Gallego-Rudolf J, Wiesman AI, Pichet Binette A, Villeneuve S, Baillet S, PREVENT-AD Research Group. Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults. Nat Neurosci. 2024 Sep 18; PubMed.
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University College London
This study provides important evidence supporting a biphasic neurophysiological model of Alzheimer’s disease (AD) progression, as previously proposed by Harris et al., 2020. Several studies from multiple laboratories have established a clear sequence in mouse models in which Aβ accumulation causes neuronal hyperactivity/hypersynchrony, while tau pathology subsequently leads to neuronal silencing. This framework suggests the existence of a critical tipping point in AD progression, where tau pathology shifts neuronal dynamics from a hyperactive to a hypoactive state.
Employing MEG to analyse whole-brain spectral band power alongside quantitative PET imaging of Aβ and tau, the current study extends these findings to a human cohort. Cognitively unimpaired individuals with high Aβ deposition, but no significant tau pathology, exhibited enhanced fast-frequency (alpha-beta) oscillatory activity along with reduced slow-frequency (delta-theta) activity. In contrast, subjects with both high Aβ and tau burden demonstrated a clear shift toward slower neuronal oscillations, indicative of neurophysiological slowing. This shift was associated with a longitudinal decline in cognitive domains related to attention and memory.
These novel findings emphasize the urgent need to more precisely characterise the spatiotemporal neurophysiological changes and cellular/molecular mechanisms that determine this transition, and to develop quantifiable predictors for this “real-world” tipping-point of accelerated neural system failure, to inform early intervention strategies aimed at slowing disease progression.
References:
Harris SS, Wolf F, De Strooper B, Busche MA. Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease. Neuron. 2020 Aug 5;107(3):417-435. Epub 2020 Jun 23 PubMed.
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