March 20 2020
Posted December 13, 2018
To mark the 40th anniversary of the Science section of The New York Times, the editors made a list of their 11 most pressing science questions they would like answered in the coming years. Given the scale of Alzheimer’s diagnosis in the United States, it is no surprise that the question, “Will we ever cure Alzheimer’s?” featured prominently on their list of most pressing questions. The article featured the perspectives of researchers who have received grants from Cure Alzheimer’s Fund including Dr. John Morris the Chair of the Cure Alzheimer’s Fund Research Strategy Council and the director of the Knight Alzheimer’s Disease Research Center at the Washington University School of Medicine, Dr. Sam Gandy, a member of the Cure Alzheimer’s Fund Research Leadership Group and the Associate Director of the Mount Sinai Alzheimer’s Disease Research Center, and Dr. Rudy Tanzi, Chair of the Cure Alzheimer’s Fund Research Leadership Group.
Within the article, Dr. Morris discusses the complexities of targeting amyloid in clinical trials. Dr. Sam Gandy commented for the article that Alzheimer’s drugs need to improve patients’ daily living. The article highlights research supported by Cure Alzheimer’s Fund, and tells the story of two teams of researchers working independently to uncover a role for viruses, especially two herpes viruses, in driving the accumulation of amyloid in the brain through immune activation. The two teams included Dr. Sam Gandy’s lab as well as Dr. Rudy Tanzi and Dr. Rob Moir. Dr. Tanzi commented for the article using an analogy that amyloid serves as a match with tangles acting as a brush fire that spreads as neurons are killed. The virus in the scenario is the instigator that lights the match. The article makes the case for designing a cocktail of drugs to target different stages of the disease. To read more about what several scientists funded by Cure Alzheimer’s Fund think about the likelihood that a cure will be developed, read the full story here:
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.
By Pam Belluck November 19, 2018
It’s a rare person in America who doesn’t know of someone with Alzheimer’s 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: “It’s 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 doesn’t explain everything about Alzheimer’s — not everyone with amyloid plaques has the disease.
“It’s not that amyloid is not an important factor,” said Dr. John Morris, director of the Knight Alzheimer’s Disease Research Center at the Washington University School of Medicine in St. Louis. “On the other hand, we’ve had some 200-plus trials since 2001 that have been negative.”
Not all trials have targeted amyloid. Some have focused on tau, a protein that, in Alzheimer’s, forms threads that stick together in tangles inside neurons, sandbagging their communications with one another.
Tau tangles seem to spread after amyloid accumulates into plaques between neurons. But so far, anti-tau drugs haven’t successfully attacked Alzheimer’ “The field is desperate, and we all want something to work,” said Dr. Reisa Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston.
There was a glimpse of promise this summer, when researchers reported the results of the first large clinical trial of a drug that, in the highest of five doses tested, not only slashed amyloid levels but also seemed to slow the progression of memory and thinking problems in people in the early phases of cognitive decline.
But while several experts said they were cautiously optimistic, much more testing of the drug, known as BAN2401, is needed. These results came from a Phase 2 trial, which is considered an intermediate step to the larger and more extensive Phase 3 trials usually required for Food and Drug Administration approval.
Tau tangles seem to spread after amyloid accumulates into plaques between neurons. But so far, anti-tau drugs haven’t successfully attacked Alzheimer’s itself.
Only five drugs have been approved to treat this dementia, but they address early symptoms and none have been shown to work very well for very long. It’s been 15 years since the last one was approved.
Some issues with the study will need to be rectified in subsequent trials, including that people with a gene known to increase Alzheimer’s risk were, at the insistence of European regulators, taken out of the group that received the highest dose.
Dr. Samuel Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York, noted that so far no drugs have managed even to modestly improve Alzheimer’s patients’ ability to function, which would allow them to remain independent longer.
“We need something to affect activities of daily living, like whether they need fewer caregiving hours and that sort of thing,” he said. “Nothing has been so dramatic.”
The reason Alzheimer’s research is littered with failed clinical trials lies beyond questions of amyloid and tau. For one thing, researchers have found it difficult to engineer animals with symptoms mimicking human dementia so they can effectively try drugs on them before testing on people.
Another issue: increasingly sophisticated scanning technology has revealed that damage to the brain in people with Alzheimer’s can begin decades before dementia symptoms appear. It’s possible that trials testing drugs on people with full-fledged dementia have failed because it’s too late, not necessarily because the theory is flawed.
Because of this, in recent years many researchers began testing anti-amyloid drugs on people with very early dementia, or those who don’t have dementia or other symptoms but — because of genetic risk or amyloid levels in their spinal fluid — are at high risk of developing Alzheimer’s.
Such prevention trials will report results in the coming years, and some may provide the clearest answers yet about amyloid’s role.
At the same time, the scientific establishment has become increasingly open to new theories about the underpinnings of Alzheimer’s. Some researchers are trying to restore lost synapses; others are focusing on microglia, scavenger cells involved in the brain’s immune system.
Two teams of researchers, working separately, recently published studies suggesting that viruses, particularly two common types of herpes, could kick-start an immune response that might drive the accumulation of amyloid in the brain. Co-authors of one of the studies included longtime skeptics of a viral role in Alzheimer’s, such as Dr. Gandy and Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix.
“Whether or not the amyloid hypothesis is correct, we need to better understand Alzheimer’s disease mechanisms and risk factors and use this information to find the most effective ways to treat and prevent this disease,” Dr. Reiman said.
Two authors of the second virus study — Rudolph Tanzi, a neuroscientist at Massachusetts General Hospital and Harvard, and a colleague, Robert Moir — have pursued this line of research for years.
“We spent too long thinking about amyloid as plumbing — how much do you produce, how much do you clear,” Dr. Tanzi said. “Then we came along and were saying infection is actually driving the amyloid hypothesis. Amyloid’s a match, the tangles are a brush fire being spread as they kill neurons, and the virus is lighting the match.”
Research on caregiving has found that helping stimulate positive emotions with activities, music, comfort food, and exercise can make patients feel better and experience less anxiety and frustration.
But, of course, that is not the same as turning back the tide of the disease.
He and others suggest that the therapeutic answer might ultimately be a cocktail of medications. “Drugs to hit amyloid early on, drugs to hit tangles early on, drugs to hit inflammation,” Dr. Tanzi said. “And you might want to add antivirals.”
A Texas businessman with a family history of dementia recently announced he would award $4 million in prize money to researchers who search through published scientific studies and knit the findings together into a unified explanation of how Alzheimer’s works.
An effective Alzheimer’s therapy can’t come soon enough. Now, with no drugs for advanced Alzheimer’s and clinical trials mostly focusing on earlier stages, the troops on the front line of treatment are caregivers.
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