Functional Neurophysiological Biomarkers of Early‐Stage Alzheimer’s Disease: An Experimental Perspective of Network Hyperexcitability in Disease Progression and Pharmacological Interventions

Abstract

AbstractBackgroundNeuronal network hyperexcitability and related alterations in the excitation‐inhibition balance hold promise as early functional biomarkers of network dysfunction and as prodromal indicators of Alzheimer’s disease (AD) pathogenesis. However, the translational validity of hyperexcitability as found in some AD pathology animal models seems restricted by their limited capacity to encompass the complexity of clinical AD.MethodA comparison was made between different AD pathology mouse models with respect to the development of neuronal network hyperexcitability (LFPs) and epileptiform EEG. To this end, amyloid APP‐KI and APP/PS1 mice were assessed with and without hippocampal seeding of (human‐derived) pathological tau conformers at different ages (3‐6 months) and post‐seeding periods (1‐5 months) concerning alterations in amyloid and tau pathology in relation to hyperexcitability‐related, vigilance‐controlled neurophysiological changes.ResultsAnimals from both AD models progressively developed AT8‐tau pathology that is amplified by the presence of amyloid pathology, but that only in APP/PS1 is further intensified by the starting amount of amyloid pathology. Alterations in EEG gamma oscillations appears to be associated with the development of amyloid and tau pathology, and may be an indicator of neuropathology, of neuronal network dysfunction, and of a potential disposition to future deposition of pathogenic amyloids. Immediate localized alterations in hippocampal EEG power spectra associated with tau seeding were found, while a lack of longitudinal changes in neuronal hypersynchrony was noted: hyperexcitability as indicated by increased broadband power spectra was noted in APP/PS1 but not APP‐KI animals at baseline. These differential findings between AD models exemplify the difficulty and complexity associated with identifying physiologically relevant and translatable early biomarkers of AD dysfunction.ConclusionFunctional neurophysiological biomarkers based on early alterations in neuronal circuits, including hyperexcitability, in combination with dysfunctional (GABA‐ergic) inhibitory control of cortical pyramidal neurons should be assessed and validated in the complex context of neurodegeneration, specific amyloid/tau pathology, as well as neuroinflammation and disturbed sleep‐related processes like glymphatic clearance. This complexity constitutes both an additional challenge and a novel opportunity to AD pathology rodent models, in which such an integrative approach is feasible, but whose translational validity is still to be determined in the development of neuroprotective and neurorestorative therapeutic strategies.