Excitation–inhibition homeostasis in Alzheimer’s disease: a selective multiscale review of mechanisms, sex differences, and therapeutic opportunities

Alzheimer's disease is increasingly viewed as a breakdown of balanced excitation-inhibition (E/I) homeostasis layered atop classical proteinopathy. Restoring circuit-level neural excitation and inhibition is rapidly becoming a tractable therapeutic strategy, guiding trials of circuit-modulating drugs such as levetiracetam. To date, however, findings across species and modalities remain fragmented, and it is unclear how to contextualize AD-focused E/I findings across scales and methodologies. Synthesizing over 150 studies of E/I homeostasis in AD, we organize the results into several prevailing themes: excitatory/inhibitory effects of amyloid and tau, whether hyperexcitation precedes amyloid plaque deposition, progressive oscillatory slowing (a shift of aggregate neural signal frequencies towards lower frequencies) as AD worsens, early preclinical hyperexcitation peaking in MCI and transitioning to hypoexcitation in AD, sex differences in E/I trajectories, APOE4 as a mediating factor, the contribution of neuroinflammation and metabolic dysfunction to E/I imbalance, and E/I-focused trials/experiments, particularly involving levetiracetam. These dominant themes are interpreted in a framework of multidimensional E/I homeostasis, rather than a single-axis imbalance. To support this integration, we first outline the microscale, mesoscale, and macroscale techniques used to assess E/I in AD, ranging from patch clamping and extracellular recordings to EEG/MEG and fMRI. By charting these multiscale E/I shifts, our synthesis offers a unifying framework to guide future experimental work and accelerate the design of biomarker-driven trials of E/I-targeted therapies in Alzheimer's disease.