Background

NeuroADTM rTMS is a non-invasive neuromodulation system. It combines brief trains of 10 Hz electric pulses to brain regions affected in AD, i.e., frontal, temporal, and parietal regions, alternating with sessions of computerized cognitive training designed to engage those same regions. Pulses are delivered by a figure-eight-shaped magnetic coil placed outside the head, near the scalp. Six brain regions are stimulated separately. A course of treatment consists of two or more weeks of daily sessions. 

High frequency TMS (10 Hz or greater) increases cortical excitability, induces LTP-like changes in synaptic strength, and increases brain-derived neurotrophic factor levels. The end effects vary based on the frequency and intensity of the pulses, and the brain areas targeted.

NeuroAD is one of several rTMS protocols that have been evaluated for Alzheimer’s disease. Multiple meta-analyses indicate that, overall, this form of neuromodulation can improve cognitive function in people with mild to moderate AD, although trials have not shown a consistent benefit from concurrent cognitive training (e.g., see Menardi et al., 2022; Wang et al., 2020 ; Lin et al., 2019). One study suggests that rTMS is less effective in ApoE4 carriers than noncarriers (Wei and Chen, 2021).

rTMS targeted to the left dorsolateral prefrontal cortex is approved for the treatment of refractory depression worldwide. In Europe, rTMS is approved for treatment of Alzheimer’s, Parkinson’s, and other conditions. rTMS is considered safe, with minor side effects including headache, scalp discomfort at the stimulation site, tingling, spasms or twitching of facial muscles, toothache, neck pain, and lightheadedness.

Findings

Early studies on the NeuroAD device claimed improvements in ADAS-Cog scores after six weeks of daily 10 Hz TMS stimulation of the right and left dorsolateral prefrontal cortex, the left frontal and left posterior temporal lobe, and the right and left parietal somatosensory association cortex, plus computerized cognitive training, but lacked a sham comparison group (e.g., see Bentwich et al., 2011). Additional open-label studies subsequently reported improvements in cognition and long-term positive effects on apathy, with high treatment completion rates and no safety issues (Rabey and Dobronevsky, 2016; Nguyen et al., 2017; Suarez Moreno et al., 2022).

Two placebo-controlled trials compared the active treatment with sham rTMS and sham cognitive training. The first, run in Israel from January 2010 to September 2011, involved 15 patients with early to moderate AD. The placebo consisted of a mock stimulation procedure using an inactive coil, and viewing a nature movie instead of cognitive training. Treatment was in one-hour sessions five days a week for six weeks, followed by three months of biweekly maintenance sessions. The study reported improvement in the primary outcome of ADAS-Cog by 3.76 points after six weeks compared to 0.47 on placebo; and a 3.52-point improvement after 4.5 months compared to a worsening in the placebo group (Rabey et al., 2012). The second trial, in 2013, used the same treatment and control paradigm in 28 patients in Korea; it likewise reported an improvement in the ADAS-Cog after six weeks in the treated compared to sham control group (Lee et al., 2016).

A study run from 2010 to 2015 incorporated an additional control group to test the effect of cognitive training alone. Thirty-four participants were divided into three groups: One received six weeks of 10 Hz stimulation and cognitive training, while the others received sham stimulation paired with real or sham cognitive training, against a primary outcome of ADAS-Cog one month after treatment. In this study, the stimulation/training group improved their ADAS-Cog scores compared to sham/sham, while the patients who got cognitive training alone did not (Brem et al., 2020). 

In 2012, NeuroAD™ was approved in Europe to treat AD, and was distributed in Europe, Australia, and Israel.

Between October 2013 and January 2016, Neuronix conducted a pivotal trial for U.S. FDA approval. It enrolled 131 people with mild to moderate AD at 10 sites in the U.S. and Israel, comparing six weeks of NeuroAD to the sham treatment. The study failed to show any difference in the primary outcome of change in ADAS-Cog from baseline to week 7. In a posthoc analysis of only people with milder AD, those whose baseline ADAS-Cog score was below 30 had a significant improvement of 2.11 points with treatment, compared to 0.32 points in the sham group (see Apr 2017 conference news; Sabbagh et al., 2020). 

A study planned to start in November 2014 enrolling 40 patients and comparing the same two groups was terminated after just one was enrolled, citing an administrative decision.

An application for marketing approval was rejected by the U.S. FDA in June 2018. The company filed an appeal and the FDA denied it again in March 2019, citing a lack of demonstrated benefit in clinical trials (Mar 2019 news). Neuronix closed in late 2019.

For details of these trials, see clinicaltrials.gov