Title : Neurophysiological change and cognitive response to levetiracetam in Alzheimer disease: Testing the missing mechanistic link
Abstract:
Background:
Network hyperexcitability and subclinical epileptiform activity occur in a subset of patients with Alzheimer disease (AD) and have emerged as candidate therapeutic targets. Low-dose levetiracetam (LEV) has not demonstrated overall cognitive benefit in AD, although exploratory cognitive signals have been reported in electrophysiologically defined subgroups. LEV also produces measurable neurophysiological effects. Whether treatment-associated neural and cognitive responses are coupled within individual patients remains unresolved.
Objective:
To evaluate whether existing human intervention evidence establishes subject-level coupling between LEV-associated neurophysiological and cognitive responses in AD and to identify the analysis required to test this proposed mechanistic link.
Methods:
A 2025 systematic review identified five qualifying human LEV intervention studies in AD or mild cognitive impairment from 1,091 screened publications. This intervention literature, together with subsequent AD neurophysiological studies identified through September 2026, was examined for four mechanistic elements: baseline electrophysiological phenotype, treatment-associated neural response, cognitive response, and subject-level neural-cognitive coupling. Conventional epileptiform events, high-frequency oscillations (HFOs), hippocampal activation, oscillatory connectivity, and perfusion were considered distinct measures rather than interchangeable indicators of network hyperexcitability.
Results:
In LEV-AD, low-dose LEV did not improve the primary cognitive outcome overall, while exploratory executive and spatial-memory benefits were observed among participants with epileptiform activity. Subsequent MEG analysis of 14 LEV-AD participants demonstrated phenotype-dependent HFO responses, including regional ripple decreases in AD with epileptiform activity and increases in some HFO measures among participants without detected epileptiform activity. Studies in amnestic mild cognitive impairment provide mechanistic precedent for treatment-associated reduction of hippocampal hyperactivation accompanying improved memory performance. Despite evidence for baseline phenotype effects, treatment-associated neurophysiological changes, and heterogeneous cognitive responses, no published AD study identified through September 2026 established subject-level coupling between treatment-related neural and cognitive responses.
Conclusion:
Baseline electrophysiological phenotype may help identify who responds to LEV, but this does not establish whether treatment-associated neurophysiological change is related to cognitive response. Existing and recently completed multimodal LEV datasets may permit hypothesis-generating subject-level analyses using prespecified, modality-specific neural and cognitive measures. Such analyses should estimate association without inferring causality, with regional patterns treated as exploratory. Reproducible neural-cognitive coupling would support prospectively powered biomarker-stratified studies, whereas repeated dissociation would weaken a network-mediated explanation of LEV-associated cognitive effects.
Keywords: Alzheimer disease; levetiracetam; network hyperexcitability; epileptiform activity; high-frequency oscillations; cognition.
