Advancements In Amyloid And Tau
All thats not to say the treatment theories that held so much promise in the 90s and early 2000s have been totally abandoned, despite decades of failed clinical trials. Much of the research in the field continues to focus on amyloid, as well as tau another hallmark protein of Alzheimers disease that forms tangles inside the neurons.
This year, all eyes are on aducanumab, an anti-amyloid drug that is headed to the Food and Drug Administration for review. It was shown in clinical trials to reduce the amount of amyloid in the brains of people with early Alzheimers disease. U.S. drugmaker Biogen reports that participants who received high doses of the antibody saw improvements in memory and thinking skills, and were better able to perform activities of daily living, such as laundry and personal finances. If approved, aducanumab will be the first drug available to treat people with Alzheimers disease. Currently, the handful of dementia drugs available help only to alleviate symptoms.
Christopher H. van Dyck, M.D., professor of psychiatry, neurology and neuroscience and director of the Alzheimers Disease Research Unit at the Yale School of Medicine, points to two other amyloid-clearing therapies that are far along in the clinical trial process BAN2401 and gantenerumab . If aducanumab doesnt clear FDA review, youd bet on one of these becoming the first available treatment for Alzheimers disease, he says.
Q: If Drugs Against Amyloid Arent The Answer What Is
Back in the 80s and 90s, genetic tools weren’t quite developed enough to address the real question we had: What genes are involved in most cases of Alzheimers disease?
Techniques have advanced and we can now answer this question. New studiesmany led by Richard Mayeux, MD have been pointing to other processes in the brain. We also have better biological tools that can reveal the basic problem inside neurons.
Based on this research, the new consensus in the field is that there are two other pathways that cause the disease.
One involves protein trafficking, which is how proteins are shipped to different sites within a single cell. The health of neurons, more so than other cells, depends on protein trafficking in and out of one particular site: the endosome.
In Alzheimers, the flow of proteins out of the endosome is blocked, and we think that causes the other problems we see in the disease: the amyloid, the tau tangles also common in the Alzheimers brain, and the neurodegeneration. Essentially it’s a plumbing problem.
Our research here at Columbia provided some early evidence for an endosomal trafficking problem in Alzheimers. And genetic studiesincluding those led by Dr. Mayeuxhave now found that some endosomal genes are linked to Alzheimers, which provides more support.
What’s The Bottom Line On Alzheimer’s Prevention
Alzheimer’s disease is complex, and the best strategy to prevent or delay it may turn out to be a combination of measures. In the meantime, you can do many things that may keep your brain healthy and your body fit.
You also can help scientists learn more by volunteering to participate in research. Clinical trials and studies are looking for all kinds of peoplehealthy volunteers, cognitively normal participants with a family history of Alzheimer’s, people with MCI, and people diagnosed with Alzheimer’s disease or a related dementia.
To find study sites near you, contact NIA’s Alzheimer’s and related Dementias Education and Referral Center at 1-800-438-4380 or . Or, visit the Alzheimers.gov Clinical Trials Finder to search for trials and studies.
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Could Drugs Prevent Alzheimers These Trials Aim To Find Out
Trial coordinator Eric McDade assesses participant Marty Reiswig for cognitive ability.Credit: Matt Miller/Washington University School of Medicine
Every two weeks, a nurse visits 43-year-old Marty Reiswig in Denver, Colorado, and injects him with an experimental drug called gantenerumab. Every month, Reiswig drives into town for a brain scan to make sure the drug has not caused any bleeds. And every year he flies to St Louis, Missouri, for four days of brain scans, spinal taps, blood analyses and exhaustive tests of his memory and reasoning capacity.
Reiswig is fit and healthy and runs two local businesses. He goes through all of this because he has a rare genetic mutation that almost guarantees he will develop early-onset Alzheimers disease. He hopes that the international clinical trial he has been part of for nine years might prevent, or at least delay, the onset of symptoms that will otherwise arise in just a few years time.
I always do my best to give the researchers as much as I can even if it turns out not to help me, it might help my children, he says.
But Aisen foresees a future maybe just a decade or so down the line in which much of the burden of Alzheimers disease might actually be prevented. Were heading towards screening people from middle age on with blood tests, and treating those who show amyloid abnormalities with drugs that reduce the generation of amyloid plaques, he says. I am optimistic.
A Case Study By Dr Mary Newport
Dr. Mary Newport
Image courtesy of Dr. Mary Newport
Steve and Mary Newport
There is a growing epidemic of obesity, type II diabetes, cardiovascular disease, and predictions that 15,000,000 people in the United States alone will have Alzheimer’s Disease by the year 2050.
In 2001, Dr. Richard L. Veech of the NIH, and others, published an article entitled, “Ketone bodies, potential therapeutic uses.”1 In 2003, George F. Cahill, Jr. and Richard Veech authored, “Ketoacids? Good Medicine?”2 and in 2004, Richard Veech published a review of the therapeutic implications of ketone bodies.3 These articles are not found in journals that the average physician would read, much less the lay public. Unless you are researching the topic, it is unlikely that you would ever randomly come across this information.
My husband Steve, age 58, has had progressive dementia for at least five years. He had an MRI in May 2008 showing a diffuse involutional change of the frontal and parietal lobes and moderate left-sided and severe right-sided amygdala and hippocampal atrophy with no ischemic change, which would support a clinical diagnosis of Alzheimer’s Disease.
Image courtesy of Dr. Mary Newport
Clocks drawn by Steve Newport showing improvement after starting coconut oil.
Until Dr. Veech’s beta-hydroxybutyrate is tested and available for use, a simple dietary change to coconut oil could make a difference for people who believe they are at risk and for those who already have one of these diseases.
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Large And Longer Trials
These findings allowed Biogen to conduct larger clinical trials of Aducanumab. Two trials, called ENGAGE and EMERGE, collectively enrolled over 2,500 people with MCI or early-stage dementia caused by Alzheimers disease.
The changes in the brain caused by Alzheimers disease tend to start many years before symptoms show. This means that earlier treatment is likely to have a better chance of being effective. The main aim of the ENGAGE and EMERGE trials was to see if Aducanumab could reduce signs of cognitive decline in the people with MCI and mild dementia. Participants received different doses of the drug and were compared to people receiving a placebo treatment. The placebo contained no active ingredient.
The two large Aducanumab trials began in 2015 but were cut short in March 2019. Although the EMERGE trial was said to be trending positive in terms of potential outcomes, early results indicated the ENGAGE study was not going to be successful. In order to progress, Biogen had specified that both trials needed to be heading in the right direction. The results meant that both trials were terminated.
How Do You Take The Drug And Is It Safe
To take the drug, you need an intravenous infusion every four weeks forever. Thirty percent of those who took the drug had a reversible swelling of the brain, and more than 10% had tiny brain bleeds. These side effects need to be watched closely by an expert neurology/radiology team who understand how to monitor for these events and know when to pause or stop the drug.
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We Cant Even Accurately Diagnose This Disease
Public Domain on Wikimedia Commons
While it is widely known that it is not possible to diagnose Alzheimers accurately during life, a dirty little secret of Alzheimers research is that a significant fraction of patients cannot be categorized
repair mechanisms. So when we talk about Alzheimers treatments, we mean prevention not reversal.
The natural history of Alzheimers is such that preventive therapy will need to be started early in the course of the disease. This will add years to the drug development cycle. A decade from discovery to bedside would be good news for an Alzheimers drug.
But history teaches us that the delays could be even worse. Shortly after the discovery of genetic engineering in the early 1980s, it was common to tell patients with diseases like sickle cell that a genetic cure was just a some time. The organ system involved is easy to access. Thirty years later we have still not successfully cured diseases like sickle cell, and the hubris of those early predictions are painful memories for older physicians like myself.
The situation with Alzheimers looks much worse than sickle cell disease looked back in the 1980s. We dont know the cause which is likely multifactorial – and its in a hard to get at organ. And neurological diseases are a particular challenge because the brain is protected behind something called the blood-brain barrier. Even if you have a potentially effective drug, it may not reach its target.
Reminiscence And Life Story Work
Reminiscence work involves talking about things and events from your past. It usually involves using props such as photos, favourite possessions or music.
Life story work involves a compilation of photos, notes and keepsakes from your childhood to the present day. It can be either a physical book or a digital version.
These approaches are sometimes combined. Evidence shows they can improve mood and wellbeing.
Page last reviewed: 05 July 2021 Next review due: 05 July 2024
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Early Stage Smaller Trials
After initial trials showed that Aducanumab was safe to use in humans, a further trial called PRIME assessed if the drug could slow the progression of Alzheimers disease in people who were in the early stages of the disease. This included people who had mild cognitive impairment or early-stage dementia.
The PRIME trial started in 2012. Biogen, the pharmaceutical company who developed the drug, reported that treatment led to a reduction in amyloid levels in the brain. The company said the drug appeared to slow the rate of cognitive decline for people with mild Alzheimers disease receiving the drug.
Seeking The Diseases Source
To figure out how to treat and prevent Alzheimers disease, scientists first have to learn what causes the condition.
Although theres a growing wealth of data on the topic, it hasnt been enough to present a single, cohesive picture.
I think cloudy and piecemeal actually is a fairly good description of where the fields understanding of Alzheimers disease , said Dr. Keith Fargo, director of scientific programs and outreach at the Alzheimers Association, in an interview with Healthline.
You look at HIV, and thats something where its a virus, and we know the virus that causes AIDS, explained Fargo. And so thats something very simple to link onto and research. With Alzheimers disease, thats not the case. Its probably going to be very multi-factorial.
Much of the research is currently focusing on amyloid and tau proteins, whose malformation are classic characteristics of Alzheimers disease. But Fargo says other factors likely also play a role, including vascular health, inflammation, lifestyle, and possibly even viral causes.
Age, Fargo says, is the number-one culprit.
And even the two starring proteins, amyloid and tau, are laden with mystery.
They are more likely to malfunction with increasing age, and certain genetic mutations have been linked to their deformation in a percentage of patients. But the root cause of what prompts them to begin malfunctioning in the first place remains unknown.
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Fdas Accelerated Approval Program
Aducanumab was approved through the FDAs Accelerated Approval Program, which provides a path for earlier approval of drugs that treat certain serious conditions. This helps people living with the disease gain earlier access to the treatment. The approval of aducanumab was based on the ability of the drug to reduce amyloid in the brain. When using the accelerated approval pathway, drug companies are required to conduct additional studies to determine whether there is in fact clinical benefit after the drug is approved. If the follow-up trial fails to verify clinical benefit, the FDA may withdraw approval of the drug. Results of the phase 4 clinical trial for aducanumab are expected to be available by early 2030.
Main Goals Of Treatment
The main goals of Alzheimers disease treatments are: to preserve independent functioning and maximize functioning maintain quality of life help cognition, mood, and behavior provide a safe environment and when possible, encourage social engagement.2 This requires regular evaluation of functioning and evaluation to see if treatments are working as the disease progresses. If a treatment is not as effective as it once was, the treatment needs to change.
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Will We Ever Cure Alzheimers
Few drugs have been approved for treatment of this dementia, and none works very well. It has become one of the most intractable problems in medicine.
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By Pam Belluck
Its a rare person in America who doesnt know of someone with Alzheimers disease. The most common type of dementia, it afflicts about 44 million people worldwide, including 5.5 million in the United States.
Experts predict those numbers could triple by 2050 as the older population increases. So why is there still no effective treatment for it, and no proven way to prevent or delay its effects?
Why is there still no comprehensive understanding of what causes the disease or who is destined to develop it?
The answer, you could say, is: Its complicated. And that is certainly part of it.
For nearly two decades, researchers, funding agencies and clinical trials have largely focused on one strategy: trying to clear the brain of the clumps of beta amyloid protein that form the plaques integrally linked to the disease.
But while some drugs have reduced the accumulation of amyloid, none have yet succeeded in stopping or reversing dementia. And amyloid doesnt explain everything about Alzheimers not everyone with amyloid plaques has the disease.
But, of course, that is not the same as turning back the tide of the disease.
A Cure For Alzheimers Is Taking Longer Than Expected Heres Why
Anne Robinson, Head of Carnegie Mellons Chemical Engineering Department, conducts research in her lab
ChemE Department Head Anne Robinson and Postdoctoral Scholar Liqing Song review data in a lab at CMU’s Doherty Hall
In all neurodegenerative diseases, degeneration begins in one part of the brain and is transmitted to other areas, causing widespread damage and loss of brain tissue. In Alzheimers, several things, such as the presence of A-beta peptide or an injury, can cause taua protein in neurons responsible for stabilizing those neuronsto begin shaping itself in dysfunctional ways the first in a cascade of events. Scientists, however, are still unsure how this pathogenic tau is transferred from cell to cell, thus spreading across the brain and wreaking havoc. Understanding how to contain the disease to a small area of the brain could help slow its progression and halt the cognitive degeneration associated with Alzheimers.
Schematic illustration of the intracellular responses affected by monomeric tau endocytosis. Monomeric tau is rapidly internalized by both neuronal and glial cells, mediated by the actin-dependent macropinocytosis pathway.
Journal of Molecular NeuroscienceFor media inquiries, please contact Ryan Noone at
Department of Chemical Engineering
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How Much Does It Cost And How Soon Can I Get It
Biogen, the company that makes aducanumab, estimates its cost at $56,000 per year. It is not yet clear whether Medicare, Medicaid, or private insurance companies will pay for this medication. In its press release, Biogen noted that they are working on an agreement with the Veterans Health Administration to cover this medication for veterans enrolled in VA healthcare. Aducanumab is not currently available, but the company is working to make the drug available quickly, perhaps in a few months.
Will A Treatment For Alzheimers Ever Be Found
In the 90s, Alzheimers researchers were full of optimism. New genetic studies all pointed to one culprithard clumps of protein, called amyloid, that litter the brains of people with the disease.
With the emergence of the first tangible target, pharmaceutical companies jumped in to develop drugs to clear amyloid from the brain. In animals, the drugs appeared to improve memory. But the results of human clinical trials that followed were disheartening: One after one, these drugsall designed to target amyloidhave failed to slow the disease.
The onslaught of news about these failures has left the public wondering whether amyloid has anything to do with Alzheimersand whether a new approach is needed.
The field has already begun to redirect its focus, says Scott Small, MD, director of Columbias Alzheimers Disease Research Center and the Boris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons.
Theres now reason to be cautiously optimismistic, he says, because we have uncovered new pathways that lead to the disease, and we know that they truly make a difference.
The CUIMC Newsroom spoke with Small about the current state of research into Alzheimers treatments and prevention.
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