Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the most common form of dementia. It is typically characterized by the accumulation of beta-amyloid plaques and tau neurofibrillary tangles, which disrupt neural pathways and cause symptoms that worsen over time, from mild symptoms such as memory loss, to more severe symptoms like cognitive impairment which interferes with an individual’s everyday activities. There are currently more than 55 million people living with dementia globally, and this number is expected to increase to 139 million by 2050, implying a substantial economic and healthcare burden associated with increased medical expenses and costs for patient care. This highlights the need for advancements in treatment and discovery of novel therapies to alleviate this impending crisis and improve the quality of life of those affected worldwide.
The primary approach for treating AD typically involves drug therapies or medications. For instance, recent developments in anti-amyloid immunotherapies such as Lecanemab, seek to treat AD by reducing beta-amyloid aggregation and slowing down disease progression. Nevertheless, with the ever-evolving technological landscape and ongoing stream of breakthroughs, there has been a growing emphasis on the application of medical devices or digital therapeutics that can directly target the neuronal pathophysiology of AD, and may be an alternative approach to treating neurodegenerative diseases. Below are some current technologies that hold immense promise for advancing AD treatment.
Electroencephalogram (EEG) recordings have shown that AD leads to disruptions to the oscillatory patterns of the neuronal networks in the hippocampus, including reduced gamma and beta activity, with gamma wave activities in particular being associated with memory access. Neurologists have identified these abnormal neuronal network electrical activities as a therapeutic target, and interventions to modulate such activity could reverse AD pathophysiology and improve functional outcomes. However, the potential for this approach was limited by the risks associated with implanting electrodes on patient brains through surgical means, which calls for the need to develop non-invasive techniques for neuromodulation.
Cognito Therapeutics, a company that aims to create novel disease-modifying digital therapeutics for neurodegenerative disorders, have developed a non-invasive wearable device that delivers both light and sound-based neurostimulation at the gamma frequency of 40Hz. The pilot study for this technology was carried out using AD mouse models, with results showing a reduction in disease pathology, indicated by a decrease in amyloid and tau levels. Clinical evidence has also shown that treated human patients have a reduced rate of brain atrophy, as well as improved functional and cognitive outcomes.
This technology has been granted Breakthrough Device Designation from the U.S. Food and Drug Administration (FDA) in 2021.
NeuroEM Therapeutics, a medical device company has developed the technology known as Transcranial ElectroMagnetic Treatment (TEMT). TEMT is administered through MemorEM™, a device that wraps around the skull of patients, delivering radio frequency electromagnetic (EM) waves of around 1000 MHz through eight emitters, which is capable of breaking up amyloid plaques and phosphorylated tau, thereby reducing AD pathology as well as its symptomatology.
In a small clinical trial, eight mild to moderate stage AD patients received hour-long treatments twice a day for a period of 2 months. After the treatment period, the cognitive function of patients was assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog). Researchers concluded that seven out of eight patients had improved their ADAS-cog scores by an average of 4 points, which is the equivalent of regaining 12 months of memory, and this significant improvement was maintained even 2 weeks after treatment. The disaggregation of both plaques and tangles were also evident after analysis of blood and cerebrospinal fluid samples collected from patients, validating the breaking up effects of aggregates using TEMT.
NeuroEM was also given a Breakthrough Device Designation back in 2020 by the FDA for pioneering this technology.
Temporal Interference (TI) is a form of deep brain stimulation that involves applying electrodes to the scalp of patients, and the delivery of electrical stimulation which can selectively target deep brain areas such as the hippocampus, a region that is key for learning and memory and is recognized as one of the initial structures affected by early stage AD pathology.
Researchers at Imperial College London first described TI in 2017, and its working principle was demonstrated using mouse models. Recent work modeled electric fields in post-mortem brain tissue to verify the possibility of focusing stimulation on the hippocampus. Functional magnetic resonance imaging (fMRI) was also used to measure hippocampal activity in healthy individuals performing behavioral experiments following TI stimulation, showing enhancements in memory accuracy and thereby, validating the practicality of this technology in disease treatment.
There is an ongoing clinical trial led by Dr Nir Grossman at the UK Dementia Research Institute (UK DRI) which seeks to investigate the effects of TI stimulation on patients with early-stage AD.
Deep Brain Fiber
The National Institutes of Health (NIH) have recently awarded a high priority, short-term grant for Xiaoting Jia, a professor at Virginia Tech, and collaborators to develop a multipurpose, deep brain fiber. Jia is joined by two researchers – Harald Sontheimer of University of Virginia and Song Hu of Washington University in St. Louis. The team has 12-months to develop a minimally-invasive, long-lasting polymer that is around the thickness of a strand of hair, with two main goals in mind.
The first goal involves a dual-mode endoscope within the core of the fiber to visualize amyloid plaques in the hippocampus, providing information about neuroactivity and blood flow in the vessels, with the aim of analyzing the relationship between amyloid-deposition and the onset of AD symptoms. The second goal is the delivery of electrical stimulation, followed by administering drugs in an attempt to restore function by reoxygenating affected neurons through the re-establishment of blood flow. Researchers are optimistic that this fiber will be capable of improving memory and the quality of life of AD patients.
To conclude, medical devices and digital therapeutics show immense promise in advancing AD treatment. Innovations such as MemorEM™, enhance the practicality and accessibility of therapeutics by enabling treatment in the comfort of patients’ homes, whereas other initiatives such as the Deep Brain Fiber, seek for a more comprehensive treatment approach by merging pharmacological treatment with electrical stimulation. The multifaceted and dynamic nature of such advancements instills hope for enhanced outcomes and an improved quality of life for patients dealing with this disease.