Hyperexcitability in Older Adults with Elevated Beta-Amyloid

Abstract

Background: Growing evidence links beta-amyloid (Aβ) and neuronal hyperexcitability in preclinical mouse models of Alzheimer’s disease (AD). The aim of this study was to compare neuronal excitability between cognitively normal amyloid positive (CNAβ+) and those without elevated amyloid (CNAβ-) older adults. We hypothesized CNAβ+ participants would show hyperexcitability, indexed by greater peak P3 event-related potential peak amplitude, shorter peak latency, and changes in event-related power, compared to CNAβ-.Methods: CNAβ+ participants (n = 17, age: 73 ± 5, 11 women, MOCA scores 26 ± 2) and 17 CNAβ- participants group-matched for age, sex, and MOCA completed the a working memory task (n-back with n = 0, 1, 2) test while wearing a 256-channel EEG net. P3 peak amplitude and latency of the nontarget, target and task difference (nontarget – target), and event-related power, extracted from Fz (main outcome), Cz, and Pz were compared between groups using linear mixed models. Mean Aβ standard uptake value ratios (SUVR) were correlated with P3 amplitude and latency using Pearson r.Results: P3 peak amplitude of the task difference (p = 0.048) and P3 peak latency of non-targets trials (p = 0.006) at Fz differed between groups. Similarly, power was lower in the delta band (p = 0.04) for nontargets at Fz in CNAβ+ participants. CNAβ+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between mean Aβ SUVR and latency of the 1-back (r = -0.69; p = 0.003) and 2-back (r = -0.69; p = 0.004) of the task difference at channel Fz in the CNAβ+ group.Conclusions: Our pilot data suggests that elevated amyloid in cognitive normal older adults is associated with hyperexcitability in P3 ERP. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.

A multi-scale model explains oscillatory slowing and neuronal hyperactivity in Alzheimer’s disease

“…It is presently challenging to make comparisons with clinical data, as early-stage hyperactivation in human AD and its effect on E/MEG spectra are yet to be fully explored. Recent studies, however, have found increases in alpha power in healthy Aβ-burdened and amnesic older adults specifically in the parietal region [47,49], the region which our simulations predict to show the greatest early alpha power increase. Moreover, there is preliminary evidence for hyperactivation in the default-mode network in early-stage AD patients [45].…”

“…Recent findings indicate that oscillatory slowing is prominent in frontal and parietal regions and correlates with subjective cognitive decline [47] and clinical tests for dementia [48]. Moreover, momentary increases in alpha power have been observed for early-stage AD patients [45] and amnesic [47], Aβ-burdened healthy adults [49]. Hyperactivity induced by Aβ and damage-related compensatory mechanisms may be the cause of such early-stage power increases.…”