This study demonstrates that among cognitively normal subjects, a family history of Alzheimer’s disease and the APOE-4 genotype contribute independently and additively to cortical thinning in the hippocampal region. An additive effect of family history and APOE genotype could not be found in the entorhinal cortex, where either risk factor produced decreased cortical thickness, but a second risk factor did not alter the degree of atrophy. Family history accounted for a greater percent of the unique variance in global hippocampal thickness as explained by the APOE genotype and was associated with a thinner cortex in the hippocampal cornu ammonis field 1, subiculum, entorhinal cortex, and parahippocampal cortex. In line with our previous results (23
), APOE-4 carriers, when compared with noncarriers, showed a thinner subiculum and entorhinal cortex, and we additionally detected a thinner parahippocampal cortex and fusiform gyrus.
Despite the fact that family history of Alzheimer’s disease and APOE genotype contributed independently to the variance in cortical thickness, they affected the same cortical regions, which are those reported to show the earliest signs of the disease-related pathology (19
). For clinicians, it is important to notice that the family history risk factor contributes substantially to structural brain differences within the medial temporal lobe among healthy relatives of Alzheimer’s disease patients, highlighting the significance of the diagnosis for these relatives. For researchers, it could be critically important to control for family history effects in studies investigating other Alzheimer’s disease risk factors (14
It has been hypothesized that there are yet unknown susceptibility genes for late-onset Alzheimer’s disease of perhaps equal or larger effect size relative to that for APOE-4 (31
). We can assume that these unknown genetic factors would be represented in family history risk. The co-occurrence and overlap of both risks could mask APOE-4-related contributions that could or could not differ from family history effects. Carrying the APOE-4 allele increases the risk of developing Alzheimer’s disease and affects the onset, but perhaps not the progress, of the disease (32
) and remains an important factor throughout the lifespan (34
). Family history also increases the risk of developing the disease (5
), but it is not known how the risk factor influences disease progression or if the effects vary with an individual’s age. Studies investigating these family history effects did not account for APOE status (35
). It is further controversial whether both risk factors interact. van Duijn et al. (10 and the authors’ response to 37) found that family history was associated with increased risk in heterozygous but not homozygous APOE-4 carriers. Others emphasize additive effects of APOE-4 and family history risks on the prediction of the disease (37
). Although we found APOE-related effects in the subiculum and entorhinal cortex, possibly reflecting these regions’ susceptibility to early Alzheimer’s disease-related pathology (19
), family history was associated with a thinner cortex also in the adjacent cornu ammonis field 1. The patterns of cortical thickness among medial temporal lobe subregions associated with family history risk or APOE-4 risk could reflect at least partially different mechanisms contributing to cortical atrophy. It has been shown that family history of Alzheimer’s disease is associated with both whole brain and medial temporal lobe cortical atrophy as well as white matter lesions (17
Differential effects of age, APOE-4 carrier status, and Alzheimer’s disease on hippocampal subfields have been reported previously. Mueller and Weiner (22
) found reduced volume in hippocampal cornu ammonis fields 1 and 3 and the dentate gyrus associated with older age, whereas APOE-4 carrier status was associated with reduced cornu ammonis field 3 and dentate gyrus volume only. Dickerson et al. (38
) revealed moderately reduced volume in the entorhinal and posterior parahippocampal cortex among healthy elderly individuals relative to younger individuals. Differences between these findings and our study may reflect that most studies examine volume measures. Volume reduction may occur because of reduced cortical surface area rather than cortical thinning among healthy elderly subjects (38
There are several limitations to this study. Our study was not primarily aimed at investigating age effects on hippocampal cortical thickness. Therefore, this could be studied more directly with a larger number of participants, balanced across different age ranges. Although based on standard clinical criteria, it is possible that relatives with dementia other than Alzheimer’s disease were included. Furthermore, healthy relatives could develop Alzheimer’s disease in the future, and the presumably heterogeneous pattern of factors contributing to family history could differ among subjects. Finally, in APOE-4 subjects with a family history, it is not possible to determine clinically whether two different risk factors are present, since these participants could have a family history because of the APOE-4 allele.
The detection of structural brain changes in preclinical stages of Alzheimer’s disease and in subjects at risk for the disease using MRI is becoming increasingly important and focuses on brain areas that are affected earliest in the disease (18
). The possibility to identify macroscopic brain structure differences associated with Alzheimer’s disease risk factors in healthy individuals could point to the future use of MRI in aging. This could range from diagnostically monitoring the dynamics of these changes to measuring effects of strategies aimed to delay or prevent cognitive decline (39
The risk for developing Alzheimer’s disease can be modulated by various and rarely studied factors, ranging from yet unidentified genes and gene-gene interactions to environmental/lifestyle contributions (40
). Neither the APOE-4 genotype nor a family history of Alzheimer’s disease are sufficient to cause the disease. Therefore, the pattern of risk factors and their relative predictive value have strong implications for a physician’s decision on how to educate, monitor, and treat an individual. We show that family history modulates brain structure independently and additively to APOE-4-associated effects in brain regions most susceptible to the disease pathology and accounts for a greater percent of the variance in global hippocampal thickness than APOE-4 risk. Follow-up investigations will be necessary to determine which individuals will ultimately develop Alzheimer’s disease. Our findings underline the importance of a family history risk factor in clinical evaluations as well as imaging genetics in people at risk for Alzheimer’s disease.