If insanity is doing the same thing over and over again but expecting different results, then the last decade or so of Alzheimer’s disease drug development has been insane. Three carefully designed, well-executed, and fully resourced trials targeting amyloid protein in the brain as the cause of Alzheimer’s disease have failed. It’s long past time to take a new approach to this mind-robbing disease.
In 1906, psychiatrist Alois Alzheimer described the case of a 50-year-old woman he had followed for five years, from her admission to a psychiatric hospital for paranoia, progressive sleep and memory disturbance, aggression, and confusion until her death. His autopsy of her brain revealed unusual plaques of amyloid and tangles of neurofibrils. Three years later he described three more cases, including one individual whose brain showed only amyloid plaque. Alzheimer’s description of the symptoms of the disease that is now named after him is accurate even today, and many have assumed over the years that the pathology — the amyloid plaques and tangles in the brain — are an important part of the disease.
After several stillborn attempts to ascribe a pathophysiology to Alzheimer’s disease, neuroscientists embraced amyloid as its cause. The amyloid hypothesis, first described in 1984, was the result of a combination of medical sleuthing and new technology for analyzing the genetic code. The natural extension of this hypothesis was the decision to target amyloid as a treatment of the disease. Medical scientists rolled up their sleeves and got to work.
Yet the harder they looked, the more difficult it became to defend the role of amyloid as a cause of Alzheimer’s. One 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 do have them.
Other confusing findings, such as the fact that amyloid levels in the cerebral spinal fluid surrounding the brain go down as people get dementia, also made for uncomfortable explanations. Although this is the opposite of what would be expected, it was explained away by experts.
A comfortable partnership developed between believers in the amyloid hypothesis, funding agencies, and drug companies, so that only programs supporting this hypothesis were funded. Even today, the largest amount of NIH funding for Alzheimer’s disease research goes to amyloid-0related research.
Following the advice of their academic advisers — most of them members of the amyloid cabal — drug companies dutifully developed drugs to target amyloid with the goal of treating Alzheimer’s disease. They believed it was only a matter of time before the Alzheimer’s problem was solved.
Other ideas were starved of funding or greeted with polite rolling of the eyes. I experienced this firsthand as CEO of FPRT Bio from 2012 to 2015. We were investigating therapies for neurodegenerative diseases, including Alzheimer’s and Parkinson’s. 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 talked to a lot of private, venture, and corporate investors, FPRT Bio failed because it could not get financing. No one, and I do mean no one, in the investor or biopharma world believed that neuroinflammation was important. While we didn’t get laughed out of the meetings — we had too much data for that — we were politely shown the door and basically told, “Don’t call us, we’ll call you.”
This is a good place to talk about groupthink, the psychological phenomenon that occurs within a group of people in which the desire for harmony or conformity results in irrational or dysfunctional decision-making. Groupthink describes the funding and execution of Alzheimer’s disease research and drug development over the last 30 years. Once amyloid became the target, all other ideas were abandoned, shunned, even ridiculed. Although I believe that this dark period is behind us, we’ve wasted three decades and billions of dollars.
Over the past seven years, first one, then two, and now three programs in advanced stages of development that targeted amyloid have failed. Other ongoing programs targeting amyloid should expect similar results. Each program was run by a pharmaceutical company with significant experience and unlimited access to expertise and the financial resources needed to ensure success.
One failed program may be bad luck. Two might be explained away. But after three or four it doesn’t take a medical scientist with many letters after his or her name and decades of research experience to conclude that amyloid is not the cause of Alzheimer’s disease.
Although these drug-development failures have been wrenching for individuals with Alzheimer’s and their family members, disproving the amyloid hypothesis may paradoxically be a positive thing for people with dementia. Instead of biopharmaceutical groupthink, in which all companies pursue the same strategy, scientists and companies will be forced to step back, evaluate the data, and commit to innovative new programs.
What’s next? A number of small companies are working on other-than-amyloid approaches to Alzheimer’s disease and dementia. Although these companies have had little success in getting the attention of investors and pharmaceutical partners, the failure of aducanumab is giving these non-amyloid strategies the attention they deserve.
One targets mitochondria, the energy source of cells. These organelles can become impaired with age, which possibly causes Alzheimer’s. Another approach targets proteins such as tau, which can misfold. These misfolded proteins can accumulate and cause damage if they aren’t repaired. Chronic inflammation is also thought to contribute to Alzheimer’s, so another approach is to develop therapies that treat inflammation.
Let’s put the problem in perspective. Cognitive decline, the hallmark of dementia and Alzheimer’s disease, is caused by the loss of nerve cells in the brain and the connections between them — so-called synaptic dysfunction. Therapies to treat Alzheimer’s disease need to target these two problems. Amyloid doesn’t cause nerve cell death or synaptic dysfunction, but it does cause inflammation, which can lead to nerve cell death and synaptic dysfunction.
The idea that Alzheimer’s is caused by chronic inflammation is supported by genome-wide association data in humans and abundant animal data. That makes targeting inflammation in and around nerve cells in the brain one of several promising strategies for treating it. No drugs have yet been approved for targeting Alzheimer’s-related inflammation, although several are in development and in clinical trials. XPro1595 , which my company, INmune Bio, has developed to target chronic inflammation in Alzheimer’s, is currently in Phase 1 clinical trials. Other drugs taking aim at inflammation, including GliaCure’s GC021109 , Alector’s AL002 and AL003, and Denali Pharmaceuticals’ DNL 747, have their own unique approaches.
What we today call Alzheimer’s disease likely stems from several different causes, so exploring multiple strategies is important. And because Alzheimer’s is such a complex disease, there is a very low probability that a single therapy will treat all patients with dementia or be effective throughout their lifetimes. This complicates things, but that’s biology and it increases the need for multiple options.
With imagination and innovation, we should be able to develop biomarkers to determine what is causing a particular patient’s Alzheimer’s disease and which treatment would be the best fit for it.
Now that the insanity of amyloid is behind us, it’s 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 disease.
I have been researching without any luck to see if there’s a connection between getting Alzheimer’s and owning a cat or dog. I have looked for statistics in vain as to the prevalence or lack thereof off pet-owning in Alsheimer’s. I’m no doctor but you might agree with me that dog owner are mostly delusional in that they blather about the unconditional love their dog gives them when we saner people know a dog likes whoever feeds it. Just wondering what you think.
If we ever needed goverent intervention we need it now. Like the Manhattan prroject to develop the A bomb. Get together the best brains in the world, preferably basic science researchers, and I bet we’ll have the cure in less than a decade.
This is an excellent article, and written so that a scientific layperson like myself can easily understand it. The information is both hopeful (perhaps now that the focus on amyloid plaques is in the process of being discarded, we can finally make some progress) and yet incredibly frustrating (the fact that the scientific community would get mired in “groupthink” for DECADES means that they ignored the evidence and thus abandoned their scientific principles).
I do have a few thoughts. Since so many conditions, including HIV/AIDS, respond best to a cocktail of therapies, I hope that this approach will be tried in Alzheimer’s. Perhaps being treated with a therapy that fights brain inflammation AND something that addresses Mitochondria dysfunction AND something that addresses Tau buid-up is the way to go. And even if Amyloid plaques is not the sole cause of AD, perhaps it nevertheless still contributes to it, so using an anti-amyloid therapy as an additional component in a combination therapy approach might prove to be beneficial.
One depressing fact seems obvious. Given the extraordinarily lengthy drug discovery and approval process, one implication of having to go “back to the drawing boards” is that countless numbers of additional people will suffer and die from this disease before effective treatment(s) will become widely available.
Good article , I enjoyed the new information and wish you success.
I teach classes in basic neuroscience and aging for senior citizens
Two long shots that deserve some thought: role of parathyroid peptides on calcium channel blockers, disruptors of blood brain barrier and relation to causes of leaky gut.
Hopefully sensible approaches like that of Dr. Tesi will open up investor’s minds to new angles of attack on Alzheimer’s. Three decennia of self-inflicted short-sightedness in this field is much longer than the blinders-on stages for many other, more accute-illness areas of research. With so many Alzheimer’s patients, and so much ignored long-existing evidence of the wrong approach, I applaud Dr. Tesi’s fresh open-minded and logical research.
Scientists keep working around the edges of Alzheimer’s disease. The principal cause of Alzheimer’s disease is likely nitro-oxidative stress. Amyloid oligomers contribute to nitro-oxidative stress but so too do many other factors including various environmental toxins, an unhealthy diet, psychological stress, and genetics.
Activated microglia (the brain’s main immune cells) are both a cause and consequence of nitro-oxidative stress. Deal with this stress (by scavenging the nitro-oxidant peroxynitrite, for instance) and activated microglia do very little damage to the brain.
A variety of peroxynitrite scavengers, including various essential oils via aromatherapy (bay laurel, rosemary, lemon balm, and clove, for instance), CBD oil, panax ginseng, and feru-guard (ferulic acid in Angelica archangelica and rice bran oil) have all shown potential for improving certain forms of memory and in some cases improving mood and behavior in people with Alzheimer’s disease
The generation of biomolecules (amyloid oligomers and biomarkers of ‘nitro-oxidative stress’) appear to be substantially influenced by psychological factors (such as stress anxiety, depression, etc.). Other factors (e.g. environmental toxins, genetics, food, etc.) – only play a very minor role. In terms of genetics – check out the article titled “APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.” (PLoS medicine vol. 14.). The current primary research focus on BIOLOGICAL factors (for combating Alzheimer’s), is largely driven by profit-oriented big pharma.
So! Is there any hope .?
https://www.sciencedaily.com/releases/2019/05/190501153358.htm
Double prion disease?
Intriguing but ominous.
If so medicine is currently at a complete loss as to how to treat, let alone cure, prion associated diseases.
Yes, sounds good. I think diet, exercise and sunshine are basic to good health, and most would agree. Further than that vitamin B12 levels in the west are half the minima acceptable in Japan, which raised it to 500 pmol/L, in the west it’s something around 150. I’m having trouble convincing my GP that that is too low and that despite having Intrinsic Factor, I do not have the Extrinsic Factor (I don’t eat meat) and the reason for my current neuronal cognitive, (short-term memory) decline and not Age.