Personalized Neuromodulation Slows AD Progression

New research supports the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) for Alzheimer’s disease (AD).

In a 52-week phase 2 trial, personalized rTMS applied over the precuneus, a core component of the default mode network (DMN), slowed the progression of cognitive and functional decline in patients with mild to moderate AD.

As reported previously by Medscape Medical News, the 52-week results align with the results seen at 24 weeks.

“These latest results provide new additional evidence…supporting the potential for neuromodulation of the DMN to slow the impairment of cognitive functions, preserve activities of daily living, and reduce behavioral disturbances in Alzheimer’s patients, with no significant side effects,” Giacomo Koch, MD, PhD, professor of physiology, University of Ferrara, Ferrara, Italy, and director of the Brain Stimulation Laboratory, Santa Lucia Foundation, said in a statement.

The results were presented at the 17th Clinical Trials on Alzheimer’s Disease (CTAD) Conference.

Personalized Neuromodulation

The DMN is responsible for memory and shows preferential accumulation of amyloid beta and tau vs other brain regions. The precuneus is the key hub in the DMN, and patients with AD show alterations of this key functional area, Koch explained.

The phase 2 trial enrolled 48 patients (mean age, 72 years; 56% women) with mild to moderate AD on acetylcholinesterase inhibitor therapy for at least 6 months.

They received an initial 2-week intensive course of rTMS or sham rTMS applied over the precuneus five times per week for 2 weeks (10 sessions, 1600 pulses, 20 Hz), followed by a 50-week maintenance phase, in which the same stimulation was applied once weekly.

Personalization of the rTMS treatment was established using single-pulse TMS concurrently in combination with electroencephalography (TMS-EEG) based on the recording, processing, and proprietary analysis of transcranial evoked potentials and patient MRI data.

A total of 32 patients (68%) completed the study.

The study showed that personalized rTMS of the precuneus had a significant effect on the primary outcome of change from baseline to week 52 of the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).

The estimated mean change in CDR-SB after 52 weeks was 1.36 in the rTMS group vs 2.45 in the sham rTMS group (P = .038) — representing a 44% slowing of AD’s progression over 12 months.

There were also statistically significant effects of rTMS on key secondary outcome measures of the AD Assessment Scale-Cognitive Subscale (P = .02), AD Cooperative Study-Activities of Daily Living scale (P P = .05), and Neuropsychiatric Inventory (P = .048) scores.

The study also showed an increase in functional connectivity within the DMN in the active rTMS group but not in the sham group.

rTMS was safe and well tolerated with only a few minor adverse events reported, including mild headache, skin or scalp discomfort, and neck pain.

Limitations of the study included the small sample size, single-center design, and lack of cerebrospinal fluid or blood-based biomarkers that would provide evidence for the biological effects of rTMS.

Koch said personalized noninvasive brain stimulation of the DMN “could represent a novel therapeutic approach in AD patients.”

He noted that “personalization is a key factor,” and his group is working on algorithms that may “automatize the selection of individual parameters.”

The technology has received breakthrough device designation by the US Food and Drug Administration. The researchers plan to launch a pivotal randomized controlled clinical trial in 2025.

‘Exciting Frontier’

Reached for comment, Shaheen Lakhan, MD, PhD, neurologist and researcher based in Miami, noted that the “personalized nature of the rTMS intervention in this Alzheimer’s study is a particularly exciting aspect.”

“By using TMS-EEG to optimize the stimulation parameters for each individual patient, the researchers were able to potentially maximize the benefits of this noninvasive neuromodulation technique,” said Lakhan, who wasn’t involved in the research.

“This approach aligns well with the growing recognition that Alzheimer’s disease is not a single, monolithic condition, but rather an amalgam of different, smaller diseases based on genetics, protein signatures, structural and functional neuroanatomy, behavioral profiles, and other phenomic factors,” Lakhan told Medscape Medical News.

He said the field is increasingly understanding that so-called “common” diseases like AD are highly heterogeneous, with diverse underlying mechanisms driving the observed clinical presentation.

“This heterogeneity necessitates a move away from one-size-fits-all treatments towards more personalized, precision-based interventions. If these findings continue to demonstrate the promise of personalized, biomarker-guided neuromodulation, it could pave the way for the development of digital therapeutics that can achieve similar levels of individualization,” Lakhan predicted.

“The ability to precisely modulate brain networks based on each patient’s unique neurophysiology represents an exciting frontier in the search for more effective, patient-centered approaches to managing these complex neurodegenerative disorders,” he added.

Funding for the study was provided in part by the BrightFocus Foundation, the Italian Ministry of Health, European Commission, Alzheimer’s Drug Discovery Foundation, and Sinaptica Therapeutics. Koch is a scientific co-founder and holds stocks of Sinaptica Therapeutics; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Epitech, Roche, and Novo Nordisk; holds a patent on the use of rotigotine in combination with cholinesterase inhibitors in patients with AD and another on systems and methods for providing personalized targeted noninvasive stimulation to a brain network. Lakhan had no relevant disclosures.