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Investigational transcranial magnetic stimulation that targeted a brain network involved in memory slowed progression in mild-to-moderate Alzheimer's disease, data from a small phase II study suggested.

At 1 year, noninvasive personalized stimulation of the default mode network (DMN) led to an estimated mean change of 1.3 points on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), compared with 2.4 points for sham treatment (P=0.038), reported Giacomo Koch, MD, PhD, of the University of Ferrara in Italy at the Clinical Trials on Alzheimer's Disease annual meeting in Madrid.

CDR-SB scores -- the primary outcome in this single-center study -- range from 0 to 18, with higher scores indicating greater impairment.

Repetitive stimulation also led to significantly better scores on a key secondary measure of activities of daily living compared with sham (P<0.001) at 1 year.

The findings confirm the potential of transcranial magnetic stimulation to enhance neuroplasticity, gamma activity, and network connectivity in the DMN, Koch said. "Personalized noninvasive brain stimulation of the DMN could represent a novel therapeutic approach in Alzheimer's disease patients," he stated.

The results add to prior supporting neuromodulation to slow cognitive impairment and preserve activities of daily living, he added.

"I'm encouraged by consistency of the efficacy signals across endpoints in this 1-year monocentric placebo-controlled study," noted Jeffrey Cummings, MD, ScD, of University of Nevada in Las Vegas. "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."

The DMN is responsible for memory and has preferential accumulation of amyloid-beta and tau versus other regions, Koch noted. The precuneus is a key DMN hub.

"We are targeting synaptic dysfunction in Alzheimer's disease," Koch said. "The synaptic dysfunction is the consequence of complex interactions between amyloid deposition, tau, and neuroinflammation that occurs during several years. And at some point, it progressively affects the communication with neurons and disrupts synaptic activity at different levels."

The randomized 48 people with mild-to-moderate Alzheimer's disease to treatment or sham for 52 weeks. It included 31 patients from the randomized trial who extended therapy to 12 months; 17 new participants also received the identical protocol for 12 months. A number of people were lost to follow-up during the COVID-19 pandemic, and a total of 32 participants ultimately completed the 12-month study.

Personalization was established using single-pulse transcranial magnetic stimulation concurrently with electroencephalography (EEG) and MRI data to define the best spot to engage connectivity. The therapy consisted of 20 Hz pulses and was delivered daily for 10 sessions during an induction phase, then in weekly 20-minute sessions for the next 50 weeks.

EEGs showed that transcranial magnetic stimulation increased functional connectivity within the DMN, which correlated with clinical outcomes, Koch said. The procedure was safe and well tolerated, he noted; adverse events included headache, scalp or skin discomfort, and neck pain or stiffness.

Study limitations include a small sample size and mixed enrollment methods. In an upcoming trial, treatment will be calibrated quarterly using transcranial magnetic stimulation and EEG concurrently in combination with MRI-guided navigation.