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Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers.

Abstract : INTRODUCTION: 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.
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Submitted on : Tuesday, November 26, 2013 - 11:13:18 AM
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Gaël Chételat, Marine Fouquet. Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers.. Revue Neurologique, Elsevier Masson, 2013, 169 (10), pp.729-36. ⟨10.1016/j.neurol.2013.07.025⟩. ⟨inserm-00909398⟩



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