Abstract
Huge investments continue to be made in treatment for Alzheimer’s disease (AD), with more than one hundred drugs currently in development. Pharmacological approaches and drug development, particularly those targeting amyloid-β, have dominated the therapeutic landscape. At the same time, there is also a growing interest in devices for treating AD. This review aimed to identify and describe devices under development for AD treatment. In this review, we queried the devices that are in development for the treatment of AD. PubMed was searched through the end of 2021 using the terms “device,” “therapeutics,” and “Alzheimer’s” for articles that report on devices to treat AD. Ten devices with 31 references were identified as actively being developed for the treatment of AD. Many of these devices are far along in development. Device-based therapies are often overlooked when evaluating treatment approaches to AD. However, many devices for treating AD are in development and some show promising results.
INTRODUCTION
More than 6 million individuals in the United States have Alzheimer’s disease (AD), and this number is predicted to increase to 13 million by 2050 [1]. Because the life expectancy of the general population has increased in the past decades to more than 80 years, it is alarming that AD is increasingly prevalent among older individuals, with 72% of those diagnosed with AD dementia being 75 years old or older [2]. The primary symptoms of AD include deficits in short-term and long-term memory, loss of executive function, and several psychiatric symptoms, and the course of the disease eventually leads to premature death [3]. The hallmarks of the brain pathology of AD are extracellular senile plaques composed of amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau proteins, and central inflammation. Over time, these entities contribute to the neurodegenerative process that leads to the characteristic brain atrophy observed in individuals with AD [1].
As of January 25, 2022, 143 pharmacological agents were in 172 clinical trials for AD. These pharmacological agents included 31 agents in 47 phase 3 trials, 82 agents in 94 phase 2 trials, and 30 agents in 31 phase 1 trials. Disease-modifying therapies represented 83% of the total number of pharmacological agents in trials, which mainly targeted Aβ and abnormal tau; symptomatic cognitive enhancing treatments represented 10% of these agents; and drugs for the treatment of neuropsychiatric symptoms represented 6.9% of these agents [4].
In addition to pharmacological and behavioral interventions, electromagnetic devices are being investigated to treat AD. To the best of our knowledge, this is the first review to summarize this growing body of literature. These devices employ techniques to identify predetermined regional targets, and they use different mechanisms of action to achieve therapeutic effects. Most device-related strategies focus on ameliorating cognitive symptoms rather than on modifying the disease.
METHODS
In this study, we reviewed the devices that are currently being investigated for the treatment of AD. We queried the devices that are in development for the treatment of AD. PubMed was searched through the end of 2022 using the terms “device,” “therapeutics,” and “Alzheimer’s” for articles that report on devices to treat AD. Because of institutional accessibility, PubMed was the only database accessed. An overview of these methods and the 10 devices identified is presented in Table 1 (noninvasive devices) and Table 2 (invasive devices) [5–36], and additional information is provided in the text. We have divided the devices into two categories: 1) noninvasive tools that are applied externally, and 2) invasive techniques that require surgery for the internal implantation of electrodes that are connected to external or subcutaneous battery-powered stimulators that can be fine-tuned by expert physicians in a precision medicine context.
Summary of studies on noninvasive devices for the treatment of Alzheimer’s disease
AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADL, activities of daily living; Aβ, amyloid-β; BEHAVE-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; BMI, body mass index; CGIC, Clinical Global Impression of Change scale; CSF, cerebrospinal fluid; DLPFC, dorsolateral prefrontal cortex; EEG, electroencephalogram; FDG-PET, 18F-fluoro-2-deoxyglucose positron emission tomography; GDS, Geriatric Depression Scale; HAMA, Hamilton Anxiety Scale; IADL, Instrumental Activities of Daily Living; MADRS, Montgomery-Asberg Depression Rating Scale; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; NC, neuropathologic change; NPI, Neuropsychiatric Inventory; PBM, photobiomodulation stimulation; pSAC, parietal somatosensory association cortex; PSQI, Pittsburgh Sleep Quality Index; QOL-AD, Quality of Life in Alzheimer’s Disease Scale; RAVLT, Rey Auditory Verbal Learning Test; rCMRglc, regional cerebral metabolic rate for glucose; rTMS, repetitive transcranial magnetic stimulation; SOC, standard of care; tACS, transcranial alternating current stimulation; TESS, Treatment Emergent Symptom Scale; TMS, transcranial magnetic stimulation; VRM, Visual Recognition Memory.
Summary of studies on invasive devices for the treatment of Alzheimer’s disease
AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; CDR-SB, Clinical Dementia Rating Sum of Boxes; CSF, cerebrospinal fluid; CT, computed tomography; DBS, deep brain stimulation; EEG, electroencephalogram; FDG-PET, 18F-fluoro-2-deoxyglucose positron emission tomography; MADRS, Montgomery-Asberg Depression Rating Scale; MMSE, Mini-Mental State Examination; PET, positron emission tomography; QOL-AD, Quality of Life in Alzheimer’s Disease Scale; VNS, vagus nerve stimulation.
NONINVASIVE TECHNIQUES
Repetitive transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a noninvasive technique that uses a coil positioned against the scalp to briefly apply an oscillating magnetic field (up to 2 Tesla) to a focal area of the brain [37]. It has been suggested that the magnetic field conducts an electric current 2 to 3 cm into the cranium perpendicular to the coil that can depolarize neurons within the targeted stimulation site [38]. Consequently, TMS may promote neuroplastic changes in the brain via several mechanisms, such as modulation of the levels of excitatory and inhibitory neurotransmitters [39], induction of gene expression [40], decrease in the resting motor threshold [41], and modification of the widespread excitability of the sensorimotor system [42]. TMS can be delivered via either high frequency (≥10 Hz) or intermittent theta-burst stimulation to excite cortical tissues, or via either low frequency (≤1 Hz) or continuous theta-burst stimulation (3.5–7.5 Hz) to inhibit neuronal activity [43]. Single-pulse TMS has been well researched for its use in treating migraine [44]. In contrast to single-pulse TMS, patterned repetitive TMS delivers a series of pulses repetitively and rhythmically. Unlike single-pulse TMS, it has long-lasting effects that can induce neuroplastic changes in the brain [45], and it is therefore preferred for the treatment of chronic neurodegenerative conditions that affect memory.
Repetitive TMS (rTMS) commonly targets the left, right, or bilateral dorsolateral prefrontal cortex (DLPFC), the right inferior frontal gyrus, or temporoparietal regions [46], Stimulation of the DLPFC and temporoparietal regions targets memory circuits to improve memory function. Stimulation of the right inferior frontal gyrus target is intended to improve executive function. Significant improvement in cognitive function has been found in studies of both single and multiple sessions of rTMS. For example, rTMS was found to improve both short-term and long-term (4–12 weeks later) cognitive functions [46]. Another studied treatment strategy involves rTMS coupled with cognitive training exercises. This strategy is based on the hypothesis that rTMS serves as a primer that later induces neuroplastic changes [10, 11]. This method was found to have therapeutic value among patients with mild AD compared to patients on standard of care therapy [11]. Although this technique only targets superficial brain areas, its modulatory effects have been detected in deeper brain regions, likely due to the stimulation of interconnected networks [47].
rTMS is currently being used to treat neuropsychiatric diseases such as medication-resistant depression [48]. Potential applications of rTMS to treat AD are being investigated. Animal models in mice have shown that both high frequency [49] and low frequency [50] rTMS can improve hippocampal functions linked to learning and memory. A meta-analysis by Chou and colleagues found improved memory functions in patients with AD treated with high frequency rTMS in the left DLPFC combined with low frequency rTMS in the right DLPFC [46]. Some studies have also shown improved executive functioning when the right inferior frontal gyri of patients with mild cognitive impairment or AD are stimulated with high frequency rTMS [46]. Another meta-analysis that investigated the use of high-frequency rTMS in patients with mild AD found significant improvements in cognitive function compared to sham treatment [51]. However, the study found no significant improvement on the Mini-Mental State Examination (MMSE) and no improvement in mood on the Geriatric Depression Scale. Similar studies have also found no significant improvement in instrumental activities of daily living [5–9, 51].
Based on the current literature, it is our opinion that rTMS has the potential to improve cognitive function in AD. However, additional rigorous investigations are necessary to determine whether this treatment can significantly improve quality of life and long-term health outcomes in these patients. Possible drawbacks to this treatment method include adverse effects such as headaches, scalp pain, syncope, transient psychiatric symptoms, and a risk for seizure [52], although rTMS has consistently been found to be safe and well-tolerated by patients overall. Of note, rTMS has been shown to be less effective in patients concurrently taking N-methyl-D-aspartate (NMDA) receptor antagonists such as amantadine [53], further suggesting that the therapeutic action of rTMS involves neuroplastic mechanisms.
Transcranial direct current stimulation
Transcranial direct current stimulation (tDCS) delivers weak electrical currents via sponge electrodes soaked with a saline buffer placed on the scalp in precise locations [54]. This method typically delivers a small electrical current (usually 1–2 mA) in a radial pattern that passes through the skull. It can be applied either via anodal stimulation to increase cortical excitability or via cathodal stimulation to decrease neuronal activity, although the modulation of the neuronal activity can vary based on the brain regions targeted and their preponderant neurotransmitters (i.e., excitatory or inhibitory) [43, 54]. tDCS can be applied from a simple compact device that is portable, safe, and inexpensive. It can be self-administered by patients themselves in their home [14], although there is a mild risk of skin lesions from the electrodes, as well as the possibility of dizziness and headaches [43]. A compelling point is that the effects of tDCS on cognitive function as measured by motor cortical excitability were enhanced by partial NMDA agonists, such as d-cycloserine. In addition, similar to rTMS, tDCS had limited effects in patients concurrently taking NMDA antagonists [55]. Overall, tDCS has been shown to be safe, even in longitudinal regimens [14].
Several studies have indicated that tDCS may improve global cognition [12, 57], recognition memory [12], verbal fluency [14, 16], executive function [14], and depression [15] in patients with AD. Interestingly, a single session of tDCS in the area of the left DLPFC in AD patients demonstrated enhanced recognition memory [12]. Notably, after ten sessions of tDCS over bilateral temporoparietal regions, it was observed that patient scores on cognitive and depression scales were improved, and these improvements correlated with an increase in plasma Aβ42 compared to a sham-treated group [15]. In patients with AD, the plasma levels of Aβ42 are generally lower in comparison to healthy individuals, making it a useful biomarker of this disease [15]. Patients who self-administered tDCS for 6 months showed significant improvements in global cognition, language, and stabilized glucose metabolism in the left middle/inferior temporal gyrus [14]. Patients’ executive function and attention remained stable; however, there were no differences in delayed recall performance between the tDCS treatment group and the sham treatment group [14]. Moreover, an AD case study reported by Bystad et al. showed that daily tDCS use for 8 months resulted in improved memory and stabilized cognitive decline [13]. A meta-analysis of 27 randomized-control trials comparing tDCS to rTMS in AD and mild cognitive impairment subjects found a significant improvement in global cognition in AD, but no significant difference in participants with mild cognitive impairment [57]. This finding suggests that the effects of these methods maybe more adapted to mild stages of AD rather than early stages, though the potential cognitive benefits in patients with mild cognitive impairment could be partly masked by the use of cognitive scales not sensitive enough to detect small improvements. Noticeably, patients in the rTMS-treated groups showed greater improvement in global cognition than the patients in the tDCS-treated groups [57]. Overall, tDCS is a potentially effective, portable, and safe noninvasive external stimulation technique that seems to be most efficient in treating patients with mild-to-moderate AD.
Transcranial alternating current stimulation
Transcranial alternating current stimulation (tACS) uses low amplitude alternating electrical currents applied outside the skull to modulate brain oscillations in selected brain regions. It can selectively enhance theta or gamma oscillations [58]. This technique is suspected to function by increasing synaptic plasticity, and the effects are long lasting [59]. It can be administered either during cognitive tasks (“online tACS”) or before or between cognitive tasks (“offline tACS”). However, further research is needed to determine the optimal method of administration for clinical benefits [60].
In a clinical trial setting, a single session of gamma-frequency tACS resulted in improvements in immediate and delayed recall memory in AD patients compared to a sham-treated group [19]. It has also been found to significantly increase blood perfusion bilaterally in the temporal lobes on positron emission tomography, which correlated with improvement in episodic memory [18]. A pilot study using a home-based tACS paradigm on two AD patients suggested potential memory enhancement when stimulating the left angular gyrus and the potential feasibility of this technique [17]. As with tDCS, initial research of tACS has been shown to be safe, portable, inexpensive, and potentially effective in the treatment of AD; however, additional investigations are needed to demonstrate clinical utility.
Photobiomodulation stimulation
Photobiomodulation stimulation (PBM) works by using light-emitting diodes to transcranially or intranasally emit low levels of red or near-infrared light to modulate neural oscillations [61]. It has also been referred to as low-level light therapy. It is currently being explored in the treatment of dementia [62], traumatic brain injury [63], stroke [63], Parkinson’s disease [64], and other neurological conditions. In a review of PBM on animal models using mice and rats with AD [65], PBM has been found to reduce the accumulation of Aβ [66–69], improve cognitive function [66, 70], reduce inflammatory response and oxidative stress [66, 71], and enhance mitochondrial function [66, 70]. Unfortunately, many different paradigms are used in a large number of studies, making it difficult to objectively compare the results and determine the optimal methods for clinical practice. Nonetheless, transcranial infrared brain stimulation is becoming the preferred method of PBM for AD because it has been shown to lead to improved cognition and emotional states [72].
In a case series reported by Saltmarche et al. [20], five patients with mild-to-moderate AD were treated for 12 weeks with a combination of weekly transcranial-intranasal PBM delivered in the clinic and daily intranasal PBM delivered in the patients’ homes. Patients showed significant improvement in subjective symptoms such as sleep, anger, and anxiety and objective improvement in cognitive function. No adverse effects caused by the treatment were observed [20]. Some protocols have also studied the benefits of using PBM in conjunction with aerobic exercise therapy in patients with AD and anemia [21]. It was reported that the use of these two therapies together induced a significant improvement in cognitive functions and quality of life compared to aerobic exercise alone [21]. Thus, clinical trials suggest that PBM may be a valuable treatment option for patients with AD.
Ultrasound stimulation
Ultrasound stimulation of the brain has been found to effectively and precisely deliver excitatory or inhibitory stimuli to specifically targeted brain regions [73]. It can be applied using many different settings, such as high-intensity or low-intensity ultrasound. High-intensity stimulation creates permanent focal lesions in the brain, whereas low-intensity waves excite or inhibit areas of the brain reversibly [73]. Other methods of ultrasound stimulation include transcranial pulse stimulation (TPS) [22] and transcranial focused ultrasound stimulation [74]. Research for these two treatment modalities appears promising for movement disorders; however, more exploration is needed to determine their potential in cognitive disorders, including the refinement of administration methods, safety profiles, and efficacy [75].
In a clinical trial using TPS, which uses very short ultrasound pulses to stimulate brain regions, 35 patients with AD were treated for 2 to 4 weeks and had significant improvements in cognitive function that lasted up to 3 months. Functional magnetic resonance imaging data showed corresponding memory network upregulation after treatment [22].
Auditory stimulation
Various types of auditory stimulation, such as white and pink noises, are being explored for their effects on sleep and memory disturbances [76]. Positive outcomes have been noted, although more evidence is needed [76]. One study of pink noise in cognitively normal older adults has observed significantly improved word recall in comparison to sham-treated groups [77]. The same investigators went on to study pink noise in patients with mild cognitive impairment and showed a similar improvement in morning word recall [78]. Based on this pilot concept, a clinical trial was started to determine whether pink noise may help improve memory consolidation and retention in patients with AD, although results have not yet been published [23].
Transcranial electromagnetic treatment
Transcranial electromagnetic treatment (TEMT) uses perpendicular magnetic and electric waves emitted from a transducer. Compared to previous methods, TEMT is capable of acting on the main AD pathologies by disaggregating Aβ and p-tau oligomers, as well as enhancing brain mitochondria [24, 79–81]. TEMT has been studied using the MemorEM device by NeuroEM Therapeutics, Inc. under clinical trial settings. This device has the advantage of being portable and can thus be administered by the patients’ caregivers in their homes for daily treatment regimens [24]. In a phase 2 pilot trial over a 2-month period, no subjective or objective adverse effects were noted in the eight AD subjects that used the device twice daily [24]. Given the positive initial results, this trial was extended for a total time period of 2.5 years [25]. Cognitive functions in these patients were stabilized without further decline during that period. Cerebrospinal fluid analysis showed reduced levels of p-tau-217, Aβ40, Aβ42, and C-reactive protein. No adverse effects were observed with the extended treatment [25]. In summary, the extended trial found that TEMT is generally safe, enhances cognitive functions, and stabilizes brain functions overall [24, 25].
Gamma frequency sensory stimulation
The role of gamma brain activity (approximately 25–100 Hz) in cognitive function, including memory, is well known, and it is fundamental for healthy brain activity and intrabrain communication. Electrically, AD is characterized by reductions in brain oscillations in the gamma band (γ, >30 Hz). Noninvasive gamma entrainment using sensory stimulation (GENUS) through auditory and visual sensory stimulation at 40 Hz reduces AD pathology, such as amyloid and tau levels; prevents cerebral atrophy; and improves behavioral testing performance in mouse models of AD. Mechanistically, this might occur through calcium-mediated activation of myelin and synaptic genes [82].
Therefore, GENUS is among the most promising approaches for AD treatment [83]. A phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) was conducted in cognitively normal volunteers (
The next study was a single-blinded, randomized, placebo-controlled phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (
INVASIVE TECHNIQUES
Deep brain stimulation
Deep brain stimulation (DBS) has been used to treat several movement disorders and psychiatric disorders, and it has been used as an experimental treatment for obesity, anorexia, chronic pain, and AD [84]. DBS requires trepanation for the surgical placement of wire leads and electrodes to stimulate targeted deep brain structures. The electrical fields can then be adjusted by trained experts throughout the treatment course of the patient. Electricity is supplied by a battery-driven power supply that is placed subcutaneously near the collarbone. In patients with AD, DBS is thought to work through neuromodulation of memory circuits by directly stimulating deep brain structures involved in memory formation and recall [28]. Previous studies have shown a strong correlation between cognitive decline in patients with AD and decreased cerebral glucose metabolism in their brain cortices [85, 86]. Pilot clinical trials on AD patients have been conducted to stimulate the nucleus basalis of Meynert [30], the fornix [27–29, 34], and the hypothalamus [27]. These studies have reported the reversal of impaired glucose utilization [27–29, 31] and a slower cognitive decline [27–30]. However, other studies using DBS showed no improvement in the cognitive function of patients or had at least some patients who showed no improvement. Altogether, these studies suggest that DBS may be more beneficial in patients more than 65 years old [30, 34].
Serious adverse effects have been reported, including infection, the need for electrode repositioning, chronic subdural hematoma, syncope, seizures, altered mental status, rigidity, and agitation [32–34]. On the other hand, several studies have reported no serious or permanent adverse effects [27, 31]. In the multicenter ADvance Trial, only 5 of 42 patients experienced serious adverse events, including infection, the need for electrode repositioning, and chronic subdural hematoma [32, 34]. In addition, there are several ethical considerations of DBS treatment that are currently being discussed regarding psychiatric and cognitive adverse effects, and about obtaining objective informed consent [84, 88]. More studies are needed to determine the efficacy of DBS for treating patients with AD. The optimal stimulation parameters for treating patients with AD must also be determined.
Vagus nerve stimulation
Vagus nerve stimulation (VNS) involves a surgery in which a unidirectional wire is wrapped around the vagus nerve in the cervical area and connected to a battery-powered device implanted subcutaneously in the anterior chest wall [43, 89]. The device emits intermittent electrical currents through the vagus nerve projecting to the locus coeruleus, a brain nucleus rich in noradrenergic neurons. Consequently, it is anticipated that VNS may stimulate noradrenergic afferences to modulate synaptic plasticity in the hippocampus and other memory-related brain regions [90]. Stimulation of the vagus nerve has been shown to improve cognition [91] and memory [90] and cause changes in neuronal activity in deep brain structures such as the thalamus, hippocampus, and amygdala [92, 93]. The effect of VNS is commonly assessed via functional magnetic resonance imaging as it can immediately show increased blood flow to regions activated during VNS [94]. Pilot studies of VNS on AD patients have shown improvements in memory or no significant decline after 3 months or 1 year of treatment [35, 36]. They also found VNS to be well tolerated by patients.
DISCUSSION
There is growing interest in seeking nonpharmacological solutions for AD. Many devices in development are noninvasive, which adds an element of safety. Surveillance can also be easier with a device than with pharmacological treatment if the device needs to be applied. The downside of such treatment is that many devices require frequent visits to the clinic. They can be expensive to acquire, and the cost of treatment might not be reimbursed by insurance companies. Because some devices require frequent visits to the hospital, there might be an added burden on caregivers.
Ideally, the future of AD therapeutics will be combination therapy. None of the noninvasive devices would exclude the use of anti-amyloid monoclonal antibodies, which can be deployed simultaneously in practice. However, device-based therapies might complicate research by confounding the interpretation of clinical benefit.
An unresolved question is whether device-based therapies are symptomatic or disease-modifying. There is little autopsy data available with which to assess whether pathology was altered, and biomarker evidence is not widely available. Therefore, it is likely that the clinical implication is that most efficacy from these devices is symptomatic.
Priorities for the deployment of device-based nonpharmacological treatment of AD should be subdivided into research outlooks and clinical implications. Among the latter, a further subgrouping may be important to distinguish immediate clinical implications from typical geriatric multidimensional implications, such as effects on gait instability and cognitive impairment.
CONCLUSION
Many devices are in development for the treatment of AD. Treatments using devices have potential advantages over other therapeutic intervention modalities, including a time-limited window of treatment exposure, signs of efficacy that may be detected more quickly, and motivated patients, improving adherence to treatment. Power calculations and regulatory pathways indicate that the clinical trial sample sizes necessary to be considered approvable are often in the hundreds rather than the thousands. Many devices are reasonably well tolerated. Some are repurposed from treatments for other neurological conditions. The disadvantages of device-related treatments include frequency of treatment, potential invasiveness, and cost. Priorities for the nonpharmacological treatment of AD should be subdivided into research outlooks and clinical implications. Research outlooks provide a context for further development of a device based on a mechanism of action without a specific path to commercialization and approval. Clinical implications center on the likelihood of seeing devices introduced into clinical practice. Among the latter, a further subgrouping is necessary to distinguish immediate clinical implications from typical geriatric multidimensional ones, in particular the effects on gait instability and cognitive impairment. Many devices could be seen as potentially having subacute effects on cognition but could also have effects on other aspects of the neuroaxis, such as gait and mobility (e.g., DBS). Part of the determination of clinical effect is the localization of where the technology is applied. Clinical implications also need to be considered in the context of how devices would be used in clinical settings. Would they be considered as adjunct therapy to disease modifying therapies? There is the growing concept of the multi-targeted approach to AD treatments.
Although they show great promise, it is our opinion that more research is needed to determine the maximum length of therapeutic effects for these techniques, the optimal administration methods, and efficacy compared to neuropharmacological agents (including how the effects may be modulated by pharmaceuticals), and the potential of combination treatment methods [95].
Footnotes
ACKNOWLEDGMENTS
We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.
FUNDING
Supported by National Institutes of Health grants R01AG059008, and R01AG073212, and P30 AG072980, and by the Barrow Neurological Foundation.
CONFLICT OF INTEREST
Dr. Sleem has no conflicts of interest to report. Dr. DeCourt declares that he is a consultant for Seq Biomarque. Dr. Sabbagh discloses that he has ownership interest (stock or stock options) in NeuroTau, uMethod Health, Lighthouse Pharmaceuticals, and Athira; he consults for Alzheon, Biogen, Roche-Genentech, T3D, Novo Nordisk, Signant Health, Prothena, Eisai, Lilly, and KeifeRx. Dr. Sabbagh is an editorial board member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.