MEG RESTING STATE TRANSIENT BETA EVENTS EXHIBIT AN INVERTED-U TRAJECTORY ACROSS ALZHEIMER’S DISEASE PROGRESSION LINKED TO PHYSIOLOGICAL CHANGES WITH THE HUMAN NEOCORTICAL NEUROSOLVER

Alzheimer’s disease (AD) develops over decades, with neurophysiological alterations emerging long before clinical symptoms. M/EEG is powerful for identifying sensitive, non-invasive brain-based early stage biomarkers. Recent studies suggest that electrophysiological signatures of AD exhibit non-linear dynamics, consistent with the Aβ/tau cascade hypothesis.

We’ve recently shown that features of transient 13-30Hz beta events in resting MEG oscillations from precuneus (PC) are decreased in a prodromal cohort of mild cognitive impairment patients (MCI) that convert to AD within 2.5 years (CONV;n=41) compared to those who do not (NOCONV;n=44). Here, we expanded our analysis to earlier at risk populations, including a preclinical cohort of first-degree relatives of AD patients (FH;n=10) and healthy controls (NR;n=10).

Preliminary analyses (F1A) show that asymptomatic FH exhibit increased beta-event durations compared to NR (p < 0.05), with similar trends for beta-event rate and power. When compared to the differential effects in CONV who showed reduced beta-event expression compared to NOCONV (p<0.05), together with poorer cognitive performance, an inverted-U pattern is observed across the AD continuum.

The Human Neocortical Neurosolver (HNN) neural modeling software designed for cellular and circuit level interpretation of M/EEG was used to explore candidate mechanisms underlying these patterns (F1B). Simulations show that combined alterations in pyramidal neuron calcium conductance, thalamocortical drive synchrony, and inhibitory synaptic strength (F1C) can reproduce the inverted-U patterns (F1D). These findings position transient beta events as mechanistically-interpretable biomarkers of early AD risk, linking electrophysiology to AD pathophysiology.