Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

G. Chételat, M. Fouquet
2013 Revue neurologique (Paris)  
Introduction. The E4 allele of the apolipoprotein E (APOE4) is the major known genetic risk factor for 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 seek 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
more » ... for AD, i.e. atrophy with structural MRI, hypometabolism with FDG-PET, and amyloid deposition with amyloid-PET imaging. State of art. There is 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 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 would tell whether the mechanisms and sequences evidenced in carriers is comparable to those found in non carriers, but it is likely that APOE4 not only influences the risk for AD, but also modulates the physiopathological 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 physiopathology of the disease, although precaution is needed for interpretation in AD at large. Keywords: Apolipoprotein E4, structural MRI, FDG-PET, amyloid PET imaging, preclinical stage, early diagnosis, atrophy de l'APOE4 pourrait être sous-tendu par des processus Aβ-dépendants et Aβ-indépendants. Perspectives et conclusion. D'autres études devront être conduites pour déterminer si les mécanismes et la séquence d'événements sont les mêmes chez les porteurs et chez les non porteurs, mais il semble que l'APOE4 n'influence pas uniquement le risque mais pourrait également modifier la cascade d'événements conduisant à la MA. Dans l'ensemble, ces études soulignent l'intérêt des populations APOE4 pour évaluer les changements cérébraux survenant aux stades les plus précoces de la MA, même si toute généralisation des résultats chez les APOE4 à la MA en général doit être considérée avec prudence. Mots clés : apolipoprotéine E4, IRM structurale, FDG-TEP, imagerie amyloïde, stade préclinique, diagnostic précoce, atrophie
doi:10.1016/j.neurol.2013.07.025 pmid:24016463 fatcat:lv2yfqk6dzhbxmnvm64rz5udau