It's time to change tactics to treat Alzheimer's disease

IIf madness does the same thing over and over, but expects different results, the last decade of development of a drug against Alzheimer's has been crazy. Three carefully designed, well-executed and resource-intensive trials targeting amyloid protein in the brain as a cause of Alzheimer's disease have failed. It is high time to take a new approach to this devastating disease.

In 1906, psychiatrist Alois Alzheimer described the case of a 50-year-old woman whom he had been following for five years, since being admitted to a psychiatric hospital for paranoia, progressive sleep and memory disorders, aggression and confusion until his death. The autopsy of his brain revealed unusual plaques of amyloid and neurofibrous tangles. Three years later, he described three other cases, including one whose brain had only amyloid plaque. Alzheimer's description of the symptoms of the disease that now bears his name is accurate, and many have assumed over the years that pathology – amyloid plaques and entanglements in the brain – was an important part of the disease.

After several attempts to attribute a pathophysiology to Alzheimer's disease, neuroscientists chose amyloid as the cause. The hypothesis of amyloid, first described in 1984, resulted from a combination of medical research and a new genetic code analysis technology. The natural extension of this hypothesis has been the decision to target amyloid in the treatment of the disease. Medical scientists rolled up their sleeves and got to work.

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Yet the more they watched, the more difficult it became to defend the role of amyloid as a cause of Alzheimer's disease. A big problem is that almost 40% of patients with dementia do not have amyloid plaques in their brains while many people who die with normal cognition have them.

Other confusing results, such as the fact that amyloid levels in the cerebrospinal fluid surrounding the brain decrease as people develop dementia, have also been taken into consideration for unpleasant explanations. Although this is the opposite of what one would expect, experts have explained it.

A comfortable partnership has developed between proponents of the hypothesis of amyloid, funding agencies and pharmaceutical companies, so that only programs supporting this hypothesis have been funded. Even today, the largest amount of NIH funding for Alzheimer's research goes to amyloid-related research.

Following the advice of their educational advisers – most of them members of the amyloid cabal – pharmaceutical companies have conscientiously developed drugs to fight against amyloid disease in order to treat Alzheimer's disease. They thought that solving the problem of Alzheimer's was only a matter of time.

Other ideas have been deprived of funding or greeted with a polite roll of the eyes. I myself have lived this experience as CEO of FPRT Bio from 2012 to 2015. We were studying treatments for neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Our therapeutic strategy was to target microglial cells (a population of immune cells that live in the central nervous system) to eliminate neuroinflammation. Although we have talked to many private investors, companies and companies, FPRT Bio has failed because it could not get funding. Nobody, and I mean nobody, in the world of investors or the biopharmaceutical sector, believed that neuroinflammation was important. Although we did not laugh at meetings – we had too much data for that – we were politely shown at the door and basically said, "Do not call us, we'll call you."

It is a good place to talk about group thinking, a psychological phenomenon that occurs within a group of people and in which the desire for harmony or conformity leads to irrational or dysfunctional decision-making. Groupthink describes the funding and execution of research on Alzheimer's disease and drug development over the last 30 years. Once amyloid became the target, all other ideas were dropped, rejected, even ridiculed. Although I think this dark period is behind us, we have lost three decades and billions of dollars.

In the past seven years, one, two, and then three programs in advanced development targeting amyloid have failed. Other ongoing programs targeting amyloid should expect similar results. Each program was managed by a pharmaceutical company with significant experience and unlimited access to the expertise and financial resources necessary to ensure its success.

A program that has failed may be bad luck. Two could be explained. But after three or four years, it is no longer necessary for a medical scientist with many letters after his name and decades of research experience to conclude that amyloid is not the cause of the disease. Alzheimer.

Although these drug development failures have put a strain on people with Alzheimer's disease and their family members, refuting the amyloid hypothesis may paradoxically be a good thing for people with dementia. Instead of biopharmaceutical group thinking, in which all companies pursue the same strategy, scientists and companies will be forced to step back, evaluate the data and engage in new innovative programs.

And after? A number of small businesses are working on approaches other than amyloid of Alzheimer's disease and dementia. Although these companies have not been successful in attracting the attention of investors and pharmaceutical partners, the failure of aducanumab gives these non-amyloid strategies the attention they deserve.

One of them targets the mitochondria, the source of energy of the cells. These organelles can become altered with age, which can cause Alzheimer's disease. Another approach targets proteins such as tau protein, which can be misfolded. These misfolded proteins can accumulate and cause damage if they are not repaired. It is also thought that chronic inflammation contributes to Alzheimer's disease. Another approach is to develop treatments to treat inflammation.

Let's put the problem in perspective. The cognitive decline, characteristic of dementia and Alzheimer's disease, is due to the loss of nerve cells in the brain and their connections, called synaptic dysfunctions. Therapies to treat Alzheimer's disease must target both of these problems. Amyloid does not cause nerve cell death or synaptic dysfunction, but causes inflammation that can lead to nerve cell death and synaptic dysfunction.

The idea that Alzheimer's is caused by chronic inflammation is corroborated by association data for the entire genome in humans and abundant animal data. This makes the targeting of inflammation in and around nerve cells of the brain one of the promising strategies for treating it. No drug has yet been approved to target inflammation related to Alzheimer's disease, although many are under development and in clinical trials. XPro1595, which my company, INmune Bio, has developed to combat chronic inflammation in Alzheimer's disease, is currently in Phase 1 clinical trials. Other inflammation medications, including GliaCure's GC021109, Alector's AL002 and AL003, and Denali Pharmaceuticals' DNL 747, each have their own unique approach.

What we now call Alzheimer's disease probably comes from many different causes. It is therefore important to explore multiple strategies. And because Alzheimer's is such a complex disease, it is very unlikely that a single treatment will treat all patients with dementia or be effective throughout their lives. This complicates things, but it is biology and it increases the need for multiple options.

With imagination and innovation, we should be able to develop biomarkers to determine the cause of Alzheimer's disease in a given patient and the most appropriate treatment.

Now that the madness of amyloid is behind us, it is time to make real progress.

RJ Tesi, M.D., is CEO and co-founder of Inmune Bio (NASDAQ: INMB), a publicly traded, clinical-stage biotechnology company developing therapies that target the innate immune system to fight the disease.