White matter is altered with parental family history of Alzheimer's disease

Abstract

Background: Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E (APOE) varepsilon4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE varepsilon4 on brain integrity, in addition to assessing possible additive effects of these two risk factors.

Methods: Diffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE varepsilon4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (lambda1, lambda2, lambda3) to provide potential additional insight on underlying tissue differences.

Results: Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE varepsilon4; however, there was an additive effect of family history and APOE varepsilon4 in which family history-positive participants who were also APOE varepsilon4 carriers had the lowest FA compared with the other groups.

Conclusions: The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.

Figure 1

Main effect of family history Microstructural differences were detected in participants with a parental family history of AD compared to controls. These participants had lower fractional anisotropy in right posterior hippocampus (region 1), left posterior hippocampus (region 2), right posterior cingulum bundle (region 3), left anterior corona radiata and right anterior corona radiata (region 4), left uncinate fasciculus/inferior fronto-occipital fasciculus, left superior corona radiata, left superior longitudinal fasciculus, bilateral posterior corona radiata, and small portions of the body of the corpus callosum. Analyses of FA were adjusted for age, sex, and education. Brain sections are displayed in radiological orientation and the color bar shows the magnitude of the t statistic. Results are shown at p<.005 uncorrected.

Figure 2

Maternal family history The maternal family history group (n = 46) had significantly lower fractional anisotropy in right sided white matter posterior to the hippocampus compared to participants who were FH and ε4 negative (n = 63). There was no significant difference between any of the other groups. The fractional anisotropy values were adjusted for age, sex, and education.