. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. PubMed.


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  1. This is a highly interesting study on the association between the ApoE4-genotype (which encodes for an elevated risk to develop Alzheimer’s disease) and changes in functional connectivity in the brain. In healthy subjects carrying the ApoE4-genotype, the authors were able to demonstrate subtle abnormalities of functional connectivity in the brain in a similar regional pattern as observed in patients with mild cognitive impairment and in manifest Alzheimer’s disease (AD). These findings complement results from several recent studies which were able to demonstrate abnormalities in different neuroimaging measures in healthy ApoE4-positive subjects without cognitive symptoms. This includes regional hypometabolism (with [18F]FDG-PET) or minor amyloid-deposition (with [11C]PIB) (1,2). Also, reduced functional connectivity has been previously demonstrated in amyloid-positive healthy controls (3). Most of these studies had in common that the detected abnormalities in ApoE4-positives were similar to findings in manifest Alzheimer’s disease, although less pronounced.

    A particularly intriguing finding of the current study is that the authors were able to demonstrate abnormalities in healthy subjects which were negative for amyloid-deposition in the brain. This finding raises a number of questions with regard to the order and, thus, the causal association of pathologies.

    This result indicates that reduced functional connectivity may actually be a precursor rather than a consequence of amyloid pathology in the brain. This somewhat counterintuitive finding is indeed of very high relevance regarding the pathophysiological hypothesis of Alzheimer’s disease. In the amyloid hypothesis, it has been assumed that amyloid pathology is the leading pathologic entity in AD, and that most other pathologies occur downstream and potentially as causal consequences (4). The current study offers three possible conclusions: 1) changes of neuronal communication, i.e., functional changes, may precede or even lead to amyloid pathology in the brain; 2) early amyloid pathology (in particular, soluble oligomers of β amyloid), which has not been tangible with (11C)PIB-PET imaging, may have been present in the examined ApoE4-positive population and lead to synaptic dysfunction with the consequence of reduced connectivity. “PIB-measurable” amyloid-deposition in the form of amyloid plaques may be a later phenomenon following these early changes in connectivity; 3) functional changes in the brain occur independently from amyloid pathology. In this context, other recent findings appear in a new light: It has been demonstrated that cerebral hypometabolic abnormalities as a measure of neuronal dysfunction increase and regionally expand continuously even in later stages of AD, whereas amyloid deposition appears to reach a relative plateau at some point (5). Additionally, amyloid deposition, as measured with PIB-PET, does not show strong correlation with cognitive decrease.

    Finally, it cannot be excluded that the abnormalities in functional connectivity detected in the ApoE4-positive subjects in the current study do not represent actual early AD pathology, but rather reflect constitutional differences between ApoE4-positives and negatives, which may predispose for but not necessarily result in AD. This seems less probable, regarding the fact that similar but more pronounced abnormalities have also been documented in manifest AD (6,7).

    In summary, this study has contributed some very important new insights, and it strongly encourages further work into the causal interaction between different pathologies involved in this disease, particularly in early, or asymptomatic, stages.


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