The E4 allele of the
apolipoprotein E (
APOE4) is the major known genetic risk factor for
Alzheimer's disease (AD), with a dramatic increase in the risk of developing AD as the number of
APOE4 alleles increases from 0 to 2. For this reason, asymptomatic
APOE4 carriers as a group offer a great opportunity to search for the presence of early
biomarkers for AD. The present article reviews neuroimaging studies on
APOE4 carriers, focusing on cognitively normal individuals and on the main neuroimaging
biomarkers for AD, i.e.
atrophy with structural MRI, hypometabolism with FDG-PET, and
amyloid deposition with
amyloid-PET imaging.
STATE OF THE ART: There are a great number of studies on the effect of
APOE4 on brain structures, and they tend to show significant
atrophy in
APOE4 carriers compared to non-carriers especially in regions susceptible to AD pathology such as the hippocampus. However, results are rather discrepant which suggests that the effect of
APOE4 on brain structure is subtle. As for FDG-PET metabolism, the few available studies show decreased metabolism, again especially in AD-sensitive regions such as posterior associative parietal areas, with a dose-dependent effect (i.e. worsening as the number of
APOE4 alleles increases). Finally, there is a unanimous and major effect of
APOE4 on
amyloid deposition with an increase in Aβ load as the number of
APOE4 alleles increases and a decrease in the age of predicted
amyloid-positivity in
APOE4 carriers. This graded effect of
APOE4 on
atrophy, hypometabolism, and
amyloid deposition is consistent with multimodal neuroimaging studies suggestive of a predominant effect of
APOE4 on
amyloid rather than tau-related injury and on brain metabolism rather than brain structure. Neuroimaging studies also suggest that
APOE4 effects may be mediated by both Aβ-dependent and Aβ-independent
pathological processes. This contradicts the view that Aβ pathology is a necessary upstream event to neuronal injury in AD.
PERSPECTIVES AND CONCLUSION: Future studies should tell whether the mechanisms and sequences evidenced in carriers are comparable to those found in non-carriers, but it is likely that
APOE4 not only influences the risk for AD, but also modulates the pathophysiological cascade. Altogether,
APOE4 carriers offer a great opportunity to investigate brain changes in the asymptomatic stages of AD and to further our understanding of the pathophysiology of the disease, although precaution is needed for interpretation in AD at large.