the functional implication for the differential hemispheric vulnerability in the hippocampus remains incompletely understood.
The finding of significantly greater volume loss associated with ApoE ε4 genotype in this healthy “younger-elderly” sample cannot be easily explained given that neuronal loss is not associated with aging [53
]. On the other hand, the process of age-related myelin breakdown and loss has been thoroughly demonstrated [55
]. When compared with other structural indices of brain health, age-related degenerative changes are most pronounced in late-myelinating regions [62
], such as the frontal lobe white matter (FLwm) that contain higher proportions of smaller thinly-myelinated axons [58
Histopathological studies have demonstrated white matter degeneration in AD, independent of gray matter lesions or vascular disease [65
]. Specifically, myelin staining is reduced in the perforant pathway, the main input fibers projecting neocortical information from the entorhinal cortex to the granule cells of the dentate gyrus in the hippocampal formation [66
]. Absence of myelin due to poor development can reduce overall hippocampal volume despite normal numbers of neurons [67
], and the reverse is also possible as hippocampal volume can increase despite neuronal loss [69
]. ApoE is the principal brain cholesterol transporter and is essential to the process of “recycling” cholesterol by helping reclaim it from damaged myelin and supplying it for rapid membrane biogenesis during re-myelination [70
]. The number of ApoE molecules necessary for this recycling process is lowest in ε4 carriers and highest in individuals with the ε2 allele [72
]. Therefore, the mechanism underlying the connection between the ApoE gene and the pathophysiology of AD, namely hippocampal atrophy, may be better understood by examining the role of ApoE in myelin maintenance and repair.
The strengths of the present study include the longitudinal design in which each subject acts as his/her own control and measurement of intra-individual rates of change yields greater sensitivity for detection of subtle brain changes over time. Furthermore, TBM may have an advantage over standard ROI-based, manual tracing methods for detecting subtle or highly localized differences. Several study limitations should also be acknowledged. The absence of a ε3ε3 group limits the interpretation on the protective effects of the ε2 allele. Another important limitation is the small sample size, thus replication with larger sample sizes is warranted; however, the number of participants in the present study is comparable to most longitudinal MRI studies of the ApoE effect on brain changes with sample sizes ranging from 25 to 42 participants [15
]. The heterozygous makeup of the ε4 group may limit the generalizability of the findings to homozygous ε4 carriers, but several cross-sectional studies have demonstrated a dose effect such that homozygous ε4 groups exert a greater influence on brain changes than heterozygous ε4 carriers and non-carriers [13
]. Another limitation is the difference in MR instrument for the baseline and follow-up scans due to machine change, but the registration method for fluid alignment in our version of TBM optimizes the mutual information between images, which is a cost function that is deliberately designed to be robust under changes in image contrast. It is also important to emphasize that the study design is balanced such that the scanner change affects all subjects and is not specific to one genetic group. The maps of annual change thus reflect both aging and the scanner effect; this would be a concern for interpreting age-related change but should not be a problem for interpreting modulators or correlates of change including ApoE genotype. In addition, while the relatively strict inclusion criteria (no AD family history, no cardiovascular disease, no obesity) reduce the number of factors that may contribute to the brain changes, it also makes the results less generalizable to the overall US population.
Analysis of serial MRI scans using TBM appears to be sensitive in tracking age-related progression of brain changes and the modifying effects of the ApoE gene on this process. The ApoE ε4 gene appears to exert its impact via accelerated atrophy that is not reliably detected upon cross-sectional study. Additionally, greater right hippocampal reduction may suggest that ApoE genotypic risk is manifested in a reduction in normal hippocampal asymmetry. Therefore, longitudinal decline in hippocampal volume as well as hippocampal asymmetry may hold more promise as possible biomarkers of an approaching cognitive decline than absolute differences within either left or right hippocampus examined at only one time point.