Neuromodulation for Treating Alzheimer’s Disease — Why Not Now?

INTRODUCTION

My Mom died of complications from Alzheimer’s Disease (AD) after about a 15 year battle. My mother-in-law has suffered AD-related decline for at least 5 years, and went into memory care this past year. What has struck me most about their situations is that there is essentially no change in guidance of how to live with AD, no better advice in how to approach being a caregiver, and especially that there has been no advance in 20 years in how to treat the disease, slow the decline or reverse the effects.

This seems an opportune time to try some more innovative and lower cost approaches that large health care companies are not financially motivated enough to pursue, or too risk-averse to try.

BIG PHARMA FAILURE

After close to 10 years of donating money to the Fisher Center for Alzheimer’s Research, I observed that very little in the way of progress has come out of their research. Indeed, their regular newsletter chirps about doing crossword puzzles and staying fit to ward off dementia, but you know I can get that from the Sunday newspaper Parade magazine insert.

Doing a review of research yields much the same conclusion. Treatments aimed at preventing or reducing beta-amyloids thought to cause AD have been studied for going on 20 years. More recently, in 2019, Nature published a review of four different anti-amyloid antibody trials that all failed to show effectiveness.

Also, in 2019 drug companies Biogen and Eisai announced they were scrapping two phase 3 trials of the investigational anti-amyloid agent called aducanumab based on an interim “futility analysis”. In 2021, the companies cited new data from the studies and are seeking FDA approval again — basically, one of the studies had positive results and one did not. News coverage seems to cite financial pressures to come up with positive news, which indeed spiked their stock price.

And so, this is not to say efforts don’t continue. A 2020 survey article is a good assessment of the future of treatment in the wake of failures. The Alzheimer’s Association is another organization that continues to fund research and some new approaches, for example of drugs aimed at preventing onset. AA is focused on pharmacological approaches, but still doesn’t seem to have much to show in the way of results.

In general, big pharma and the large non-profit organizations aren’t nimble for a variety of reasons — the need for long term research, high barriers to entry, and the need for large potential profits to justify the investments. (My conclusions are based on a market analysis that may be found here.

WHAT ABOUT NEUROMODULATION?

Could neuromodulation help slow effects of Alzheimer’s?

A recent study from Johns Hopkins suggests that “patients with late-onset Alzheimer’s may show some long-term benefit” from deep brain stimulation.” The study is quick to caveat that there is no demonstrated benefit for early onset Alzheimer’s patients, as if not to appear too positive about the technology that may seem too edgy.

Not unlike Big Pharma, there are three major (market cap in the billions of dollars) neuromodulation players — Abbott, Boston Scientific and Medtronic — who have a substantial portfolio of neuromodulation treatments that are almost entirely aimed at the market for chronic pain relief. These treatments generally are surgically implanted, and so satisfy the high-risk, high-reward nature of the companies. The treatments are also backed by substantial clinical studies carried out over a period of years.

As one of few examples that target cognitive decline, FDA awarded “Breakthrough Device” status to Boston Scientific’s deep brain stimulation (DBS) systems in people aged 65 years and older with mild probable AD. Functional Neuromodulation, whose founder led the Johns Hopkins study cited above, is in a strategic investment partnership with Boston Scientific. This approach aligns with Boston Scientific’s expertise and business model for surgically implanted devices.

But for the most part, the big 3 companies provide a handful of promising treatments for non-pain-relief conditions such as Parkinson’s or epilepsy. But treatments for those types of conditions tend to be more the province of smaller medical technology companies, with market caps more in the $10 million to $100 million range. (See A Guide to the Neuromodulation Market.)

And until recently, the market for neuromodulation in the service of treating cognitive decline was largely non-existent. But in the past 5 years, a few start-ups have moved in this direction, and made some significant recent progress. Many are not surgical approaches. Some of them have emerged from university research and can point to some clinical testing. Others have produced products without the resources to do extensive testing, but that are based on similar technical approaches that have shown progress.

On a personal level, given the lack of help for people and families who have been suffering over the last 10 to 20 years, and given the near hopeless situation of people in the archipelago of memory care warehouses, I ask why shouldn’t any and all possible solutions be given the green light in some expedited fashion?

WEARABLE NEUROMODULATION SOLUTIONS

Cognito Therapeutics announced in January 2021 that its non-invasive neurostimulation device has received breakthrough status from the FDA, to treat cognitive and functional symptoms associated with AD. The company said the device is the first in its pipeline of digital therapeutics for neurodegenerative diseases and other chronic indications.

“Knowing that in Alzheimer’s Disease there is a deficiency in certain brainwave frequencies, our founders discovered that stimulating the brain at a specific frequency (gamma, or 40 Hz) had the effect of reactivating the immune system in the brain. This effect correlated with a reduction in amyloid plaques and tau tangles, typical hallmarks of the disease.”

NeuroEM Therapeutics has announced that MemorEM, a bioengineered head device that has been associated with enhanced cognitive function in a small pilot study of patients with mild-to-moderate Alzheimer’s Disease, was granted an FDA breakthrough designation in 2020.

“The device, consisting of a cap and arm control box, is worn twice a day for an hour at a time, and is designed to allow patients to move around their home as usual. MemorEM features the company’s proprietary transcranial electromagnetic treatment (TEMT) technology, which works by breaking up small aggregates of beta-amyloid and tau proteins. “The electromagnetic waves emanating from multiple emitters within [the device] easily penetrate the human brain and gently disassociate the toxic oligomers inside neurons, resulting in a reversal of Alzheimer’s memory impairment in key tasks used to evaluate cognitive performance,” the company said.”

Gamma Wave Technologies is a new start-up company that has introduced a wearable headset called , which appears to target sleep problems in general. But the company also notes in their advertising that insufficient sleep is associated with onset of dementia. The product is also claimed to enhance “slow wave” activity in the brain that clinical research has associated with the consolidation of new memories. Gamma Wave cites “neuromod techniques” that enhance slow wave techniques for mindfulness, similar to focused states of flow reported by long term meditators.

Gamma Light is a new product in the form of a “40Hz light bulb.” Based loosely on the research cited by the previous companies, this “light therapy” product is used external to the individual. The company notes that “research suggests that exposure to a light or sound at 40Hz (40 times per second) promotes gamma brain wave activity through the entrainment phenomenon… One of the most promising areas of interest is the use of waves to activate critical cleaning cells in the brain that could lessen beta amyloid.” The more general market for the device seems to be “healthy individuals have also reported using gamma brain waves to increase focus (brain hacking), improve meditation/relaxation, and to promote lucid dreams.”

I have no direct experience with Gamma Light, and on its face, it seems a little too simple to be true, but again, absent any damaging effects, why not try?

Neuroglee Therapeutics, a seed stage company launched in late 2020, has developed “an investigational prescription digital therapeutic (DTx) that can be used independently or in conjunction with a pharmacotherapy for treating neurodegenerative diseases. Unlike more general wellness apps, digital therapeutics are designed to be used under the supervision of a clinician and undergo regulatory review/clearance for treating a specific disease. Neuroglee “incorporates engaging gamification techniques” and cognitive tasks on a digital tablet, allowing physicians to remotely monitor their patients’ cognitive function and intervene using personalised cognitive rehabilitation approaches. This is included here as an on-point, non-pharma approach, even though there is no neuromodulation component in this product.

Neurogeneces is a start-up that has developed a headband worn during sleep to improve memory consolidation during sleep. It employs neuromodulation delivered via a sound modality. They also mention that memory consolidation happens during slow-wave sleep. “While you sleep, we emit precision-timed sounds during memory consolidation to help your brain stay in the consolidation state longer, increasing memory retention” The Neurogeneces pitch closes with “No drugs, no side effects, no effort.” Sounds good to me.

The companies in this article are probably not a comprehensive list, but they demonstrate a variety of promising neuromodulation approaches to cognitive improvement that are less invasive (and expensive) than large conventional med tech companies. In a folksy acronym referenced by everyone from Fortune Magazine to Dr. Oz, Professor Rudy Tanzi at the Harvard Medical School recommends protecting your brain from Alzheimer’s with the “SHIELD” formula. The “H” stands for “Handle Stress”, the “I” stands for “Interact with Others”, and so on, and all good advice, if elementary. But the “S” in SHIELD stands for “Sleep” — “amyloid plaque is generated to protect brain cells, but too much plaque hurts the brain and nerves. Plaque production slows down during sleep, when the brain cleans itself up and eliminates excess plaque — that’s why you need to sleep 7–8 hours every night.”

I’d like to believe it is as simple as that, but why not layer some reasonable amount of neuromodulation on top of that common sense regime of memory preservation, and offering something that more advanced sufferers can use for a condition that simply sleeping more hasn’t solved?

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The mission of Neurosphere Technologies (NST) is to further develop digital technology and businesses in the service of mentalhealth, wellbeing, and human potential. The company has a particular focus on improved consumer pricing for Brain-Computer Interface (BCI) technology.

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Don Dulchinos

Experienced senior tech exec. Now leading TransTech Boulder, building tech for mental wellness, emotional wellbeing, and human flourishing.