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Could Precision Treatments Cure Alzheimer’s Disease?

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Summary: Brain scientists suggest precision treatments with a cocktail of drugs as the best way to fight Alzheimer’s disease. [This article first appeared on LongevityFacts. Author: Brady Hartman. ]

A group of brain scientists at New York’s Mount Sinai advocates the development of precision treatments with multiple drugs as a novel cure for Alzheimer’s disease.

The full force of brain researchers and the pharmaceutical industry have focused on finding a cure for Alzheimer’s disease. However, they are focusing on the wrong culprit, say scientists in a recent opinion piece. Instead, the authors propose the development of novel precision treatments with multiple medications to ward off the ravages of Alzheimer’s disease.

Alzheimer's Treatment
Credit: Gerd Altmann

In 1906, German physician Alois Alzheimer first described the disease that would go on to bear his name. It wasn’t until 1984 when George Glenner and Cai’ne Wong identified a peptide called amyloid beta (Aβ) — the chief component of Alzheimer’s brain plaques and blamed it for triggering nerve cell damage.

The leading hypothesis among scientists is that reducing Aβ in the brain will prevent or slow the progression of memory problems. The primary focus of brain researchers for the past 30 plus years has been testing this ‘amyloid beta hypothesis’. Aβ has remained prime suspect in Alzheimer’s Disease (AD), and researchers have focused their research efforts on finding drugs that eliminate the peptide.

Three decades later we have compounds that significantly reduce amyloid beta in the brain, yet none of them seem to work. In an opinion piece published in Scientific American, a group of brain scientists argued that amyloid beta hypothesis is a “dead end” and should be retired. As the authors say,

“So far, the exclusive manipulation of Aβ levels in research and clinical trials has only resulted in a series of high-profile failures of drugs targeting Aβ.“ adding “All clinical trials using molecules that reduce the accumulation of Aβ in the brain do not bring relief of AD symptoms and do not restore memory.”

The authors include Tamas Bartfai, a professor of neurochemistry at the University of Stockholm. Graham Lees, the owner of Finnish publisher Corpus Alienum Oy. Sam Gandy, a professor of neurology and psychiatry at the Icahn School of Medicine at Mount Sinai in New York City (ISM-MSNY). As well as Mary Sano, a professor of psychiatry and the director of the National Institute on Aging-Designated Alzheimer’s Disease Research Center also at ISM-MSNY.

The authors are not the first group of experts to argue against the amyloid hypothesis, but perhaps the most eloquent in a growing chorus of voices. Instead of trying to eradicate amyloid beta, the authors say, researchers should focus their efforts on other Alzheimer’s treatments, such as those that attack tau tangles and brain inflammation.

Researchers are not entirely sure what causes Alzheimer’s disease, however, according to the Alzheimer’s Association, beta-amyloid plaques and tau protein tangles are prime suspects in the loss of function and cell death in the brains of patients.

If you peer inside the brain of most Alzheimer’s patients, you’ll see plaques crowding the space in between the brain cells. These plaques are made out of the amyloid beta peptide, a significant type of extracellular junk that builds up in our brains as we age. The most damaging form of amyloid beta may be the small clusters of a few pieces rather than the large plaques. These tiny clumps may block nerve signaling and may also trigger chronic inflammation and activate immune system cells that devour crippled brain cells.

The Mount Sinai authors claim that despite the drug failures, the idea of removing amyloid beta remains attractive. A mutation in Aβ in some Icelanders reduces its levels by half throughout their lives. These fortunate Icelanders virtually never develop Alzheimer’s disease.

Alzheimer's cases are expected to triple.
Alzheimer’s cases are expected to triple. Credit: Gerd Altmann

Alzheimer’s is the most common form of dementia, a group of brain disorders, which affect behavior, thinking, memory, and emotion. Due to physical changes in the brain, Alzheimer’s and other forms of dementia lead to the gradual deterioration in our ability to think and remember things. Alzheimer’s and other forms of dementia are massive problems that are about to get a whole lot bigger, according to the April report by the World Health Organization that expects Alzheimer’s rates to triple by 2050.

As we grow older, our odds of getting Alzheimer’s – or any other type of dementia – increase with every passing year. In fact, some form of dementia affects about half of the population age 85 years or older.

Given the prospect of a massive payday, the pharmaceutical industry continues to search for a cure for Alzheimer’s disease. Big Pharma cannot afford to turn its back on the condition because any successful treatment would be a guaranteed blockbuster. No major pharmaceutical company wants to miss out on a drug that will be used for around 25 years by about 30 percent of the population.

Despite the enormous pot of gold at the end of the rainbow, a cold hard truth remains: all clinical trials that reduce amyloid beta have failed. As authors Bartfai, Gandy, Lees, and Mano point out,

“The giant pharmaceutical companies—Pfizer, Lily, Novartis, Astra-Zeneca, Roche and, most recently, Merck—have experienced failed clinical trials, even in cases when the drug succeeds in in removing amyloid, as revealed by amyloid imaging.“

The authors give many explanations for these failures, saying perhaps patients are not taking amyloid-reducing drugs soon enough. Another explanation is that the amyloid hypothesis is flat out wrong and yet another reason is that for amyloid-reduction to be helpful, it must be combined with drugs that treat the other Alzheimer’s pathologies.

Dr. Bartfai & Company call for increased research efforts into other ways to attack the problem other than amyloid-clearing drugs. It seems these authors are getting their wish, according to a recent report, on novel treatments to cure Alzheimer’s.

Researchers are increasingly focusing on alternative ways to fight Alzheimer’s such as addressing the tau protein, battling chronic inflammation and handling synapse dysfunction. Scientists are reporting new findings frequently, such as last week’s announcement by researchers that discovered a key to Alzheimer’s Disease.

Too Little, Too Late

Another explanation is that patients are not taking the amyloid-reducing drugs soon enough. The Mount Sinai authors say that current trials admit patients over 65 who already have with signs of amyloid plaques and

“There is no evidence so far to prove that current Aβ-lowering trials (beginning at age 65 or above) will show any meaningful benefit for memory or other brain functions. “

Instead, the authors argue for taking these drugs beginning at age 55, as Bartfai & Co explain,

“To counter the organ’s slow decline, simple math suggests that drug prevention of AD might ideally begin at the latest by 55 years of age, calculated from knowing the 50 percent risk of symptoms by age 85, then subtracting from that number the 30 years during which brain amyloid is often silent. “

The authors argue that the age of 55 is a time when “cardiovascular, physical, mental and lipid factors” foster amyloid build-up and that is an ideal time to begin preventative treatment to reduce the build-up.

The strategy calls for hampering the build-up during a period in which “brain amyloid is present but silent.”

We have the technology to do it. Using an imaging machine called positron emission tomography (PET), scientists can image the brain to detect the smallest amyloid deposits and, in theory, prevent Alzheimer’s before it has a chance to do damage.

However, the MSNY authors add that this approach may not be feasible because pharmaceutical firms are reluctant to conduct half-decade-long trials in relatively healthy people, exposing the patients to possible side effects while burdening the pharmaceutical companies with enormous costs. Furthermore, the benefits of the treatment may not outweigh the potential side effects and expense of the treatment. Giving the nickname of ‘Plan A’ to the strategy of early detection and reduction of amyloid beta, Bartfai & Co argue that,

“Any new medication for AD that is worth the risk of ingestion for decades must be effective and must do no harm anywhere in the body. The Aβ-lowering drugs in the current pipeline fall well short of this goal. As yet, there is no reason to expose patients to risky and expensive drugs showing only incremental benefits that are not meaningful. This Plan A is beginning to look like a dead end at least in the protocols employed so far. “

Some pharmaceutical firms are ignoring the costs and risks of pursuing this ‘Plan A,’ and instead, are conducting Alzheimer’s early intervention trials in their quest to cure the disease.

The ideal Alzheimer's treatment may be a combination of many drugs.
The future Alzheimer’s treatment may be a combination. Credit: One trick pony 768 via FLICKR.

One Trick Pony

Dr. Bartfai & Co say that the current approach of testing one drug at a time is ineffective. The authors suggest that one day, physicians will prevent Alzheimer’s disease in the same way they ward off heart disease and other chronic diseases – with a cocktail of drugs.

The proposal makes a lot of sense. Most patients with high blood pressure or diabetes are treated with a combination of two or three drugs acting on different molecular targets. In other words, these patients are given precision treatments based on their blood pressure readings, cholesterol levels, blood sugar levels and many other factors. Instead of focusing on only amyloid beta, perhaps the Alzheimer’s drug regimen of the future will also involve a cocktail of medications, as Dr. Bartfai & Co argue

“For the best chances of success, we are likely to require additional drugs that interact with other molecules besides Aβ.”

Could the Amyloid Hypothesis Be Wrong?

The amyloid beta hypothesis has three main problems, say Dr. Bartfai & Co. First of all, amyloid beta does not always cause Alzheimer’s immediately. Research has shown that a patient can have amyloid deposits for three decades or longer before symptoms begin and doctors make a diagnosis. The amyloid accumulation may never cause any symptoms.  In fact, some people die with full-blown Alzheimer’s pathology but no symptoms.

Second, the authors argue, thirty years of research says that amyloid beta does not have a uniform effect on different groups of people. Recently, scientists have analyzed the evolution of brain amyloidoses and discovered unexpected and unexplained variations in their nature and time course.

Lastly, say the authors, about one-third of patients with clinical Alzheimer’s disease have negative amyloid imaging. This includes patients who have all the symptoms, including atrophy of brain tissue and abnormal glucose uptake by neurons.

The MSNY authors suggest an explanation. Perhaps the answer is that there are two subtypes of Alzheimer’s, an “amyloid-first” form of the disease, in which amyloid builds up before the symptoms, and an “amyloid-later” form, where the symptoms and cellular destruction precede the arrival of amyloid. The authors suggest that if these subtypes exist, they could be best approached with precision treatments.

Precision treatments for Alzheimer's may be the future solution.
Precision treatments for Alzheimer’s may be the future solution.

Precision Treatments for Alzheimer’s

The authors make the point that there may be different subtypes of Alzheimer’s disease and that a tailored cocktail of drugs could target each subtype. Dr. Bartfai & Company call for the use of a

“precision approach” to “treat or prevent each subtype of dementia based on its molecular profile.”

In using the term “precision approach,” it seems that the MSNY authors are referring the concept of precision medicine, in which precision treatments are tailored to the patients’ specific genetic profile and history. However, the authors didn’t specify whole genome sequencing, an integral part of precision medicine, and presumably, precision treatments as well.

The authors give examples to explain their approach, saying “treatments could be marshaled with different classes of drugs, some aimed at diminishing amyloid accumulation. Others could target brain blood vessel changes due to the accumulation of amyloid or cholesterol in the blood vessel wall—and both classes might be useful in some patients.” adding “Tangle-reducing and/or inflammation-modulating drugs could be added to our cocktails if appropriate to the molecular profile.”

Scientists use big data to uncover the best Alzheimer's treatments.
Big data may uncover the best Alzheimer’s treatments. Credit: Gerd Altmann

The authors base their suggestion on the recent findings of researchers Bin Zhang and Eric Schadt and colleagues at Mount Sinai in New York. Zhang and Schadt employed a big data approach to analyzing the expression of genes at various disease stages and across multiple brain regions of hundreds of patients with Alzheimer’s disease. Using this method, the Zhang and Schadt identified networks of genes in which key molecules, called hubs or drivers, appeared to be controlling the progression of Alzheimer’s disease.

The authors recommend exercise to prevent Alzheimer's.
The authors recommend exercise to prevent Alzheimer’s. Credit: Canva

Bartfai & Co on Preventing Alzheimer’s

In what is by no means a complete list, the MSNY authors suggest a few ways to prevent Alzheimer’s. In the main, the authors felt that a healthy lifestyle was the best way prevent the disease, saying

“Heart-healthy diet, lifestyle and cardiovascular status during midlife are important in determining when dementia appears in late life.” adding “Physical exercise is perhaps the single most important factor that can have an impact on late-life dementia risk.”

Dr. Bartfai & Company admitted that the ability of lifestyle changes to reduce dementia was not conclusively supported by the research evidence when they added

“A U.S. National Academies of Sciences, Engineering and Medicine study recently declared that the possible cognitive benefits of modifying lifestyle and diet were promising but the current evidence for benefits of diet and lifestyle modification were insufficiently robust to warrant an endorsement for general public health recommendation.”

Additional Ways to Prevent Alzheimer’s

Dr. Bartfai & Company only gave a brief overview of ways to prevent Alzheimer’s but neglected to mention that a recent meta-analysis of observational studies shows that caffeinated coffee drinkers have a lower rate of Alzheimer’s and Parkinson’s.

Moreover, researchers have shown that there are a many other ways to prevent Alzheimer’s disease in mice, and suggest these may be applied to humans. In other words, rather than precision treatments, these scientists suggest a cocktail of geroprotective drugs to ward off Alzheimer’s. These approaches will be covered in the upcoming part 3 of this series.

Bottom Line

Currently, there is no known cure for Alzheimer’s and existing drugs slightly slow symptoms at best.

Rather than pinning our hopes on a single breakthrough drug, future precision treatments for Alzheimer’s will probably involve a combination of strategies. This combination may include early detection and intervention, identification of the particular strain of Alzheimer’s or the specific genetic makeup of the patient, and then using any number of precision treatments consisting of a cocktail of drugs.

Until these precision treatments emerge, according to Dr. Bartfai and company, our best way of warding off dementia is a healthy lifestyle, especially one that includes regular physical exercise. And although Bartfai and company didn’t mention it, data from observational studies point to a significantly reduced risk of Alzheimer’s for coffee drinkers.

This is part two of a three-part series.

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References

Cover photo: Getty Images.

Sam Gandy, Tamas Bartfai, Graham Lees, Mary Sano. “What Would It Take to Get an Effective Alzheimer’s Drug?” Scientific American. July 17, 2017. Web. Retrieved 25 Nov. 2017. Link.

Huang, Yadong, and Lennart Mucke. “Alzheimer Mechanisms and Therapeutic Strategies.” Cell 148.6 (2012): 1204–1222. PMC. Web. 25 Nov. 2017. Link.

Chesser, Adrianne S., Susanne M. Pritchard, and Gail V. W. Johnson. “Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease.” Frontiers in Neurology 4 (2013): 122. PMC. Web. 24 Nov. 2017. Link.

Disclaimer

Diagnosis, Treatment, and Advice:  This article is intended for educational and informational purposes only and is not a substitute for qualified, professional medical advice.  The information and opinions provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. Experimental therapies carry a much higher risk than FDA-approved ones.  Consult a licensed and qualified physician for the diagnosis and treatment of any and all medical conditions. Call 911, or an equivalent emergency hotline number, for all medical emergencies. As well, consult a licensed, qualified physician before changing your diet, supplement or exercise programs. Photos, Endorsements, & External Links:  This article is not intended to endorse organizations, companies, or their products. Links to external websites, mention or depiction of company names or brands, are intended for illustration only and do not constitute endorsements.

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