Developing Topics.

Abstract

Alzheimer's disease is characterized by cortical hyperexcitability in the early stages, which may be attributed to the intricate interplay between tau and amyloid β pathologies. To combat the propagation of tau pathology and cognitive decline, it may be beneficial to maintain a high degree of functional brain network segregation. Additionally, the use of non-invasive brain stimulation techniques to alter cortical excitability could help alleviate cognitive deficits. However, it is unclear how these interventions are related to tau or amyloid biomarkers. In this study, 530 participants aged 40 to 65 from the Barcelona Brain Health Initiative cohort were analyzed to investigate the connection between plasma concentration of tau phosphorylated at amino acid 181 (pTau181), cortical excitability, and segregation of functional brain networks. Participants had functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and pTau181 available. A subset of 47 participants also underwent transcranial magnetic stimulation with concurrent EEG (TMS-EEG). Cortical excitability was assessed using the one-over-f slope of the EEG power spectrum (1/f-slope) and evoked response to a TMS perturbation (TEP) of the left prefrontal cortex (L-PFC) between 160-240ms post single-pulse TMS. The degree of segregation between major functional networks was measured from fMRI data using the system segregation statistic. A generalized linear model with a gamma distribution (Table 1) revealed that steeper 1/f-slope correlated with higher pTau181 concentration, particularly in participants older than 53 years of age (Figure 1.A), or system segregation below 0.28 (Figure 1.B). A multiple linear regression within the TMS-EEG subsample (Table 2) revealed that the TEP response correlated positively with pTau181 as age increased, and that this model, despite including a smaller sample size, better explained pTau181 concentrations. The study shows that cortical excitability is related to pTau181 based on age and system segregation. The TEP response is a more sensitive marker than unperturbed EEG metrics in explaining the relation between excitability and pTau181 concentrations. Combined TMS with EEG could potentially be an inexpensive and scalable approach for early identification and longitudinal tracking of middle-aged adults at risk for cognitive decline and dementia.