A systems-level model of sleep-dependent memory-consolidation failure in neurodegeneration: the spindle–slow-oscillation decoupling cascade dissociates amyloid and tau
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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 oscillation power, is what the plasticity gate depends on within the model. A β and tau impair memory through orthogonal signatures (A β collapses slow-wave power while sparing replay order, tau the reverse) and this orthogonality holds across the entire A β × tau plane and survives simultaneous ±50% resampling of every mapping coefficient (40/40 samples), so it is not an artefact of a single calibration point. The model yields a falsifiable clinical prediction: closed-loop slow-oscillation enhancement rescues memory only when the deficit is amplitude/coupling-dominated, not when it is replay(tau)-dominated, despite normalising slow-wave power in both cases. Because the therapy arms dissociate coupling from memory benefit, the model also cautions against adopting SO–spindle coupling as a standalone surrogate endpoint.
Author summary
Sleep strengthens new memories through a precisely timed dialogue between three brain rhythms: cortical slow waves, thalamic sleep spindles, and hippocampal ripples. This timing breaks down in Alzheimer’s disease, but it has been unclear how the two hallmark pathologies of the disease (amyloid plaques and tau tangles) each contribute, and whether the same treatment would help both. We built a computer model that reproduces the rhythms and, crucially, lets the measured timing between slow waves and spindles control how strongly memories are written into cortex. As we gradually increase simulated pathology, the rhythms uncouple, memory consolidation fails, and overnight the model begins to forget rather than remember, exactly the trajectory seen in patients. When we scramble only the timing of the rhythms while leaving their strength untouched, consolidation collapses, showing that timing itself carries the memory benefit. The model separates amyloid (which weakens slow waves) from tau (which corrupts the hippocampal replay that timing is supposed to gate), and predicts that a leading experimental therapy (slow-wave stimulation during sleep) will help amyloid-dominated patients but fail tau-dominated patients even though it restores their slow waves. This prediction is directly testable and could guide patient selection for sleep-based interventions.
