Fig. 1: Time-course of pathological changes along the AD continuum.

The traces represent the possible evolution of pathological changes across the AD continuum, with the new hypothesis of an early shift in neurophysiological activity from acceleration to slowing during the preclinical phase. Aβ deposition begins early in the preclinical stage of the disease, preceding tau deposition, subsequent neurodegeneration and presentation of cognitive symptoms. According to the proposed model, early Aβ deposition is related to a transient acceleration of neurophysiological activity, while the later joint deposition of Aβ and tau would be associated with a shift towards neurophysiological slowing. The left axis in blue corresponds to the acceleration and slowing of neurophysiological activity, while right black axis depicts more generally the nature of AD pathological changes from normal to abnormal. The double arrows highlight the uncertainty around the onset of the neurophysiological acceleration and slowing with respect to other early pathological changes.