Mapping memory binding onto the connectome's temporal dynamics: toward a combined biomarker for Alzheimer's disease

The classical amyloid cascade hypothesis of Alzheimer's disease (AD) has driven research and clinical practice for several decades. It states that the deposition of the amyloid-β peptide in the brain parenchyma initiates a sequence of events that ultimately lead to atrophy and AD dementia. This proposal stimulated the study of specific brain regions mapped along the neurodegeneration sequence (e.g., hippocampus) and their associated impaired functions (e.g., episodic memory). Although anticipated by Mesulam more than 20 years ago (e.g., Mesulam and Asuncion Moran, 1987), it was not until recently that this view has started to change, largely due to the disappointing results of trials relying on the beta-amyloid cascade hypothesis and its variants, e.g., the synaptic beta-amyloid hypothesis.