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Will we ever cure Alzheimer’s?

NEW YORK TIMES

Few drugs have been approved for treatment of Alzheimer’s disease, and none works very well. It has become one of the most intractable problems in medicine.

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’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.

Desperate for a cure

“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.

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 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.”

Failed trials

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.

Some hope

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 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,” Reiman said.

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.

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.

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