everthing

The battle against Alzheimer’s disease: where are we now?

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“It was the summer of ’86. I was 27 years old,” Tanzi recalls. “I remember thinking that for the first time since Dr. Alois described Alzheimer’s amyloid in 1906, we now have an idea of ​​its origin.”

The discoveries never stopped. Scientists around the world have continued to strip away the genetic underpinnings of this heartbreaking disease that steals the mind and leaves the body empty of its former self.

Many roads lead to Alzheimer’s disease

With so many genes contributing to the development of Alzheimer’s disease and other dementias, scientists are convinced that each person’s journey may be different.

“There’s a saying, if you’ve seen one person with Alzheimer’s disease, you’ve seen one person with Alzheimer’s,” says Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic at the Center for Brain Health at Florida Atlantic University’s Schmidt College. Medicine.

“Alzheimer’s disease is a multifactorial disease, consisting of different pathologies, and each person has their own path. The disease presents differently and progresses differently in different people.”

An important genetic pathway is APOE ε4, a gene variant responsible for encoding proteins that transport cholesterol in the brain. Having one copy of the gene puts people over 65 at risk, while having two copies is considered the strongest risk factor for the future development of Alzheimer’s disease in that age group.

But it is not a given. Some people with APOE ε4 do not develop Alzheimer’s, while others without the gene may develop the hallmark signs of tau tangles and beta-amyloid plaques.

Another pathway to Alzheimer’s is inflammation, “which is common to all chronic diseases,” Farrer said. Several new genes discovered this year appear to play a role in how the body’s immune system clears damaged cells from the brain.

A boost in financing

To support the research, federal funding in the United States for Alzheimer’s research has increased sevenfold to more than $3.4 billion a year since 2011, said Rebecca Edelmayer, senior director of scientific engagement at the Alzheimer’s Association.

One focus of research is finding therapies that target the immune system and inflammation in the brain, Edelmayer said, while other research examines cell metabolism and how cells use energy.

Scientists are also trying to understand more about how brain cells are connected and communicate through synapses, and “we’re even seeing studies looking at the gut and brain connection, which is another interesting approach,” she said.

Researchers are rushing to find breakthroughs pending, aided by additional funding in recent years from the public and private sectors, Edelmayer added. The Chicago-based Alzheimer’s Association alone provides more than $300 million in funding for more than 920 projects in 45 countries.

“We want to focus on strategies that are both culturally appropriate, but also effective and scalable across the globe,” Edelmayer said.

Search for existing medicines

Another focus of the research is examining existing drugs that can prevent Alzheimer’s disease from taking root in the brain.

In his lab, Harvard’s Tanzi uses small organoids composed of human brain cells that can develop the typical amyloid plaques and tau tangles of Alzheimer’s disease in just over a month. Tanzi and Harvard co-creators Doo Yeon Kim and Se Hoon Choi published a groundbreaking article about their discovery in 2014, calling it “Alzheimer’s in a dish.”
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Tanzi and his team spent seven years testing drugs that the U.S. Food and Drug Administration has already approved on the “brain” in the dish. Because the FDA has already verified the safety of those drugs, finding a candidate from that group would accelerate federal approval of the drug for Alzheimer’s disease, allowing patients to be treated more quickly, he said.

Tanzi also tested natural products, such as herbs, spices, vitamins, minerals and antioxidants, for their ability to affect the plaques and tangles in his mini-brain creation.

“We were able to quickly screen every approved drug and more than 1,000 natural products,” Tanzi said. “And now we have more than 150 identified drugs and natural products that can be tested in clinical trials to target plaques, tangles or neuroinflammation.”

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He and his team at the MassGeneral Institute for Neurodegenerative Disease in Boston hope to begin clinical trials soon and work with other scientists to see which of the potential candidates could yield results.

“It’s all about hitting the right person with the right drug at the right time in the course of their illness,” he told CNN.

“A lot of people may not know this, but after 40 years almost all of us start building up the incipient pathology of Alzheimer’s disease, which is amyloid plaque in the brain and the neurofibrillary tangles,” he continued. “It’s part of life, just as most of us start to build up a little bit of plaque in our arteries from cholesterol.”

In fact, Tanzi estimates that some 30 million to 40 million Americans currently have enough amyloid in their brains to benefit from a drug to lower it — if science had the ability to do so safely and affordably.

“I like to say that the amyloid is like the matchstick, and the tangles are like wildfires that spread and spread over decades,” Tanzi said. “And along the way you start big wildfires. That’s neuroinflammation.”

By the time someone shows signs of cognitive decline, he added, “The wildfire of neuroinflammation is flaring up,” and it’s too late to significantly save the brain and improve thinking and memory skills.

“The elephant in the room is that we wait for the brain to deteriorate to the point of dysfunction before treating this disease,” Tanzi said. “That’s like saying wait until you lose half the beta cells in your pancreas before we diagnose diabetes.”

One of the reasons clinical drug trials in past decades failed to control amyloid buildup was because many of the study participants were in more advanced stages of the disease when “too much destruction had been done,” Edelmayer said.

“Removing amyloid at the time wasn’t necessarily helpful,” she said. “It has taken us some time to really understand at what point in the disease process we need to specifically target amyloid with drugs.”

Medicare limits coverage of controversial Alzheimer's drug to that in clinical trials
Example: The controversial amyloid-removing drug aducanumab, which was sold under the brand name Aduhelm, was only tested on people with mild cognitive impairment. The FDA approved the use of aducanumab in 2021, despite all but one members of an independent panel of experts charged with assessing the drug’s effectiveness voting against its approval.
Although aducanumab removed amyloid, the clinical trial showed only a small improvement in cognition in one subset of patients. Some doctors and medical institutions across the country decided not to offer aducanumab to their patients after weighing the drug’s poor performance against its cost and significant side effects.
In April, Medicare announced that it would only cover the cost of the drug of $56,000 per year if the person was enrolled in a study approved by the Centers for Medicare & Medicaid Services. In the same month, Biogen, the company that developed the drug, withdrew the drug’s approval in the European Union. In May, the company announced it would stop supporting the drug.
“I want to make it clear to people that in order to end Alzheimer’s, we need early detection and early intervention, about 10, 20 years before the symptoms show,” Tanzi said. “And what about the 6 million people in this country with this disease right now? For them, we need to put out the fire, stop the neuroinflammation, stop killing neurons.”

Lifestyle interventions

Alzheimer’s screening tools would speed up research and help clinicians find early-stage Alzheimer’s cases. However, most current tests are invasive, such as epidural, or hugely expensive, such as positron emission tomography or PET scans, which insurance companies often refuse to cover.

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“Ultimately, we need screening tools that will be scalable and non-invasive and certainly something that is cost-effective for patients and their families,” Edelmayer said. “A blood test is really the holy grail if we can get there. We’re not there yet, but we’re getting closer. Ask me in another two years.”

Preventive methods are a major focus of much of the current research. Lifestyle changes such as improving exercise, eating a plant-based diet, addressing sleep deprivation, reducing stress, improving social connections and engagement, and some types of cognitive training all show impressive results for early-stage people of the disease process. Controlling cholesterol and blood sugar at a young age is also key to good brain health.
Two recent studies in the US have shown that such lifestyle interventions, along with medications, vitamins and supplements, can prevent decline and also improve memory and thinking ability.

“There were actually cognitive improvements at 18 months in both women and men compared to the control populations,” said Isaacson, who wrote the studies. Even people who carried the Alzheimer’s gene APOE ε4, which increases the risk of dementia later in life, saw benefits in cognition, he said.

More than 25 countries are conducting similar lifestyle interventions in multiple domains as part of the World Wide FINGER network, Edelmayer said. FINGER stands for the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. According to the study, people who participated improved their cognition by 25% in two years.

“I’m very careful about using words like heal,” Isaacson said. “But if we use all these different tools early, during the pre-dementia years, I think prevention is a cure. And hopefully risk reduction can slow the pathology long enough that the person will die of something else before they ever develop.” Dementia.”

All of these research approaches “bring us to the threshold of a transformational new era in Alzheimer’s research,” Edelmayer said. “It’s just time now that we take a stand, especially for those currently living with the disease.”

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