NeuroEM for Alzheimer’s

This post explores a “mechanistic” mouse study of NeuroEM’s device for treating Alzheimer’s Disease. [1] It should be noted that the Assisi radio frequency PEMF device was designed to target the Ca²⁺ calmodulin interaction. The Neuro EM device appears to target complex IV of the mitochondrial electron transport chain. A diurnal component of very low frequency PEMF has been presented in the Schumann Resonance post. The really interesting about this study is that the time of day seems to influence body and brain temperatures in transgenic and neurotypical mice. Fast forward to low sample size human clinical trials, things look very different. The post ends by bringing in a very biophysical review. Things are promising and so very complicated.

Healthy lysosomes do these things

The link will take the reader to a copy right image that basically says that the lysosomes participate in clearing

• amyloid deposits from outside the glia/neurons in Alzheimer’s Disease
• misfolded super oxide dismutase in ALS
• and defective mitochondria in Parkinson’s disease.

It should be noted that the NeuroEM publications [1,2} did not favor this model at the time. One of the protein implicated in the above figure Udayar 2022 is Vps34, .

Reddy and Oliver 2019 have a review along the same lines that a defect in mitophagy contributes to Alzheimer’s Disease.

Radio frequency PEMF mitochondria in FAD mice [1]

The familial Alzheimer’s Disease mice

All mice in these studies were derived from The Florida Alzheimer’s Disease Research Center’s colony. Each mouse had a mixed background, that is to say, pretty out bred and hopefully more resembling a typical human except that it has the so called “Swedish Mutation”

APP K670N, M671L gene (APPsw) also known as the Swedish Mutation, is the only known mutation immediately adjacent to the β-secretase site in APP. The mice in this study were heterozygous for the Swedish APP mutation.

All mice were maintained on a 12 h dark and 12 h light cycle with ad libitum access to rodent chow and water. Mention was not made of access to exercise wheels. It is assumed that the mice were sedentary. See the last section on Circadian Rhythms and Radical pair mechanism.

Other Alzheimer’s Mutations [2]

Yan 2024 identified two mitochondrial-related candidate genes associated with mild cognitive impairment and late onset Alzheimer’s Disease: NDUFA1 and NDUFS5, [2]

• NDUFA1 is a the gene coding for NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1, of Complex I
• NDUFS5 NADH dehydrogenase [ubiquinone] iron-sulfur protein 5, also part of complex I.
• PSEN1, presenillin, is a sub unit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP.  interferes with the function of the γ-secretase complex, which alters the processing of the APP and leads to the overproduction of a longer, toxic version of Aβ peptide (Aβ42) Click to view a cartoon. The Martín-Maestro paper [3] has been reviewed in the PSEN1 and mitophagy post.
• apolipoprotein The Mutations in the APOE4 variant are associated with the most common late onset familial and sporadic forms of Alzheimer’s Disease. ApoE is basically a lipid particle transporter. The human genome as three alleles 2,3, 4 Blades 2024 recently published a report showing Impaired cellular copper regulation in the presence of ApoE4 by virtue of inhibition of the copper export protein ATP7A. The graphical abstract of this publication says much.

Perhaps the take home is that healthy mitochondria mean less work for lysosomes that degrade amyloid and/or tau neurofibrillary tangles? Here is a link to a Maverick cartoon of lysosome duties: degrading spent receptors, degrading exogenous proteins, and getting rid of dysfunctional mitochondria.

the protocol

The mice were exposed to two 1-h sessions of PREMF per day (early morning and late
afternoon).

• 918 MHz, involved modulation with Gaussian minimal-shift keying (GMSK)signal, and was non-continuous
• carrier bursts repeated every 4.6 ms, 217 Hz
• electrical field 17 – 35 V/m.
• SAR levels that varied between 0.25 and 1.05 W/kg.

the results

parameter	neurotypical	transgenic	comment
basal (State II)	slight ⇑ in cortex & hippocampus	slight ⇑ in cor hip
maximum (State V)	slight ⇑ in cortex & hipppocampus	slight ⇑ in cor hip
res cont ratio	no change	⇑ all four	~40% ⇑ hip
mitochondrial ROS	no change	no change str amy	PEMF prevents 2x ROS in cor hip
membrane potential	no change	⇑ in cor & hip	biggest ⇑ hip
mito ATP	no change	⇑ in cor hip str	largest ⇑ hip
Complex IV activity	very slight ⇑ in cor hip str	⇑ in cor hip str	>2x ⇑ hip
Body morning	35.5oC, 37oC	36oC, 37oC	PEMF ⇑ temp
noon between exp	36oC,	36oC,	PEMF no change
late afternoon	36oC, 37oC	36oC, 37oC	PEMF ⇑ temp
brain morning	35.5oC, 35.5oC	36.5oC, 34oC	PEMF ⇓ Temp Tg
noon between exp	36oC-36oC	36oC-36oC	lots of variability
late afternoon	36oC, 36oC	36.oC, 34oC	not quite sig ⇓

Many of these findings are addressed in the defects in Fig 1 in the Reddy and Oliver 2019 review on Alzheimer’s defects in mitophagy.

comment on human mitochondrial diurnal variations [3]

On the opposite of the familial AD spectrum, a Dutch study examined the muscle mitochondrial respiration in Caucasian males in their 20s [4], The expected variation in body temperature was observed, [4] Diurnal changes were seen in BMAL, Clock, and PER2. State 3 respiration with a variety of different substrates was maximal by late afternoon with a significant dawn to dusk increase. State 5 uncoupled (maximal) respiration appear to increase but was not statistically significant. There was no real change in the activity of individual complexes. Nor was there a decrease in the dawn to dusk lever of PINK. There was, however a dawn to dusk decrease in mitochondrial fusion protein OPA-1 and mitochondrial fission protein FIS-1.

PREMF promotes β-amyloid dissolution and more [4]

This follow up study used the same model and protocol as the first [1] except that there were short term and long term (2 month) treatment spans.

results

• PREMF improved the performance in the Y-maze for both the Nt and Tg mice.
• Working memory tests showed promise but were not as conclusive
• Brain and body temperatures were monitored over the course of six weeks. PREMF increased both body and brain temps in the Nt but did not ncrease these temperatures as much in the Tg mice.
• PREMF decreased regional cerebral blood flow at 2 months and at 12 days. This was particularly true in Tg mice whether the PREMF was on or off. Literature was cited claiming that soluble/monomeric Aβ is a powerful vasoconstrictor.
• In the 2 month Tg group PREMF decreased the Aβ deposition in both hippocampus and entorhinal cortex

comment on copper [5,6]

In 2012 Gary Arendash wrote an excellent review [5] on work done at the time. There are some excellent images in this publication that describe the previous studies. It is proposed that PREMF breaks up amyloid complexes.

• This review goes into great detail as to how safe this radio frequency range is.
• This review does mention PBT2, a metal chelator that suppresses metal-induced Aβ oligomerization.
• Dr Arendash reasoned that very low frequency PEMF can have deleterious effects whereas the very high frequency PEMF had not at the time of publication shown to have any biological effect. Ironically, humans are exposed to these every day with their cellphones.
• Dr Arendash cited studies showing exposure of rats to the 25-50 Hz range caused deficits in the performance of the Morris water maze.
• Mechanism(s) of NeuroEM are up regulated heat shock proteins and transthyretin. Transthyretin is an Aβ-binding protein increased by cellphone usage. Dr Arendash, back in 2012, established three different mechanisms for the cellphone frequency PEMF. See the review.
• Some studies of 50 Hz were cited.

Sarell 2009 measured the affinity of Cu²⁺ for both monomeric and fibrillar Abeta(1-42) using two independent methods. The authors examined pH dependency of copper binding and side chains involved. They concluded an extremely high “pico molar” affinity. [6] Does PEMF somehow encourage the release of copper from these agregates?

🐁 good predictor of human Alzheimer’s Disease?

NueroEM has conducted a few clinical trials in human AD patients. Do these results support the rodent model of how things work?

An 8 patient pilot study [7]

• All eight patients had ApoE genotypes of 2/3 or 3/3. No ApoE4. The genetic cause, if known, was not disclosed.
• pulsed fashion and sequentially through the 8 emitters at 915 MHz carrier frequency every 4.6 ms (e.g., a pulse repetition rate to each antenna of 217 Hz). Power levels (specific absorption rate, SAR) for each emitter were set at an average of 1.6 W/kg. 
• 60 day treatment
• Cognitive tests demonstrated meaningful improvement.
• FDG-PET analysis, “anatomic” MRI scans from pre-treatment (Baseline) and post-treatment (Day 60) were selected. FDG is a fluorine radioactive analog of glucose that is used to measure which parts of the brain have the best glucose uptake. The participates were stable in terms of glucose utilization with a few showing improvement.
• CSF and blood samples were analyzed for soluble/monomeric Aβ_1-40 and Aβ_1-42, oligomeric Aβ, total tau (t-tau), and p-tau. PREMF produced increases in cerebrospinal fluid (CSF) levels of soluble Aβ_1-40 and Aβ_1-42, cognition-related changes in CSF oligomeric Aβ, a decreased CSF p-tau/Aβ_1-42 ratio, and reduced levels of oligomeric Aβ in plasma.

Interesting and promising results, but the mouse model remains unproven. What’s more, we are dealing with different AD associated mutathions.

⚖ ️balancing cytokines, mining the first study [8]

Did the PREMF increase cognitive scores and glucose utilization just by reducing inflammation and such as that? The CSF and blood samples were analyzed for twelve cytokines.

• Table 1, no significant changes in cytokines
• Those that had the highest starting cytokines showed the greatest improvements in those cytokines after PREMF treatment.

progressing to a 2½-year study. [9]

• This group of five AD patients also had ApoE mutations.
• Fig 2 gives a diagram of this on , off, on again schedule that lasted for over two years.
• No declines in cognitive scores. It should be noted that untreated controls were not used in this study.
• PREMF was associated with reductions in the CSF levels of C-reactive protein, p-tau217, Aβ1-40, and Aβ1-42 while modulating CSF oligomeric Aβ levels.
• In the plasma, modulated/rebalanced levels of both p-tau217 and total tau were observed.

Mining the first study for vascular endothelial growth factor [7,10]

The authors reanalyzed old plasma and CSFsaples to find a strong baseline correlation between VEGF levels and AD markers (t-tau, p-tau, Aβ_1-40, Aβ_1-42) These markers were reduced by the by the treatment. Reduction in these markers correlated with increases in VEGF levels in AD subjects with low or not measurable “baseline” VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF’s actions on mLVs.

Fig. 1 A model to explain the removal of Aβ

• Meningeal lymphatic vessels (mLVs) are located within the brain’s meninges/dura, Figure 1 gives a nice diagram.
• mLVs drain half of total brain CSF and a site for a substantial amount of toxin drainage/clearance from the brain. CSF
• The location of the PREMF emitters relative to these drainages were given in Fig1.

Fig. 2

• Dilation of mLVs and their proliferation are controlled by VEGF.
• Likely sources of VEGF: choroid plexus ependymal cells, epithelial ependymal cells lining the choroid plexus, resident macrophages within the choroid
• the Assisi Loop development arose from optimizing Ca²⁺ binding to calmodulin. This PREMF possibility was not addressed.

PEMF increases VEGF production in a skeletal muscle ischemia model described in the PEMF eNOS PI3K post.

PREMF Stimulation Therapy for Alzheimer’s Disease [11]

Dr Filipe Perez MD is essentially a competitor form the University of Illinois. Dr Perez has a team of electrical engineers on the team that are focused on getting deeper penetration’s of the PREMF. The team also has a strong grasp of physical chemistry with hydrogen bonding getting a lot of page space.

Discussion was given to the over expression of GRP78, aka heat shock protein 70. decreases the level of Aβ40 and Aβ42 in mutant APP (APPsw) cells and further discussion given to autophagy mentioned at the beginning of this post. The authors expressed concern that the 915MHz cell phone frequency used in the NeuroEM studies was not sufficient to penetrate deep regions of the brain in humans. [11] Discussion was given to hydrogen bonding in nucleic acids. The dielectric effect presumably arises from molecules with positively charged regions on one end and negatively charged regions on another aligning themselves in a magnetic field. The dielectric effect may cause inhomogeneous E-field distribution, because when the E-field of an electromagnetic field interacts with tissues, it decreases the wavelength, generates electric currents, and develops wave reflection or refraction at tissue interfaces. [11]

A concluding visual from WikiCommons

In the Alzheimer’s affected brain (Image 1), abnormal levels of the beta-amyloid protein clump together to form plaques (seen in brown) that collect between neurons and disrupt cell function. Abnormal collections of the tau protein accumulate and form tangles (seen in blue) within neurons, harming synaptic communication between nerve cells. Emerging evidence suggests that Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau amyloid and beta-amyloid proteins and several other factors. It appears that abnormal tau accumulates in specific brain regions involved in memory. Beta-amyloid clumps into plaques between neurons. As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain.

The NeuroEM device seems to be a very promising with many hurdles to providing a convincing mechanism of action and penetration into human brains. Other players [11] are entering the arena.

References

The Neuro EM device seems to reduce tau and Abeta amyloid deposites, preserve cognitive health, and even improve mitochondria function in animal studies.

1. Dragicevic N, Bradshaw PC, Mamcarz M, Lin X, Wang L, Cao C, Arendash GW. Long-term electromagnetic field treatment enhances brain mitochondrial function of both Alzheimer’s transgenic mice and normal mice: a mechanism for electromagnetic field-induced cognitive benefit? Neuroscience. 2011 Jun 30;185:135-49. doi: 10.1016/j.neuroscience.2011.04.012. Epub 2011 Apr 13. PMID: 21514369. free paper
2. Yan R, Wang W, Yang W, Huang M, Xu W. Mitochondria-Related Candidate Genes and Diagnostic Model to Predict Late-Onset Alzheimer’s Disease and Mild Cognitive Impairment. J Alzheimers Dis. 2024;99(s2):S299-S315. PEMC free paper
3. van Moorsel D, Hansen J, Havekes B, Scheer FAJL, Jörgensen JA, Hoeks J, Schrauwen-Hinderling VB, Duez H, Lefebvre P, Schaper NC, Hesselink MKC, Staels B, Schrauwen P. Demonstration of a day-night rhythm in human skeletal muscle oxidative capacity. Mol Metab. 2016 Jul 1;5(8):635-645. PMC free paper
4. Arendash GW, Mori T, Dorsey M, Gonzalez R, Tajiri N, Borlongan C. Electromagnetic treatment to old Alzheimer’s mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit. PLoS One. 2012;7(4):e35751. PMC free paper
5. Arendash GW. Transcranial electromagnetic treatment against Alzheimer’s disease: why it has the potential to trump Alzheimer’s disease drug development. J Alzheimers Dis. 2012;32(2):243-66. free paper
6. Sarell CJ, Syme CD, Rigby SE, Viles JH. Copper(II) binding to amyloid-beta fibrils of Alzheimer’s disease reveals a picomolar affinity: stoichiometry and coordination geometry are independent of Abeta oligomeric form. Biochemistry. 2009 May 26;48(20):4388-402. PubMed
7. Arendash G, Cao C, Abulaban H, Baranowski R, Wisniewski G, Becerra L, Andel R, Lin X, Zhang X, Wittwer D, Moulton J, Arrington J, Smith A. A Clinical Trial of Transcranial Electromagnetic Treatment in Alzheimer’s Disease: Cognitive Enhancement and Associated Changes in Cerebrospinal Fluid, Blood, and Brain Imaging. J Alzheimers Dis. 2019;71(1):57-82. PMC free paper
8. Cao C, Abulaban H, Baranowski R, Wang Y, Bai Y, Lin X, Shen N, Zhang X, Arendash GW. Transcranial Electromagnetic Treatment “Rebalances” Blood and Brain Cytokine Levels in Alzheimer’s Patients: A New Mechanism for Reversal of Their Cognitive Impairment. Front Aging Neurosci. 2022 May 2;14:829049. PMC free paper
9. Arendash G, Abulaban H, Steen S, Andel R, Wang Y, Bai Y, Baranowski R, McGarity J, Scritsmier L, Lin X, Shen N, Aljassabi A, Li Y, Cao C. Transcranial Electromagnetic Treatment Stops Alzheimer’s Disease Cognitive Decline over a 2½-Year Period: A Pilot Study. Medicines (Basel). 2022 Aug 3;9(8):42. PMC free paper
10. Arendash GW, Lin X, Cao C. Enhanced Brain Clearance of Tau and Amyloid-β in Alzheimer’s Disease Patients by Transcranial Radiofrequency Wave Treatment: A Central Role of Vascular Endothelial Growth Factor (VEGF). J Alzheimers Dis. 2024;100(s1):S223-S241. free paper
11. Perez FP, Morisaki J, Kanakri H, Rizkalla M. Electromagnetic Field Stimulation Therapy for Alzheimer’s Disease. Neurology (Chic). 2024;3(1):1020. PMC free paper