Preliminary Evidence for Perturbation‐Based tACS‐EEG Biomarkers of Gamma Activity in Alzheimer's Disease

BACKGROUND: Alzheimer's disease (AD) is characterized by impaired inhibitory circuitry and GABAergic dysfunction, which is associated with reduced fast brain oscillations in the gamma band (γ, 30-90 Hz) in several animal models. Investigating such activity in human patients could lead to the identification of novel biomarkers of diagnostic and prognostic value. The current study aimed to test a multimodal "Perturbation-based" transcranial Alternating Current Stimulation-Electroencephalography (tACS)-EEG protocol to detect how responses to tACS in AD patients correlate with patients' clinical phenotype. METHODS: Fourteen participants with mild to moderate dementia due to AD underwent a baseline assessment including cognitive status, peripheral neuroinflammation, and resting-state (rs)EEG. The tACS-EEG recordings included brief (6') tACS blocks of gamma (i.e., 40 Hz) stimulation administered through 4 different montages, with Pre/Post 32-Channels EEG for each block. Changes in tACS-EEG and rsEEG γ band power with respect to baseline were adopted as a metric of induction and compared with cognitive scores and neuroinflammatory biomarkers. RESULTS: We found positive correlations between 40 Hz-induced γ activity in fronto-central-parietal areas and patient cognitive status and negative ones with neuroinflammatory markers. Participants with greater cognitive impairment exhibited less γ induction and higher peripheral neuroinflammation. The same analysis performed with spectral power from baseline rsEEG resulted in no significant correlations, promoting the value of tACS-based perturbation for capturing individual differences in pathology-related brain features. CONCLUSIONS: Our work suggests a link between tACS-induced γ band spectral power and clinical severity, with weaker γ induction corresponding to more severe clinical/cognitive impairment. This study provides preliminary support for the development of novel physiological biomarkers and therapeutic targets based on disease severity.