This study of a large, community-dwelling sample provides a comprehensive view of the influence of ApoE allele status on brain structure in men. Few previous studies have captured such a broad description particularly within a solely middle-aged sample. The findings suggest that carriers of the ε4 allele on average have thinner frontal cortices in middle age, without direct evidence of any significant ε4 effect on MTL regions commonly affected in AD. These frontal effects were widespread, although the effect sizes were small, suggesting that studies with smaller sample sizes may not have sufficient power to reliably detect such effects. Exploratory analyses also suggested thicker fusiform cortex in ε4+ carriers, in line with a previous study [40
]. Potential protective effects of the ε2/3 genotype were supported in part by thicker left parahippocampal cortex and broader MTL and medial orbitofrontal tendencies towards thicker cortex, relative to the ε3/3 group.
Our findings of ε4-related differences in superior and middle frontal cortical thickness are relatively unique and of interest in the context of normal aging. One cross-sectional study including middle-aged and older individuals suggested accelerated age-related thinning in ε4 carriers in the superior medial frontal gyrus; however, the majority of the participants were over the age of 60, limiting the inference of effects in middle age [40
]. Within Shaw et al.’s study of children and adolescents [38
], there were potential ε4 status effects in frontal regions, with continuous maps showing small areas of thinner orbitofrontal cortex in the ε4+ group. While the present study does not show significant orbitofrontal ROI effects, the continuous surface maps () further explore patterns without the predefined constraints of ROI boundaries, which may be relatively arbitrary with respect to the underlying cellular, functional, or developmental aspects of the brain. The maps support widespread frontal effects, and the potential influence on frontal cortex development into the adult age range may inform these regional differences.
The ε4-related effects on frontal cortical thickness are bolstered by findings from other modalities and disorders. Amyloid and tau binding PET studies in healthy individuals suggest that binding is higher for ε4+ carriers in frontal areas, as opposed to commonly reported increased temporal lobe binding in ε4+ MCI individuals [30
]. In addition, ε4 status may influence dendritic density and complexity in the cortex [64
], and may differentially influence cortical patterns of thinning based on mediating factors. In a study of AD and frontotemporal dementia, cortical atrophy was greater in both ε4+ subgroups; however, the pattern of thinning in AD represented known neuropathological areas such as the mesial temporal lobe, whereas in frontotemporal dementia, the ε4+ group evidenced greater frontal atrophy [65
]. The broad, frontal findings support the relationship between the ε4 allele and increased amyloid deposition in these areas with normal aging, although any progressive nature of such effects must be demonstrated in a longitudinal study, currently underway.
The lack of significant MTL ε4 related effects is not unexpected given conflicting previous reports and may reflect studies including a low proportion of individuals in a preclinical phase of AD and, importantly, other mediating influences on the impact of ε4 status, such as gender and hormones. While substantial support exists for ε4-related MTL effects in MCI and AD, findings in healthy individuals are inconsistent, even in older adults [23
]. There is some evidence suggesting the influence of ε4 status on MTL structures in middle age [34
] and in children and adolescents [38
]; however, other studies including middle-aged individuals have not found the same effects [35
] or have found that effects across a broad age range were driven by individuals over 60 or 65 years of age [35
]. Some of these older individuals may demonstrate poor cognitive performance relative to their non-ε4 counterparts and some may be in the prodromal stages of AD. Indeed, a recent study of cognition suggests that family history of AD and ε4 status may be additive factors, and that, with the removal of individuals known to convert to AD, only individuals with both a positive family history of AD and ε4+ status demonstrate a more rapid cognitive decline [67
]. The present sample represents individuals in their 6th
decade of life, when few are likely to be affected by dementia, although we do not have data on family history at this time. In contrast, the unique study of children and adolescents (n=174 non-ε4, n=65 ε4+; 8–21 years) provides support for the thinner left entorhinal cortex for ε4+ individuals [38
], although these effects were subtle and the variability in thickness was slightly larger within the ε4+ relative to the non-ε4 group, similar to the present study. These findings together support the hypothesis that additional factors likely mediate the influence of ε4 status on brain structure.
Other studies have demonstrated differences in ε4-related effects by gender and report potential mediating or moderating factors such as hormones. There may be an interaction between gender and ApoE ε4 status [68
] such that, in general, females are more influenced by ε4 status than males. In MCI, female ε4+ carriers have a higher risk of developing AD than men of the same genotype [14
]. A neuroimaging study reported that female, but not male, ε4+ carriers had significantly smaller hippocampal volumes relative to non-ε4 individuals; the authors suggested the potential for hormonal mediation of the influence of ε4 status [69
]. It is possible, then, that in the present male sample, ε4-related MTL effects may be reduced and/or obscured by other factors. In fact, a study of VETSA participants revealed a significant interaction between testosterone and ε4 status indicating that ε4+ men who also had low levels of testosterone have smaller hippocampal volumes [70
]. A similar interaction between ε4 status and cortisol levels or patterns also has been observed with respect to cognition in older adults [71
The present study also included a larger sample, relative to published reports [e.g., 42
], that allowed for a characterization of the influence of carrying an ε2 allele in middle-aged individuals. In contrast to ε4 status, the ε2 allele appears to have a subtle impact on thickness in MTL and medial orbitofrontal areas. The significantly thicker right parahippocampal cortex and broader tendencies for thicker cortex in these areas lend support to findings in adolescents [38
] and corroborate the protective influence of ε2 demonstrated in neuropathological and cognitive studies [8
]. Exploratory analyses suggesting thinner right supramarginal and left lingual cortex are intriguing but require further replication.
The unique VETSA cohort provided significant power to examine the influence of ApoE allele status, although the study presents some limitations to generalizability. Because our sample was solely male and largely Caucasian, we cannot be certain of the generalizability of these findings to women or ethnic minorities. Furthermore, although the sample is quite similar in health and demographics to comparably-aged men in the U.S., a minority of them did experience varying amounts of combat exposure 35 years earlier. Thus, concerns might be raised as to the effect of combat exposure or possible posttraumatic stress disorder (PTSD) on the results. As of their mid-40s, 7.7% had a lifetime diagnosis of PTSD, slightly higher than the 5.0% prevalence for men nationally [72
]. Importantly, this is unlikely to be create a confound in the present study because previous co-twin control findings indicate that smaller hippocampal volume may be a risk factor for PTSD, rather than a consequence [73
]. Another potential limitation of our study is that, with T1-based image processing approaches, it is difficult to distinguish tentorium cerebelli from cortex in some mesial and inferior temporal regions. That is, while we have made every effort to separate cortical gray matter from tentorium, thickness estimates in these regions, such as the entorhinal cortex, may be more variable than in other areas. Such an increase in variability may result in less power to detect significant effects of ApoE allele status on thickness, although we would not expect differential effects across ApoE groups.