A systems-level model of sleep-dependent memory-consolidation failure in neurodegeneration: the spindle–slow-oscillation decoupling cascade dissociates amyloid and tau
Abstract
During non-rapid-eye-movement (NREM) sleep, the temporal coupling of cortical slow oscillations (SOs), thalamic spindles, and hippocampal sharp-wave ripples drives the consolidation of declarative memories. This coupling degrades in ageing and Alzheimer’s disease (AD), and although A β and tau leave dissociable signatures in human sleep, the mechanisms by which progressive pathology dismantles the consolidation machinery are difficult to isolate experimentally, and have not to our knowledge been reproduced in a model that can be perturbed directly. We built a systems-level model in which cortical SOs and thalamic spindles are generated by reduced oscillators, hippocampal ripples replay encoded spike sequences, and the measured per-event SO–spindle timing alignment causally gates spike-timing-dependent plasticity on cortical sequence synapses. A post-sleep cued-recall test reads out consolidation. Five neurodegeneration parameters (amyloid, tau, synaptic density, GABAergic inhibition, cholinergic tone) map to distinct mechanisms grounded in the human and animal literature. The model reproduces graded healthy consolidation and a progressive collapse in which coupling, slow-wave power, spindle power and recall fall monotonically and the overnight memory effect flips from consolidation to net forgetting, with weak memories failing first. Scrambling SO–spindle timing while holding oscillation power fixed abolishes consolidation, establishing that coupling timing, rather than…
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