A randomized clinical trial published in JAMA Network Open evaluated the safety, feasibility, and biologic effects of home-based gamma transcranial alternating current stimulation in patients with prodromal or mild Alzheimer disease. The study assessed whether repeated stimulation delivered outside a clinical setting could modulate brain activity and cognitive measures without compromising safety or adherence.
The trial enrolled 50 patients with biomarker-confirmed Alzheimer disease (AD) (mean age, 67 years; 50% female) who were randomly assigned to receive either gamma transcranial alternating current stimulation (tACS) or sham stimulation for 8 weeks in a double-blind phase. This was followed by an open-label phase in which all patients received active treatment for an additional 8 weeks and were observed for 8 weeks of follow-up. Stimulation was delivered 5 days per week for 60 minutes using a portable device targeting the precuneus, a brain region involved early in AD and associated with cognitive networks.
Primary outcomes included safety, feasibility, and clinical efficacy. Secondary outcomes focused on biologic and neurophysiologic measures, including electroencephalographic (EEG) gamma power, cholinergic neurotransmission assessed using transcranial magnetic stimulation, plasma AD biomarkers, and brain connectivity on magnetic resonance imaging.
Home-based gamma tACS was well tolerated, with no serious adverse events reported. Adherence was high, with fewer than 2% of sessions missed. The most commonly reported adverse effect was transient light flickering, which did not interfere with participation. Caregiver burden related to home treatment was reported as low.
During the randomized phase, participants receiving active stimulation showed statistically significant differences compared with the sham group on several clinical measures, including global cognitive function, activities of daily living, and associative memory. Participants who crossed over from sham to active stimulation during the open-label phase showed similar improvements.
Neurophysiologic testing showed increased gamma-frequency activity on EEG over parietal and frontal regions following gamma tACS, consistent with targeted modulation of brain oscillations. Measures of cholinergic neurotransmission also improved during active stimulation and were correlated with improvements in associative memory performance. These changes were not observed during sham treatment.
In contrast, plasma biomarkers commonly used in AD assessment, including amyloid-beta, phosphorylated tau217, neurofilament light, and glial fibrillary acidic protein, did not change significantly during the study. Measures of functional brain connectivity on MRI also remained stable over the treatment period.
The investigators found no added benefit from extending treatment beyond eight weeks, as clinical and neurophysiologic measures plateaued with longer stimulation. While blood-based biomarkers did not reflect short-term changes, neurophysiologic measures provided evidence of biologic engagement.
The researchers noted that larger trials with longer follow-up will be needed to determine the durability of these effects and whether biomarker changes emerge over time. The findings support continued investigation of home-based gamma tACS in research settings but do not establish it as a diagnostic or therapeutic standard of care.
Several investigators reported research funding, advisory roles, or intellectual property related to neuromodulation and Alzheimer research; no other disclosures were reported. The study was supported by grants from the Italian Ministry of Health and European research programs.
Source: JAMA Network Open
