Meta-analysis of functional network alterations in Alzheimer's disease: Toward a network biomarker

• Current biomarkers lack sensitivity in the earliest stage of Alzheimer's disease.
• The symptomatology of Alzheimer's disease is suggestive for neural network disruption.
• Functional MRI has the potential to map whole-brain network alterations.
• This meta-analysis showed robust network changes in two important neural hubs.
• Compensation in precuneus and subcortical areas are evident before cognitive deficits.

The increasing prevalence of Alzheimer's disease (AD) emphasizes the need for sensitive biomarkers. Memory, a core deficit in AD, involves the interaction of distributed brain networks. We propose that biomarkers should be sought at the level of disease-specific disturbances in large-scale neural networks instead of alterations in a single brain region. This is the first voxel-level quantitative meta-analysis of default mode connectivity and task-related activation in 1196 patients and 1255 controls to detect robust changes in components of large-scale neural networks. We show that with disease progression, specific components of networks are widespread altered. The medial parietal regions and the subcortical areas are differentially affected depending on the disease stage. Specific compensatory mechanisms are only seen in the earliest stages, before symptoms are evident, and could become a functional network biomarker or target for interventions. These results underline the need to further fine-grain these networks spatially and temporally across disease stages. To conclude, AD should indeed be considered as a syndrome involving neural network disruption before cognitive deficits are detectable.