As researchers continue to investigate potential pharmacological treatments to prevent or treat Alzheimer disease (AD), a cure for the disease remains elusive. However, studies suggest that various nondrug strategies may hold promise in improving diagnostics and symptom management for patients with AD. In a 2022 study published in Frontiers in Neuroscience, Ning et al reviewed numerous neurotechnological approaches that could support these goals.1
“Many clinical trials are underway to test the effectiveness of emerging nonpharmacological neurotechnologies for AD, including brain stimulation technologies,” said Mehdi Jorfi, PhD, study co-author, instructor in the department of neurology at Harvard Medical School in Boston, and investigator at both the Center for Engineering in Medicine and Surgery at Massachusetts General Hospital and the Genetics and Aging Research Unit at the McCance Center for Brain Health at the MassGeneral Institute for Neurodegenerative Disease.
He highlighted that “While some of these approaches have been more robustly explored for the treatment of psychiatric diseases, they should be studied more extensively to evaluate their potential as disease-modifying interventions for AD.”
The Use of Ultrasound for Improving AD Pathology and Symptoms
Researchers have demonstrated encouraging results with the use of ultrasound technologies. Emerging research suggests that magnetic resonance-guided focused ultrasound could be combined with microbubbles to open the blood-brain barrier, with the ultimate aim of improving AD pathology and symptoms.1 In a 2021 study published in Radiology, researchers found no adverse effects using this approach in 3 patients with early-stage AD.2
In a 2019 study published in Advanced Science, Beisteiner et al observed significant improvements in neuropsychological scores persisting for up to 3 months in 35 patients with AD who underwent 2 weeks of transcranial pulse stimulation with ultrasound. These effects correlated with functional magnetic resonance imaging (fMRI) data indicating an upregulation of the memory network, and no major side effects were noted.3
Meanwhile, Jeong et al found that low-intensity transcranial focused ultrasound to the hippocampus was associated with mild improvements in memory, executive function, and global cognitive function in 4 patients with AD, with no adverse effects reported in a 2021 pilot clinical study in Ultrasonography.4 Positron emission tomography (PET) scans revealed increases in the regional cerebral metabolic rate of glucose in the superior frontal gyrus (P <.001), middle cingulate gyrus (P<0.001), and fusiform gyrus (P =.001) following ultrasound (P =.001).
The Potential Role of Deep Brain Stimulation in AD
The utility of deep brain stimulation (DBS) for symptom management in Parkinson disease is well-established, and preliminary research points to a potential role for DBS in AD as well. Researchers of a 2014 study of 6 patients with AD published in the journal Brain Stimulation, provided the first-in-human evidence that DBS may slow or reverse brain atrophy in AD. 5 The patients received 1 year of continuous DBS applied to the fornix and demonstrated slower mean hippocampal atrophy compared with a matched group of patients with AD. In addition, 2 of the 6 patients showed bilateral increases in hippocampal volume, with mean enlargements of 5.6% and 8.2%.
In a 2015 pilot study in the journal Molecular Psychiatry, researchers reported favorable results with DBS applied to the nucleus basalis of Meynert in 4 of 6 patients with AD, based on scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale, and no severe side effects were observed.6
Transcranial Magnetic Stimulation as an AD Intervention
Transcranial magnetic stimulation (TMS) represents another area of ongoing research investigating interventions for a range of psychiatric and neurological diseases, including AD. Earlier studies showed that TMS increased motor cortex excitability in patients with AD, and more recent research in animals and humans has explored the use of TMS in the management of cognitive symptoms in AD, including anomia and deficits in memory, comprehension, and spatial learning.1
In a 2021 study using a mouse model of AD, published in Acta Neuropathologica Communications, Lin et al found that repetitive TMS (rTMS) helped prevent the decline of longterm memories, increased the drainage efficiency of the glymphatic system and meningeal lymphatics, and reduced amyloid-beta deposits.Additionally, the results indicated that the clearance rate of the contrast tracer in cerebrospinal fluid could possibly be used as a biomarker to predict the efficacy of rTMS in AD.7
TMS is currently the focus of clinical trials testing the efficacy of the intervention in improving AD symptoms.8
Researchers are also continuing to explore an array of techniques in areas such as optogenetics, light stimulation, and nanotechnologies with the aim of identifying potential AD interventions.
Noting that the development of AD pathology begins long before clinical symptoms appear, it would be ideal to “intervene with the initiating AD pathologies in the preclinical phase, when there may be a greater opportunity to reverse the disease trajectory,” Dr Jorfi stated. “This clinical strategy would be analogous to managing cholesterol levels to help reduce the risk of heart disease.”
He emphasized the need for scientists, clinicians, and engineers to combine their complementary areas of expertise to optimize the development and application of neurotechnologies for AD.
“While each neurotechnology could potentially be developed into some form of treatment on its own, our current understanding of the tangled biology of AD and the human brain indicates the need to combine various technologies with existing drugs and biologics to effectively address challenges in developing and implementing effective AD therapeutics,” Dr Jorfi explained.
- Ning S, Jorfi M, Patel SR, Kim DY, Tanzi RE. Neurotechnological approaches to the diagnosis and treatment of Alzheimer’s disease. Front Neurosci. Published online March 24, 2022. doi:10.3389/fnins.2022.854992
- Mehta RI, Carpenter JS, Mehta RI, et al. Blood-brain barrier opening with MRI-guided focused ultrasound elicits meningeal venous permeability in humans with early Alzheimer disease. Radiology. Published online January 5, 2021. doi:10.1148/radiol.2021200643
- Beisteiner R, Matt E, Fan C, Baldysiak H, et al. Transcranial pulse stimulation with ultrasound in Alzheimer’s disease-A new navigated focal brain therapy. Adv Sci (Weinh). Published online December 23, 2019. doi:10.1002/advs.201902583
- Jeong H, Im JJ, Park JS, et al. A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer’s disease. Ultrasonography. Published online January 16, 2021. doi:10.14366/usg.20138
- Sankar T, Chakravarty MM, Bescos A, et al. Deep brain stimulation influences brain structure in Alzheimer’s disease. Brain Stimul. Published online December 3, 2014. doi:10.1016/j.brs.2014.11.020
- Kuhn J, Hardenacke K, Lenartz D, et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia. Mol Psychiatry. Published online May 6, 2014. doi:10.1038/mp.2014.32
- Lin Y, Jin J, Lv R, et al. Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun. Published online June 2, 2021. doi:10.1186/s40478-021-01198-3
- Menardi A, Dotti L, Ambrosini E, Vallesi A. Transcranial magnetic stimulation treatment in Alzheimer’s disease: a meta-analysis of its efficacy as a function of protocol characteristics and degree of personalization. J Neurol. Published online July 4, 2022. doi:10.1007/s00415-022-11236-2