Impact of APOE on the Healthy Aging Brain: A Voxel-Based MRI and DTI Study

Abstract

Neuroimaging studies of apolipoprotein E (APOEε4) have implicated its association with brain atrophy in Alzheimer's disease. To date, few studies have used automated morphological analysis techniques to assess APOEε4-related brain structure change in both gray and white matter in nondemented older adults. Nondemented (CDR = 0, n = 53) subjects over 60 had MRI, diffusion tensor imaging, and neurocognitive assessments. We assessed differences in cognition and brain structure associated with APOEε4 genetic variation using voxel-based morphometry techniques, and tract-based spatial statistics of fractional anisotropy change. In nondemented older adults with the ε4 allele, cognitive performance was reduced, and atrophy was present in the hippocampus and amygdala compared to APOEε4 negative participants. We also report that ε4 carriers have decreased fractional anisotropy in the left parahippocampal gyrus white matter. In conclusion, the presence of an APOEε4 allele in nondemented older adults is associated with decreases in cognition and gray and white matter changes in the medial temporal cortex. Overall we provide further evidence of the effects of genetic variance related to imaging and cognitive measures of risk for Alzheimer's disease.

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

“…Although FA was not altered, widespread significant increases in MD were observed in APOE ε4-carriers. This is in accordance with several other studies that reported effects of the APOE ε4 allele on WM integrity in brain tracts such as parahippocampal WM 38,53 and the corpus callosum 39,54 whereas a recent study did not replicate these results 55 .…”

“…59,60 Although APOE genotype effects were observed within WM regions in both the younger and the older group, we found that GM structure did not differ between APOE ε4-carriers and non-carriers. This was interesting because we expected that at least in the older group the higher risk of AD for APOE ε4-carriers would show in GM changes, especially in regions affected early by AD 61 , as was shown in two studies 20,53 . However, other studies also failed to observe APOE-related structural GM differences in healthy subjects.…”

Effects of theApolipoprotein Eε4 Allele on Functional MRI duringn-Back Working Memory Tasks in Healthy Middle-Aged Adults

“…[34][35][36][37][38][39][40][41] The present study recruited individuals without subjective or objective cognitive impairment, hence subjects with normal cognition, to test the effects of APOE4 on the brain functioning of WM by using BOLD fMRI. Performance of n-back WM was not different between groups (P ϭ .41-.85), similar to the findings of a previous publication.…”

Hippocampal Function in Healthy Carriers of theCLUAlzheimer's Disease Risk Variant

“…Neuroimaging work in patients has demonstrated reduced activation of the hippocampal formation during memory encoding and retrieval as well as altered functional coupling between hippocampus and the dorsolateral prefrontal cortex (DLPFC) (Grady et al, 2001;Allen et al, 2007;Dickerson and Sperling, 2008), but the relevance of these findings for heritable risk was undetermined. Previous genetic studies have led to the identification of APOE4 as an unequivocal susceptibility locus for late-onset AD (Farrer et al, 1997), with neuroimaging studies in APOE4 carriers suggesting compensatory increased recruitment of hippocampal and prefrontal regions (Bookheimer and Burggren, 2009) and evidence for disturbed white matter integrity (Honea et al, 2009;Sheline et al, 2010). Other genes, however, were less consistently implied.…”