Until now, Alzheimer’s Disease has been thought manageable but not curable.
That may be about to change. Two human clinical trials – one in planning, one under way – are testing two different approaches to ending this plague. Both methods have shown positive initial results, one in mice and the other in a small group of people.
It’s about time. At least 44 million people around the world have the disease. (The greatest concentration is in western Europe, with North America close behind.) It’s estimated that at least one in ten Americans over age 65 have it, with only one in four having been diagnosed.
Caring for Alzheimer’s sufferers now costs about $605 billion annually– more than $259 billion in the US alone, according to Alzheimers.net, a caregivers’ network. By 2050, if current trends continue, the annual global cost of care could top $1 trillion.
But current trends won’t continue if research physicians Dale Bredesen and Michael Fossel are right.
THREE KINDS OF ALZHEIMER’S
Alzheimer’s has eluded a cure, in part, because the illness is so complicated. Fibers of a protein known as tau tangle up inside brain cells, fouling their normal operations. Also, clots of amyloid-beta proteins clog spaces between brain cells, blocking them from sending messages to each other. Because memories are stored as patterns among brain cells, these amyloid globs are thought to be responsible for Alzheimer’s characteristic destruction of memories.
Drugs have slowed and even reduced the build-up of amyloid blocks but have never reversed the attendant memory loss or cognitive decline. That, says neurologist Dale Bredesen, is because researchers may have been asking the wrong question.
“Medicine in the 20th century was about the ‘what’,” Bredesen says. What are the symptoms? What’s the disease? Then physicians would match a drug or procedure to the diagnosis and send the patient off to get well. But, Bredesen adds, “Medicine in the 21st century is about the ‘why’.”
Specifically, Bredesen and other researchers began to ask why the brain develops these globs and tangles that define Alzheimer’s – and they’ve learned that the protein clumps are, in effect, normal responses to various assaults on the brain.
When the brain suffers insults, such as inflammation or an invading toxin, the immune system throws up amyloids as part of its defense and tau tangles are a consequence of amyloid build-up. In younger brains, these amyloid blobs are easily cleared away.
But, as we age, those mechanisms don’t work as quickly or thoroughly as they did when we were younger. If the insults persist, the proteins agglomerate faster than our biochemical housekeepers can sweep them away. They build up and the result is often what we know as Alzheimer’s Disease – but not always; some people’s brains are rife with tau tangles and amyloid plaques but they never show any symptoms of Alzheimer’s, making understanding the illness even more complicated.
Bredesen, a professor at UCLA’s School of Medicine, delved deeper. He examined the blood, urine, and brain images of Alzheimer’s patients and discovered 150 separate factors that can contribute to the disease. In the course of that work, he explained why Alzheimer’s drugs that have been tried can’t reverse the illness: no one drug can address dozens, if not all 150, factors that might underlie the ailment.
Bredesen then analyzed the 150 factors and found that he could trace virtually any case of Alzheimer’s to one of three causes. He calls them Type 1, Type 2, and Type 3 Alzheimer’s.
Type 1 is caused by inflammation, the culprit in a panoply of today’s chronic conditions from diabetes to Parkinson’s Disease. When the body detects an alien or unfriendly substance entering it, inflammation is part of our way of defending against the invader. If the invasion is unrelenting, so is the inflammation.
Over time, that can damage many of the body’s organs and systems – leading to, among other things, the disturbed proteins that mark Alzheimer’s. This chronic, systemic inflammation can be caused by anything from an attack of microbes or a leaky gut to a lack of exercise to eating the so-called “standard American diet” of white flour, white sugar, poor quality fats, and processed foods.
Type 2, or “atrophic Alzheimer’s,” is sparked by deprivation, in which the brain can’t get enough nutrients, hormones, and other necessary biochemicals to maintain peak performance. These deficits can arise from disease, deteriorations due to age, or a poor diet, among many other causes.
(Bredesen also defines a “glycotoxic” version of the disease, which he’s dubbed Alzheimer’s 1.5 because it has roots in both Type 1 and 2.)
At the root of Type 3 are chemicals, mold, and other toxins that enter the bloodstream and pass through the brain’s defenses. Bredesen has found that Type 3 is not only much rarer than the other two, but that the symptoms can show up earlier – even in people in their 20s and 30s.
The good news: knowing the causes and contributing factors, Bredesen then could prescribe ways to remove them – and it worked. In an October 2018 paper in the Journal of Alzheimer’s Disease and Parkinsonism, he and more than 20 colleagues from an international group of hospitals, universities, and research centers detailed tests with 100 patients with Alzheimer’s or pre-Alzheimer’s conditions, all of whom showed significant cognitive improvement using Bredesen’s protocol.
Most importantly, these improvements didn’t fade over time.
First, Bredesen tests a patient to gauge levels of the Alzheimer’s factors he’s identified. Then, based on seeing which factors are abnormal, he can customize a treatment to bring them back into balance: perhaps adjusting diet, recommending exercise, adding drugs or nutritional supplements, or quitting your job in the chemical factory or removing mold from inside the walls of your 1800s farmhouse.
In the recent group of 100 that tried the protocol, Alzheimer’s symptoms improved and, in some cases, disappeared. When patients drifted from the protocol, their symptoms returned. Also, Bredesen has found that the earlier the treatment is started, the stronger and more complete the effect.
Bredesen has trained over 1,500 physicians from 10 different countries in the use of his methods. Bredesen is now collaborating with three colleagues in a clinical trial.
THE SILENCED GENE
Dr. Michael Fossel, formerly a neurologist at Michigan State University and past executive director of the American Aging Association, isn’t focused on dozens of Alzheimer’s factors. Instead, he’s looking at only one – a silenced gene that, if allowed to express itself, could possibly reverse Alzheimer’s with a simple injection.
The amyloid build-up and tau tangles that characterize the disease draw attention to the neurons. But the neurons are tended and maintained by glial cells, which envelop the neurons and insulate them from each other so electrochemical signals don’t go astray. Glial cells also bring nutrition and oxygen to neurons and remove dead brain cells so the carcasses don’t cause clutter.
Fossel’s injection ultimately targets the glial cells’ telomeres.
Telomeres, little clusters of DNA, are the “end caps” of the chromosomes inside your cells. Their job is to protect the integrity of your genetic information so that every time a cell divides, the new one is a faithful copy of the old. But each time a cell divides, a bit of each telomere is lost; as we age and cells multiply over time, each new one has less telomere than its ancestors. More importantly, this gradual but relentless loss of telomere impedes genes’ ability to make proteins and other essential ingredients, leaving cells unable to deliver the peak pe
rformance they did when we were young.
Specifically, that means that shrinking telomeres in our glial cells leave them progressively less able to clear the damaged proteins, as well as deal with other changes, in and around neurons that characterize Alzheimer’s Disease.
First, the good news: an enzyme called telomerase keeps telomeres long. The bad news: the gene in glial cells that makes telomerase, like the same gene in most cells in our bodies, isn’t expressed. It’s there but it’s in lockdown, not being allowed to make the telomerase that cells need to them keep eternally youthful.
Fossel’s injection reactivates telomerase. It sends glial cells a gene that can be expressed inside glial cells, so they start making telomerase that then re-lengthens telomeres. This new lease on life enables glial cells to act young and vigorous again, briskly dispatching tau tangles and amyloid clots as they did in decades past.
Tested in mice, the injections that Fossel has developed reversed Alzheimer’s symptoms. Fossel is planning a human clinical trial to begin next year.
The implications reach far beyond Alzheimer’s disease. With few exceptions – heart, sperm and egg, a few others – none of the body’s cells express the gene that makes telomerase. If Fossel’s technique proves effective, it could be adapted to reverse the impacts of aging on skin and other organs throughout the body. TJ
Alzheimer’s has become one of the most intensively researched human diseases. Focusing a combination of gene therapy, lifestyle changes, drugs, and continued research into its causes will begin to bring Alzheimer’s under control by 2030.