Synaptic regulatory flux dynamics: Stiffness and homeostatic failure in Alzheimer's disease

Traditional electroencephalographic analysis in Alzheimer Disease focuses on spectral slowing, a terminal phenotype that overlooks the preceding functional failure of homeostasis. This study introduces Synaptic Regulatory Flux Dynamics (SRFD), a computational framework that models the EEG signal as a physical trajectory governed by the interplay between Excitatory Drive (E) and Regulatory Flux (R).

Resting state EEG recordings from 88 participants (36 CE, 23 Frontotemporal Dementia [FTD], and 29 Cognitively Normal [CN]) were analyzed. The study derived novel biophysical metrics, including Instantaneous Homeostatic Error (IHE) and the Synaptic Stiffness Index (SSI), to assess the integrity of the excitation inhibition (E/I) balance.

It found that the AD cohort exhibited a statistically significant elevation in Mean IHE compared to controls (0.557vs0.535; p=0.0115), indicating a systemic failure of inhibitory interneurons to clamp excitatory transients. This flux decoupling was accompanied by a reduced Synaptic Stiffness Index (p=0.011), predominantly affecting posterior beta band networks. Furthermore, the framework successfully differentiated the metabolic silence of AD from the high energy, disorganized hyperexcitability of FTD.

Synaptic Regulatory Flux Dynamics provides a noninvasive, mechanistic biomarker of synaptic fragility that precedes gross atrophy. By evaluating the loss of regulatory stiffness, this framework offers a functional window into the early pathophysiology of neurodegeneration, potentially enhancing early detection and therapeutic monitoring.