An investigational transcranial magnetic stimulation (TMS) approach targeting a key brain network involved in memory has demonstrated the potential to slow disease progression in individuals with mild-to-moderate Alzheimer's disease. Data from a phase II study revealed that personalized, noninvasive stimulation of the default mode network (DMN) led to a statistically significant reduction in the rate of cognitive decline over a one-year period. This innovative approach offers a potential new avenue for addressing synaptic dysfunction, a critical factor in Alzheimer's pathology.
Clinical Trial Results
The single-center study, presented at the Clinical Trials on Alzheimer's Disease (CTAD) meeting in Madrid, involved 48 participants with mild-to-moderate Alzheimer's disease. The primary outcome, measured by the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), showed that after one year, the treatment group had an estimated mean change of 1.3 points, compared to 2.4 points in the sham treatment group (P = 0.038). CDR-SB scores range from 0 to 18, with higher scores indicating greater impairment. Furthermore, the study found that repetitive stimulation resulted in significantly better scores on a key secondary measure assessing activities of daily living compared to the sham group (P < 0.001) at 1 year.
The Default Mode Network and Alzheimer's
The default mode network (DMN) is a network of brain regions known to be responsible for memory and is preferentially affected by the accumulation of amyloid-beta and tau, two key pathological hallmarks of Alzheimer's disease. Giacomo Koch, MD, PhD, of the University of Ferrara in Italy, explained that the precuneus is a key hub within the DMN, making it a strategic target for therapeutic intervention. "We are targeting synaptic dysfunction in Alzheimer's disease," Koch stated, emphasizing that this dysfunction arises from complex interactions between amyloid deposition, tau, and neuroinflammation.
Personalized Stimulation Protocol
The therapeutic approach involved personalizing the TMS protocol for each participant. Single-pulse transcranial magnetic stimulation was used concurrently with electroencephalography (EEG) and MRI data to identify the optimal location for engaging connectivity within the DMN. The therapy consisted of 20 Hz pulses, administered daily for 10 sessions during an initial induction phase, followed by weekly 20-minute sessions for the subsequent 50 weeks.
Safety and Tolerability
EEG data indicated that transcranial magnetic stimulation increased functional connectivity within the DMN, and this increase correlated with improved clinical outcomes. Importantly, the procedure was found to be safe and well-tolerated. Reported adverse events were mild and included headache, scalp or skin discomfort, and neck pain or stiffness.
Expert Commentary
Jeffrey Cummings, MD, ScD, of the University of Nevada in Las Vegas, commented on the study's findings, stating, "I'm encouraged by consistency of the efficacy signals across endpoints in this 1-year monocentric placebo-controlled study. Given its lack of serious side effects, this precision medicine neuromodulation approach represents a promising new direction for treatment research in the field of Alzheimer's."
Ongoing Research
While the results are promising, the study's limitations include a small sample size and mixed enrollment methods. The researchers are planning an upcoming trial in which treatment will be calibrated quarterly using transcranial magnetic stimulation and EEG concurrently, in combination with MRI-guided navigation.
