Our results using simple semi-quantitative scales suggest that MRI traits related to atrophy (CA and MTA) are significantly associated with AD in families. This concurs with earlier literature suggesting the use of MR measures for differentiating AD from non-AD pathology in unrelated subjects.19
Our results indicate AD siblings had greater amounts of WMH and more frequent presence of infarction than unaffected siblings despite the fact that AD subjects were ascertained through criteria that would be expected to minimize cerebrovascular findings. These associations have been previously noted19,38
suggesting that vascular injury may play a role in the AD process52,53
Age at MRI and duration of AD each confound the association between these three MRI trait measurements and AD and are important variables to consider when comparing cognitively normal subjects to AD patients. Despite the obvious significant mean differences in MRI measures seen between patients with AD and their unaffected siblings, considerable overlap between the two groups is apparent for all measures. While some of this overlap can be explained by measurement error, the shared genetic background of the cases and controls in this study may account for this overlap. Other non-genetic factors could also contribute to the overlap, but our analyses of family data and other reports of MRI traits in twin data indicate that genetic factors play a sizeable role.54,55
Studies of WMH assessing the contribution of genetic and non-genetic factors have attributed the MR distirubtion to primarily genetic factors.56,57
Therefore, these traits could therefore be used as potential endophenotypes to investigate novel genetic risk factors that may influence AD onset. As such, this dataset will be important to future genetic studies within the MIRAGE project.
The MIRAGE Study has assembled one of the largest collections of AA families with AD. Our results suggest that the magnitude of association between WMH and AD may be lower in AAs. It is possible that other risk factors for CVD, such as hypertension and diabetes which are more common in AAs than Caucasians,47,48
may explain this weaker association between AD and WMH. The association between CA and AD is greater in AAs than in Caucasians, adjusting for age at MRI. The results for MTA are less clear, but suggest that MTA is a uniform process related to aging and not to factors associated with ethnicity. These differences are subtle possibly due to the constricted number of samples available for non-Caucasian ethnic groups. Yet, statistical testing is able to take into account the variability in sample size and results still suggest that the utility of MRI measurements in association with AD will vary by ethnic background.
We found that WMH are associated with the presence of infarcts in both affected and unaffected siblings, supporting the hypothesis that WMH reflects vascular disease.49,50
Of interest, APOE ε
4 was associated with WMH only among unaffected siblings. This may reflect the increased vascular risk factor of the APOE ε
4, an effect that is overwhelmed by the robust association between ε
4 and AD in affected individuals.
Age at MRI and duration of disease (as a measure of disease severity) confound the relationship between AD and MRI traits as reported in previous studies.51
This is particularly true for CA and less so for WMH. CA differences between AD and non-AD subjects dissipate while WMH differences are steady with increasing age. This suggests concomitant CVD or white matter degeneration is part of the AD process.52,53
While both processes are possible, there continues to be considerable debate regarding the etiology of WMH in AD.50
Our family-based design which uses non-demented siblings as controls reduces greatly the potential for genetic substructure, or confounding, due to differences in underlying gene frequency distributions in affected and unaffected individuals. Family-based controls are also more likely to be similar to cases than unrelated controls in other pertinent factors including socioeconomic factors, educational, dietary, and access to medical care. If these factors are correlated with MRI traits, differential distribution of these factors among cases and controls could confound the association between MRI traits and AD.
The sensitivity and specificity of AD diagnosis could affect the univariate and regression results. Some overlap of affected an unaffected MRI values may be due to limitations of the measurements to differentiate adequately between those with and without AD. In addition, we may have taken a too conservative approach for defining AD probands. Because the overarching aim of the MIRAGE Study is to identify AD risk factors, AD probands were ascertained based on narrow NINCDA/ADRDA criteria that exclude subjects having any suggestion of vascular dementia. Thus, evidence of CVD, such as WMH or MRI infarct would not be associated with an initial diagnosis of vascular dementia. This implies that CVD in AD subjects is underreported. Another potential caveat of our findings is that some siblings categorized as unaffected actually have AD. If siblings were disproportionately misclassified as unaffected, then some MRI trait associations could have been overestimated. Finally, the sibling controls in our study may not be representative of non-demented siblings of AD cases because healthy volunteer effects could have enriched the reference group for subjects lacking brain atrophy or CVD. Lastly, the study data collected were based on self-report and proxies that may not accurately reflect an individual. Proxy measures, while essential in cognitively challenged populations, may be prone to biases. However, our own validation study suggests that proxy reporting is highly accurate.58
Our results showing strong association between MRI traits and AD in a family-based sample indicate that semi-quantitative MRI measurements will be useful endophenotypes for genetic association and other clinical and basic studies of AD.59
Each MRI trait, measured on either an ordinal or continuous scale, is an improvement over using a dichotomous AD measures as an outcome because the continuous variable contains more information than a dichotomous trait. The broader measurement scale is less sensitive to measurement error than in the binary measure and could improve study power for identifying genes that impact AD development. We expect, therefore, that genetic association findings with MRI measures of neurodegeneration and CVD will provide insights into the pathophysiology of AD.
Additional MIRAGE Study Group investigators are: C. T. Baldwin, and S. Auerbach (Boston University); Drs. A. Akomolafe, Lorin Freedman, and E. Ofili (Morehouse School of Medicine); Dr. H. Chui (University of Southern California); Dr. C. DeCarli (University of California - Davis); Dr. R. Duara (Mt. Sinai Medical Center, Miami); Drs. T. Foroud and M. Farlow (Indiana University School of Medicine); Dr. R. Friedland (Case Western Reserve University); Dr. R. Go (University of Alabama-Birmingham); Dr. A. Kurz (Technical University, Munich, Germany); Dr. T. Obisesan (Howard University); Drs. H. Petrovitch and L. White (Pacific Health Research Institute); Dr. N. Relkin (Cornell University); Dr. M. Sabbagh (Sun Health Research Institute); Dr. D. Sadovnick (University of British Columbia); and Dr. M. Tsolaki (University of Aristotle, Thessaloniki, Greece).