Evidence from a recent MRI study by Filippini et al. provides support to our findings of decreased connectivity in prefrontal regions in AD patients carrying the ε4 allele. They looked at regional atrophy and transcallosal connections in cognitively normal APOE-4 carriers, and demonstrated that APOE-4 polymorphism was associated with aging-related volume loss in the prefrontal callosal tracts [78]. A study by Brown et al. found that, compared with noncarriers, elderly subjects carrying the APOE-4 allele exhibited pronounced age-related connectivity decreases along with loss of regional cortical thickness in the lateral parietal cortex and other brain regions [29]. It is therefore conceivable that these anatomical connectivity deficits may be more accentuated in pathological aging, leading to the frontal and parietal network disruption observed among AD patients carrying the APOE-4 allele in this study. Taken together, our results and those of previous genetic studies in healthy young and elderly subjects, suggest that APOE-4, as a risk factor for AD, is associated with changes in the intrinsic functional organization of brain networks in cognitively normal carriers [31], [32], [78], [79], even in the
