As of 2022, an estimated 6.5 million Americans lived with Alzheimer’s disease (AD), and as the population ages, this number is expected to rise to 14 million by 2060. AD costs the nation $321 billion in 2022, and unless we develop an effective treatment, costs will continue to escalate, reaching $1 trillion in 2050 [1]. The standard of care for AD treatment includes cholinesterase inhibitors, memantine hydrochloride (N-methyl-D-aspartate receptor antagonist), and monoclonal antibodies (mAbs). However, these methods are unable to lower the toxic Aβ levels without causing brain swelling or microhemorrhages [2, 3], unable to stop AD progression [4], unable to reach multiple targets [5, 6], unable to easily cross the blood-brain-barrier (BBB) [7], and unable to link the aging process to AD pathology [8].

AD is described by beta-amyloid (Aβ) plaques and tangles of neurofibrillary tau proteins in the brain [9]. The amyloid hypothesis states that increases in Aβ levels cause the disease [9], specifically, the binding of Aβ oligomers to multiple cellular receptors is the probable cause of neuronal toxicity [10]. This induces mitochondrial dysfunction and oxidative stress in AD neurons [11]. A human study with 13C6-leucine demonstrated that the pathological factor in AD was a deficit in the clearance rather than the overproduction of Aβ from the central nervous system (CNS) to the periphery [12, 13]. This deficiency of plaque clearance progresses into neuronal degeneration, causing memory impairment and cognitive decline. Therefore, any therapy that has anti-amyloid properties that lower Aβ levels would likely prevent neurodegeneration [14] and cognitive impairment if it does not cause brain inflammation or bleeds. Preclinical studies showed that lowering Aβ levels by repeated electromagnetic field stimulation (REMFS) stops and reverses AD. Even though mAbs lower Aβ levels, they have not stopped AD progression due to serious side effects and the fact that they target extracellular Aβ [2, 3], instead of enhancing intracellular proteostasis or autophagy.

Numerous EMF devices have recently investigated the effects of exposure to EMFs on the underlying pathomolecular pathways of AD [15], leading to innovative therapeutic strategies into the mechanisms through which EMF modulates AD-related symptoms. Depending on the type of system, it can be classified as electric current (direct or alternating), magnetic stimulation (causes induction of electric field to depolarized neurons), and REMFS, which is based on the frequency used. EMFs can be classified in extremely low frequency (ELF) (3–30 Hz), super LF (SLF) (30–300 Hz), ultra LF (ULF) 300 Hz–3 kHz, very LF (VLF) 3–30 kHz, LF 30–300 kHz, medium frequency (MF) 3 kHz–3 MHz, high frequency (HF) 3–300 MHz, very HF (VHF) 30–300 MHz, ultra HF (UHF) 300 MHz–3 GHz, super HF (SHF) 3–30 GHz, extremely HF 30–300 GHz, and terahertz radiation 0.3–3 THz [16–18]. Electromagnetic pulses (EMPs) vs. continuous waves are another type of EMF and can be distinguished by their unique properties. Pulse EMF can affect alpha activity [16] and impair cognitive function [17, 18], whereas continuous EMF does not affect alpha activity or impair cognition. This review focuses on continuous wave REMFS. Depending on the amplitude, time of exposure, intensity, tissue characteristics, and EM frequency range, EMFs can produce no beneficial or harmful health effects within the human body.

A new anti-amyloid strategy by repeated REMFS not only stops cognitive impairment but also reverses it [19, 20]. In AD mice, REMFS at 915–2,000 MHz and power deposition with a specific absorption rate (SAR) of 0.25 to 5 W/kg [21, 22] stopped AD progression [23] by lowering Aβ levels [24] in numerous AD rodent studies [19–21, 25–35] without causing brain edema or hemorrhages [2, 3]. These exposures did not cause any cancer after two years of treatment [20], the main side effect was a body temperature rise (TR) of 1.3°C in the AD mice [20]. Since radiofrequency heat can cause tissue injury, it must be maintained at a safe level of less than 0.5°C, according to regulatory agencies [36]. These circumstances raised a primary question: Can a combination of variables (frequency, power, and antenna type) generate the required penetration depth with a safe and effective SAR to lower Aβ levels with a TR < 0.5°C in the human brain? Here, we will examine possible answers to develop an appropriate device for human exposure.

The future direction of this work lies in taking the success seen in numerous cellular and AD animal models and applying it to human clinical scenarios. The challenge comes in translation. The translational success of animal-to-human EMF studies can be achieved by analyzing the biological effects on animal cells or tissues caused by the power absorbed (SAR) and then utilizing computer simulations to apply the same SAR values to human tissues, considering human dielectric properties and geometry. This review has shown the varying results seen in both preclinical and clinical trials, in particular EMF therapy. Part of the discrepancy in results lies in the various parameters and instruments used by individual researchers. There is also the problem of how to account for differences in patient physical characteristics such as head size, brain structure, and tissue thickness. This is an area of active investigation, and our lab is using artificial intelligence (AI), specifically a convolutional neural network, a type of deep learning algorithm designed to analyze visual data like MRI images that will help find personalized EMF parameters. Another area of interest lies in how to determine the real-time effectiveness of REMFS for patients. New blood biomarkers such as phosphorylated tau 217 (p-tau 217) and Aβ42 and Aβ40 hold promise as potential future markers that can be monitored pre and post-EMF treatment [200]. Also, we will obtain MRI, positron emission tomography (PET) amyloid, and PET tau pre and post-treatment. Additionally, we will perform neuropsychological tests pre and post-treatment. Temperature monitoring remains an utmost safety concern as well. Since radiofrequency heat can cause tissue injury, it must be kept to a safe level of less than 0.5°C per regulatory agencies [60]. There need to be clearly defined parameters for a safe SAR level that does not exceed this threshold in all patients before investigating in human trials. AI again holds potential in this regard for calculating the temperature effects of EMF therapy while accounting for unique patient characteristics. Preclinical studies suggest that one hour of daily REMFS would be an effective and safe treatment in humans. However, clinical trials will be performed to determine the optimal and effective treatment length. Given the circadian production and clearance of Aβ [204], especially early in the disease course, this might affect the duration and timing of treatment.

Here, we review all the EMF neurostimulation devices that can be used to treat AD. This review shows that the factors that prevent the development of neurostimulation as a routine include a lack of well-controlled studies, equivocal experimental results, and poor methodological standardization.

This review shows that the neurostimulation EMF devices have beneficial effects in preclinical studies. However, these treatments in humans have multiple difficulties, including differences in anatomy, geometry, tissue layers, and penetration depth. Also, some devices are invasive with the consequent risks, and others do not reach simultaneously several areas affected by AD pathology [202]. For example, rTMS is usually applied unilaterally to a localized area of the brain. When it is applied bilaterally, it causes more side effects [205], still not reaching all deep brain structures of the (2–6 cm) affected early by Aβ deposition.

In brief, the main shortcoming of the EMF experimental results regarding the biological effects of radiofrequency exposures is the consistency and inconsistencies between the results of the animal and human studies. This is explained by the difference in frequencies, penetration depth, tissue’s dielectric properties, mass density, and complex 3-D E-field distribution, all of which affect the energy absorbed or power deposition on the tissues [206, 207]. The SAR measures the energy absorbed or power deposition in the tissues relevant to specific biological effects. Therefore, it is a central consideration for EMF therapy simulations [208–211]. We cannot determine the SAR only via input power-based estimation due to its dependence on these factors. A crucial factor in the EMF and biological interaction in humans is penetration depth; the penetration depth decreases when frequency increases, which gives the skin depth within which 63% of the energy is deposited. Other important factors are the conductivity and permittivity of the tissues, as they determine how much electromagnetic radiation is absorbed by the body, with higher conductivity and permittivity leading to greater absorption; essentially, these properties dictate how readily electric fields can penetrate and interact with tissue at different frequencies, depending on the tissue type and its composition, particularly water content and ion concentration. For example, the cell phone frequency of 915 MHz has a penetration depth of 3.9 cm [199], unable to reach deep brain areas, on the other hand, the MRI frequency of 64 MHz has a penetration depth of 13.5 cm [199], able to get to important deep memory areas of the human brain. Therefore, we should consider the penetration depth of the EMF frequency before we apply it to a human brain because lower radiofrequency (10–200 MHz) have deeper penetration in a human head. Also, we should consider all the tissue layers of the human head that the EMF penetrates because most of the absorbed energy occurs in the superficial tissues. We chose 64 MHz for our studies for several reasons: A) ideal penetration depth (13.5 cm) [199] and homogeneous field distribution, B) previous studies with human cells and mouse cultures did not find toxicity [132], C) it is in the range 30–200 MHz [212] at whole human body resonance, so less power is needed to obtain SAR with a lower TR [213], and D) it has been used by MRI systems for 40 years, thus, providing an established and safe framework for human exposure.

Our review suggests that the most appropriate EMF strategy for human AD is the REMFS because it provides appropriate parameters for human treatments and addresses multiple AD issues. It can stop AD progression [4] due to anti-amyloid effects without causing bleeds or edema, and it has multitarget [5, 6] effects on beneficial molecular pathways involved in AD. Also, REMFS easily crosses the BBB [7], reaches all memory areas of the human brain, and links the aging process to AD pathology [8]. The REMFS’s initial hypothesis was that aging is the main risk factor for AD [214] and that the loss of the proteostasis [215, 216] is an early event [217] in the aging process. The loss of proteostasis is potentially the primary cause of Aβ accumulation in AD [218]. Additionally, since HSF1 has a central role in proteostasis [219], autophagy [67], Aβ clearance [220], and delaying the aging process [66, 116], this prompted us to use REMFS to activate it to lower Aβ levels. Moreover, multiple studies found that REMFS is a multitarget therapeutic strategy that activates several other beneficial AD pathways [6], including autophagy [221], the ubiquitin-proteasome system [57], oxidative stress [78], cytoprotection [79], inflammation [222], microglia activation [114], and mitochondrial and neuronal activity [19] to lower Aβ levels and potentially improve AD pathology and cognition in AD patients.

Another advantage of the REMFS technology is based on the science behind the EMF-biological systems interaction [59, 223] and the similarities with the MRI radiofrequency coil [224, 225] for its effectiveness and safety profile. The MRI coils [224, 225] apply radiofrequency pulses at similar penetration depth and SAR levels but for only a few minutes, and on the contrary, REMFS applies a longer radiofrequency continuous exposure for one hour, eventually increasing the temperature, so the device will monitor the temperature with a radiometer and an MRI-type control to adjust the power in the ports adjacent to the temperature increased. Also, the difference between MRI coils and REMFS coils is the smaller size of a portable REMFS device, which requires precise optimization. Moreover, REMFS uses 64 MHz, which provides an optimal penetration depth [226, 227] of 13.5 cm able to reach the hippocampus and other deep memory areas affected early in AD, such as the posterior cingulate and the locus coeruleus [200–202] that in later stages [228] spreads to most areas of the brain [203]. This underlies the importance of achieving an optimal penetration depth and a homogeneous power deposition with an optimal SAR to prevent untreated areas or hotspots [200, 202]. Also, the fact that REMFS uses the same frequency and power depositions with SAR values as the routine MRI that has been used for decades makes it a safe and effective strategy. Another important technical factor is that a birdcage antenna produces circular polarization necessary for biological effects [229]. Most animal studies used one antenna with polarized EMFs to activate pathways that lower Aβ and improve memory in AD mice [20] studies. EMF devices with multiple transmitters generate non-polarized EMFs with destructive or constructive interference, causing nil biological effects [229]. This polarization is an important factor in the EMF-biology interaction because radiofrequency-EMF oscillation on the H-bond causes proton tunneling [59] by increasing both vibration amplitude and the distance between the proton and acceptor at the quantum level [230], creating the protonation and conformational changes (tautomers) in RNA or other biomolecules that produce biological functions [59].

In this review, we examined the contribution of different lines of research; we used cell cultures, animal experiments, and clinical studies for the potential treatment of AD. We assessed the effectiveness and safety of REFMS and its clear implications for a broader understanding of pathophysiological mechanisms for future therapeutic interventions. Evidence demonstrated that cognitive functions affected by AD can be successfully modulated by REMFS. The lack of effective human studies makes the need for REMFS clinical trials highly significant in advancing this anti-amyloid strategy for future AD treatments.