Publication in Alzheimer's & Dementia Elucidates Multimodal Mechanism of Action Underpinning Promising New Neuromodulation Therapy for Alzheimer's

Business Wire

18-06-2025

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Sinaptica Therapeutics, Inc., a clinical-stage company leading the development of a new class of personalized neuromodulation therapeutics to treat Alzheimer's and other primary neurodegenerative diseases, today announced that a comprehensive review article published in the peer-reviewed journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association delivers a landmark synthesis of evidence that positions repetitive transcranial magnetic stimulation (rTMS) as a scientifically grounded, non-invasive therapeutic strategy for Alzheimer's disease (AD).
The publication, ' The Neurobiological Foundation of Effective Repetitive Transcranial Magnetic Brain Stimulation in Alzheimer's Disease,' was authored by a multidisciplinary team led by Sinaptica scientific co-founder Dr. Giacomo Koch of the Santa Lucia Foundation, University of Ferrara, and the Italian Institute of Technology. Drawing on foundational models and recent clinical and animal data, the article charts how rTMS modulates biological systems across multiple levels—molecular, cellular, synaptic, and network-wide—to address core mechanisms of neurodegeneration.
'Our goal with this publication is to consolidate the preclinical and clinical findings to explain why rTMS isn't just symptomatic—it is actually disease modifying. This gives us a foundational understanding of how stimulation protocols can directly modulate neurotransmission, reduce inflammation, enhance plasticity, and even promote clearance of toxic proteins,' said Giacomo Koch, MD, PhD, Sinaptica scientific co-founder, Neurologist, Professor of Physiology, University of Ferrara, and Director, Non-Invasive Brain Stimulation Laboratory, Santa Lucia Foundation.
The publication reviews the evidence supporting the fundamental mechanisms of action of rTMS treatments in AD. rTMS exerts profound effects from the micro-molecular scale to the macro network-level scale. By engaging distinct pre- and post-synaptic structures within the stimulated neural network, it directly and indirectly influences various cellular and molecular components. These effects work together to stabilize and improve brain function through the following means:
Strengthens Neuronal Structures - Upregulates neurotrophic factors e.g. BDNF, leading to neuronal structural changes e.g. via remodeling of dendritic spines.
Strengthens Synapses - Modulates neurotransmitter circuits, both through increased production and sensitivity of dopaminergic-, glutamatergic-, and GABA-ergic pathways.
Neuroinflammation - Mitigates neuroinflammation by reducing microglial activation and pro-inflammatory cytokines release e.g. by promoting glutamate reuptake.
Amyloid - May counteract beta amyloid overproduction and toxic aggregation by interrupting a vicious cycle of hyperexcitability.
Tau - Potentially reduces tau hyperphosphorylation and accumulation via the GSK-3β pathway.
Clearance - Potentially increases glymphatic clearance of toxic proteins.
All of the above mechanisms contribute to restoring network-wide excitation/inhibition imbalance, restoring LTP-like mechanisms of neuroplasticity, and enhancing large-scale connectivity.
Authors of this definitive paper are Giacomo Koch (Experimental Neuropsychophysiology Lab, Department of Clinical and Behavioural Neurology, Santa Lucia Foundation IRCCS), Emiliano Santarnecchi (Gordon Center for Medical Imaging, Mass General Research Institute; Harvard Medical School), Harald Hampel (Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital), Annibale Antonioni (Department of Neuroscience and Rehabilitation, University of Ferrara), and Alessandro Martorana (Memory Clinic, Department of Systems Medicine, University of Tor Vergata).
'Based on this new publication, repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus in the brain's central Default Mode Network is an emerging element of precision medicine in neurology. Based on accumulating basic, translational, and clinical evidence, this standardized targeted non-invasive electro-magnetic brain stimulation will likely be part of the evolving clinical care landscape with different treatments and combinations,' said co-author Dr. Harald Hampel, a leading international brain researcher and Alzheimer's disease (AD) scientist. 'Further clinical studies are warranted to benefit the globally increasing population of AD patients.'
As the field moves toward more personalized and mechanistically distinct Alzheimer's therapies, this review provides a vital reference point for researchers, clinicians, and innovators. It supports the integration of rTMS into a precision medicine framework that could transform how providers manage Alzheimer's—potentially shifting the paradigm from reactive care to proactive, highly tailored, connectome-level intervention, including combination therapies.
'We are beginning to see rTMS emerge as a safe, scalable precision medicine platform for Alzheimer's,' said Emiliano Santarnecchi, PhD, co-founder of Sinaptica Therapeutics, Associate Professor of Radiology & Neurology at Harvard Medical School, as well as Director, Precision Neuroscience & Neuromodulation Program and Director, Network Control Laboratory, at Massachusetts General Hospital in Boston, MA. 'This is not just about stimulating the brain—it's about rewiring disease-affected networks with intention and scientific precision.'
The publication establishes the translational relevance of these findings, citing Phase 1 and 2 human trials in which targeted, neuronavigated rTMS protocols have boosted memory, stabilized cognitive performance, restored functional brain connectivity, and enhanced gamma rhythm activity—key markers of brain health. These protocols, particularly those focused on the Default Mode Network (DMN), are seen as promising interventions for mild cognitive impairment and Alzheimer's.
'This definitive reference illuminates an evolving paradigm shift away from simplistic linear 'nerve stimulation' toward the new and rapidly progressing field of 'network modulation,' said Ken Mariash, CEO of Sinaptica Therapeutics. 'This publication presents a higher order systems-level approach to how we think about and treat brain diseases. Sinaptica's nDMN therapy induces a cascade of network-wide effects that compound, ultimately restoring the exquisite balance of the networks involved in memory and cognition. In this new context, we can better understand how it was possible to achieve such strong and consistent clinical outcomes in previous Phase 2 trials in mild/moderate Alzheimer's patients. This important publication reinforces everything we're building at Sinaptica by elucidating the neurobiological mechanisms underlying our therapy and validating the importance of targeting the brain's network-level dysfunction with both precision and personalization.'
About the SinaptiStim ® System
The SinaptiStim ® System is an investigational new approach to treating Alzheimer's disease using non-invasive personalized precision neuromodulation. Calibrated to each individual's brain, the therapy is delivered in weekly 20-minute sessions in a recliner. The SinaptiStim system delivers safe, painless, customized neurostimulation technology targeting the Default Mode Network (DMN), an important brain network associated with episodic memory, introspection, and other cognitive functions. The technology was granted Breakthrough Device Designation by the FDA in 2022.
The company is preparing for a pivotal randomized controlled clinical trial in mild-to-moderate Alzheimer's. In this trial, the treatment will be calibrated quarterly using TMS and EEG concurrently in combination with MRI-guided neuronavigation, which enables the SinaptiStim System to achieve customized precise repeatable targeting and safe-yet-effective dosage for each patient, tracking progress and adjusting over time to achieve the best possible individualized outcomes with its nDMN therapy. The pivotal trial will also be designed to determine the effects of SinaptiStim ® System on several biomarkers measuring beta amyloid, phosphorylated tau, neuroinflammation, and synaptic dysfunction.
About Sinaptica Therapeutics
Sinaptica Therapeutics is a clinical-stage neuromodulation therapeutics company leading the development of a new class of novel personalized therapeutics to revolutionize the treatment of Alzheimer's and other primary neurodegenerative diseases. The company utilizes a patented non-invasive approach to treating Alzheimer's via precision neurostimulation of a key brain network involved in memory, the Default Mode Network. Sinaptica's scientific co-founders pioneered research on this novel approach which a growing body of evidence indicates can slow disease progression. Sinaptica's mission is to bring a safe, effective, and non-invasive neuromodulation therapy to Alzheimer's patients that can help to significantly slow the progression of cognitive, functional, and behavioral decline. Learn more at sinapticatx.com and follow us on LinkedIn and X @SinapticaTX.
The SinaptiStim ® System is for investigational use only. It has not been approved by the U.S. Food and Drug Administration and is not available for commercial sale in any geography.