Two Examples of Recent Work on Novel Drug Candidates to Treat Alzheimer's Disease

Absent any greater context on Alzheimer's disease research, one might look back at the past twenty years of clinical trials and consider this medical condition to be an insurmountable obstacle at our present stage of progress in biotechnology. The history is an unremitting series of abject and expensive failures. The underlying context is more promising, however - Alzheimer's research is the sharp, applied end of two massive, distributed research projects that are still somewhere in their middle stages. The first of these is the effort to map and understand the biochemistry and cellular function of the brain in detail. The second is the effort to produce functional, safe, reliable immunotherapies, which in turn requires researchers to map and understand the biochemistry and cellular function of the immune system in detail. At some point, immunotherapies to remove the protein aggregates associated with Alzheimer's will start to work, as tremendous progress has been made in the underlying understanding of the brain and the immune system over the past decade or two. Early signs of that stage of progress emerged last year, but they are still only early signs.

Failure has consequences, however. As the primary focus of amyloid clearance continues to fail to produce results, it is the case that ever more effort and funding flows in other directions. Some of these are quite promising and genuinely new approaches that have yet to be fully explored, such as restoration of lost drainage of cerebrospinal fluid. Others seem more like the business as usual approach of the pharmaceutical research community, which is to say (a) tinkering with ways to compensate for the disease state rather than addressing something closer to a root cause, and (b) screening and repurposing existing drugs that are already approved for use in humans, even if the effects are only marginal, because that is cheaper than looking for new approaches. That sometimes this tinkering turns up items that might be worth developing as stop-gap therapies is either a blessing or a curse: a blessing because some benefits are better than no benefits, and a curse because it distracts significant effort from addressing the causes of the condition. It is hard to say which is more the case, especially in the scenario in which a direct assault on root causes is proving to be much, much harder than expected.

The two separate lines of drug development noted below are examples of largely compensatory approaches, even though they touch on aspects of the cellular biochemistry of the brain known to change with age. They do not address the underlying causes of the dysfunctions they ameliorate, but rather try to force the behavior of brain cells and their component parts into a more youthful configuration - overriding the evolved reactions to the damage of aging. One of these approaches focuses on growth factors that govern many fundamental aspects of cellular behavior, such as replication, while the other touches on mitochondrial function. Mitochondria, the power plants of the cell, are known to suffer a general malaise of reduced function and altered dynamics in aging, and since the brain is an energy-hungry organ, it is perhaps the most profoundly affected by this form of decline.

Diabetes drug "significantly reverses memory loss" in mice with Alzheimer's

A drug developed for diabetes could be used to treat Alzheimer's after scientists found it "significantly reversed memory loss" in mice through a triple method of action. "With no new treatments in nearly 15 years, we need to find new ways of tackling Alzheimer's. It's imperative that we explore whether drugs developed to treat other conditions can benefit people with Alzheimer's and other forms of dementia. This approach to research could make it much quicker to get promising new drugs to the people who need them."

This is the first time that a triple receptor drug has been used which acts in multiple ways to protect the brain from degeneration. It combines GLP-1, GIP, and Glucagon which are all growth factors. Problems with growth factor signalling have been shown to be impaired in the brains of Alzheimer's patients. The study used APP/PS1 mice, which are transgenic mice that express human mutated genes that cause Alzheimer's. Those genes have been found in people who have a form of Alzheimer's that can be inherited. Aged transgenic mice in the advanced stages of neurodegeneration were treated. In a maze test, learning and memory formation were much improved by the drug which also: enhanced levels of a brain growth factor which protects nerve cell functioning; reduced the amount of amyloid plaques in the brain linked with Alzheimer's; reduced both chronic inflammation and oxidative stress; slowed down the rate of nerve cell loss.

Alzheimer's drug turns back clock in powerhouse of cell

The experimental drug J147 is something of a modern elixir of life; it's been shown to treat Alzheimer's disease and reverse some measures of aging in mice and is almost ready for clinical trials in humans. Now, scientists have solved the puzzle of what, exactly, J147 does. They report that the drug binds to a protein found in mitochondria, the energy-generating powerhouses of cells. In turn, they showed, it makes aging cells, mice and flies appear more youthful.

Researchers developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule (curcumin) found in the curry spice turmeric. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer's progression in mice. However, they didn't know how J147 worked at the molecular level.

In the new work, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP - the cell's energy currency - within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies. Further experiments revealed that modulating activity of ATP synthase with J147 changes the levels of a number of other molecules - including levels of ATP itself - and leads to healthier, more stable mitochondria throughout aging and in disease. The team is already performing additional studies on the molecules that are altered by J147's effect on the mitochondrial ATP synthase-which could themselves be new drug targets. J147 has completed the FDA-required toxicology testing in animals, and funds are being sought to initiate phase 1 clinical trials in humans.


Salk just keeps doing great work. And highly interesting that a modified form of humble old curcumin could have such an effect on mitochondria!

Posted by: Mark at January 10th, 2018 3:18 PM

I've heard from several sources that AD is just Type III Diabetes. Interesting stuff.

I was hoping you would post the Salk paper. Agree with the other Mark, Salk is hitting them out of the park.

Still, we have a huge wall we're going to hit very soon and if we can't get these drugs approved and accelerated, I really don't know what will happen. AD has the potential to wipe out all our health care budgets quite soon. We need something in this area badly.

Posted by: Mark Borbely at January 10th, 2018 4:30 PM

It is my understanding that Anavex Pharmaceuticals has a small molecule AD and Parkinson's drug in Phase 2 trials, that has had some success in mice studies. Their trials may be something to watch, the drug amy be something akin to curcumin. Hope they all have good results as nothing has succeeded with AD yet and we have a mountain of people that will need treatment for AD in the future.

Posted by: Biotechy at January 10th, 2018 5:37 PM

I've taken curcumin with black pepper in boiled water every day for around 3 years and drink it beside my tea.

Posted by: Norse at January 11th, 2018 5:39 AM

Examples of Pharma trying to find a profit?

There are several doctors with good clinical results halting and even reversing AD.


What about treating Alzheimer's disease with the spice turmeric? An exciting case series was published in 2012. Three Alzheimer's patients treated with turmeric, and their symptoms declined, along with the burden on their caregivers. Let me show you what these data mean in real lives. Case number one: 83 year old woman, started losing her memory, getting disoriented. Then she started having problems taking care of herself, wandering aimlessly, incontinent. After the turmeric though, her agitation, apathy, anxiety, and irritability were relieved and she had less accidents. Furthermore she began to laugh again, and sing again, and knit again. After taking turmeric for more than a year she came to recognize her family and now lives a peaceful life without a significant behavioral or psychological symptom of dementia.

Case 2 was similar, but with hallucinations and delusions and depression, which appeared relieved by turmeric. She began to recognize her family again and now lives in a peacefully serene manner. And the third case, similar as well, including an improvement in cognition. This is the first demonstration that turmeric may be effective and safe for the treatment of the behavioral and psychological symptom of dementia in Alzheimer's disease patients. They call it a drug, but it's just a spice you can walk into any grocery store and buy for a few bucks. They were giving people like a teaspoon a day, which comes out to be about 15 cents.

Two trials using curcumin supplements rather than turmeric, however, failed to show a benefit. Curcumin is just one of hundreds of phytochemicals found in turmeric. Concentrated into pill form at up to 40 times the dose, no evidence of efficacy was found. Why didn't they get the same dramatic results we saw in the three case reports? Well, those three cases may have total flukes, but on the other hand turmeric, the whole food, is greater than the sum of its parts.

There is a long list of compounds that of been isolated from turmeric, and it's possible that each component in the mixture of curcumin-like compounds plays a distinct role in making it useful against Alzheimer's disease, and hence a mixture of compounds might better represent turmeric in its medicinal value better than curcumin alone. But why concoct some artificial mixture when Mother Nature already did it for us with turmeric? Because you can't patent the spice. And if you can't patent it, how are you going to charge more than 15 cents?

Posted by: bob at January 17th, 2018 8:31 AM

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