For people with Down syndrome, a longer life, but under a cloud

But Gaffney, who has Down syndrome, loses her bravado when she talks about a looming threat to everything she has achieved, a threat to her very life: Up to 90 percent of people with the genetic condition develop Alzheimer’s disease, usually in their early 50s but sometimes in their 40s. Gaffney is 43.

“Those of us with an extra 21st chromosome have a black cloud hanging over us,” Gaffney said. “My fear is stepping up to the microphone, and forgetting why I am there, or what I should say. What if I forget how to swim? Or find my way to the pool?”

Yet, to Gaffney’s dismay, people with Down syndrome, which causes intellectual and physical disabilities, are almost never included in clinical trials for drugs to treat or prevent Alzheimer’s, a situation advocates, patients and scientists decry and are trying to change.

But with Alzheimer’s, a progressive, terminal disease that has a history of confounding scientists and families, nothing is ever straightforward, even for the group hit hardest by the disease.

In a twist few would have predicted, the plight of people with Down syndrome was illuminated as part of a furious battle over a controversial Alzheimer’s drug called Aduhelm, approved by the Food and Drug Administration last year, that might not even work and can cause significant safety problems.

The fight has gone far beyond one drug and has sparked heated debate about the roles of the FDA and Medicare in assessing medications, particularly when the agencies come to differing conclusions. The controversy also has raised questions about how to accommodate patients who might benefit from therapies but are often excluded or underrepresented in critical trials.

In January, Medicare officials took an unusual step involving an approved drug. They announced plans to sharply restrict coverage of the $28,200-a-year therapy to a small number of people who enroll in rigorous clinical trials. People with Down syndrome and other neurological conditions would not be eligible for the trials, an exclusion that drew hundreds of outraged comments from advocates who called the move discriminatory.

“We don’t want people with intellectual disabilities to be kicked out of consideration for clinical trials,” said William Mobley, a neurologist at the University of California at San Diego.

But last week, Medicare, while affirming its overall plan to limit coverage to people in clinical trials, dropped its proposed exclusion for people with Down syndrome. “There may be subpopulations that are important to study such as individuals with Down syndrome,” Medicare said.

The Down Syndrome Coalition, made up of major advocacy organizations, welcomed the decision to remove the exclusion. Still, some advocates said it remains far from assured that drug companies, as the major sponsors of Alzheimer’s trials, will enroll people with the genetic condition.

The irony of life

People with Down syndrome used to die too young to develop Alzheimer’s. In the 1980s, their life expectancy was 30. Today, it is twice that, reflecting improved medical care for congenital heart problems and other conditions. But in a gut-wrenching irony, longer lives mean aging parents are watching middle-aged children descend into dementia.

Anna Hutchinson, 76, said her son Michael, 57, began showing signs of confusion and forgetfulness a year ago. “He would forget to eat lunch, and that boy loves to eat,” Hutchinson said. Her sweet-natured son has gotten increasingly agitated.

Hutchinson, who lives in St. Louis with Michael, plans to take care of him as long as she can. “He’s my child,” she said. “It’s just me and him. He ain’t going anywhere. He couldn’t survive anywhere anyhow.”

In some cases, an older parent is caring for a child with Down syndrome and a spouse, both of whom have Alzheimer’s.

In other cases, parents who have spent their lives fighting to give their children opportunities face an agonizing question: Will their middle-aged child with Down syndrome develop dementia and need specialized care just as the parents are entering their 70s or 80s?

When Jeff and Taffy Nothnagle’s son was born in 1974, their doctor said he would “sit in a corner and suck his thumb” and die by his late 20s. The physician urged the couple to put Jay in an institution and tell friends he had died, recalled Jeff, who is 80.

Instead, the Nothnagles, who live in Cohasset, Mass., encouraged Jay’s natural optimism and athletic prowess. Jay managed the football and hockey teams in high school and won gold medals in Special Olympics. When he got his driver’s license at 22, he said he had a message for his parents’ old doctor: “Handicapped my ass!”

Today, Jay lives with a roommate and works at Stop & Shop, his longtime employer. But as he approaches 50, his parents worry his life could unravel.

“Every year on his birthday you start thinking, ‘This is the best he is going to be,’” said Taffy, who is 78. “I look for any little slip. I watch him sign his name and if he lifts his pen differently I think, ‘Oh, it’s Alzheimer’s disease.’”

Friends who have lost middle-aged children to Alzheimer’s are urging the Nothnagles to move Jay into a group home or other setting that could provide more help if he needs it. Jay is opposed, and his parents don’t want to curb his hard-earned independence.

Still, “the handwriting is on the wall,” said his mother. “This is probably already happening in his brain. Ultimately, he is probably going to get Alzheimer’s. When is this going to start and how will it affect him?”

‘A Catch-22’

Last year, the FDA made history, approving the first drug touted as a way to slow the cognitive decline caused by Alzheimer’s, not just treat symptoms.

The agency based the clearance on the drug’s impressive ability to clear plaques of amyloid beta, a sticky protein that is a hallmark of Alzheimer’s, from the brain. The agency, which used its accelerated approval process, said the lowering of amyloid was “reasonably likely” to slow deterioration.

But there is scant direct evidence Aduhelm, a monoclonal antibody designed for early-stage patients, offers any clinical benefit. Trials conducted by the its manufacturer, biotech giant Biogen, yielded confusing and highly disputed results, and it will be another four years before required confirmatory data is available.

The FDA approval of Aduhelm ignited a raging debate, with many doctors saying they would not prescribe the drug and several insurers declining to pay for it. They said previous amyloid drugs have not been helpful. But FDA officials argued that initial data from similar therapies still being tested suggest the drugs can slow cognitive decline if they remove large amounts of amyloid and are given earlier in the disease.

When Medicare, casting a skeptical eye on Aduhelm, said in January it would cover the drug and similar medications only for participants in clinical trials, a decision it affirmed last week, it was praised by those who decried the FDA approval. But it was criticized by others who said Medicare was cutting off access to a potentially helpful therapy and imperiling similar drugs in development.

The Down syndrome community organized a letter campaign to eliminate the exclusion of people with the genetic condition in clinical trials, saying trials were the only practical way for beneficiaries to get the drug. But within families, there is widespread disagreement about the value of Aduhelm itself.

The Nothnagles said they would not consider the medicine for their son because of potential side effects. Margot Rhondeau, senior director for health and wellness at the advocacy group National Down Syndrome Society, whose 4-year-old daughter has Down syndrome, argued that doctors, patients and families “should be allowed to make the choice on whether to use the drug.”

Alzheimer’s experts worry that the drug, which can cause bleeding and swelling in the brain, could put people with Down syndrome at especially high risk. Those patients have unusually large amounts of amyloid beta in their brains, and targeting it could result in microhemorrhages, they fear.

Aduhelm “should not be used in clinical practice” until doctors know more, said Michael Rafii, medical director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California. People with Down syndrome were not included in the Biogen trials.

For James Hendrix, the situation is maddening. Doctors need data on how Aduhelm affects people with Down syndrome, but there is no data because people with the condition are excluded from trials, said Hendrix, chief scientific officer of LuMind IDSC Foundation, a nonprofit that promotes research involving Down syndrome.

“It’s a Catch-22,” he said.

Hendrix and other advocates had hoped Biogen would conduct a small safety trial for people with Down syndrome after winning FDA approval for Aduhelm. But the poor sales of the badly received drug and the negative Medicare decision created tumult at the company, making it unclear whether such a study will ever occur.

Still, he said the Medicare elimination of the exclusion of people with Down syndrome in clinical trials will be helpful in talking about studies with potential sponsors of drug trials.

Samantha Budd Haeberlein, head of neurodegeneration development at Biogen, said in an interview that the company believes “we should conduct a study” in the Down syndrome population “to define the safety and efficacy in that population,” and had planned to do so. Speaking before the final Medicare ruling, she said the tentative decision had pulled the company’s attention “into other directions.”

A swift descent

When parents, scientists and advocates discuss the importance of enrolling people with Down syndrome in Alzheimer’s trials, they often argue it is in the interest of society, saying it would help everyone.

“People with Down syndrome are the canaries in the coal mine,” Jeff Nothnagle said. “They are going to have Alzheimer’s before anybody else, and they are going to respond” to treatments “before anybody else.”

Researchers have focused for years on a basic question: Is the Alzheimer’s disease that is linked to Down syndrome the same as the late-onset version in the general population or something different?

The roots of the ailments are different. People with Down syndrome have a third 21st chromosome, which is linked to the production of amyloid beta. The extra chromosome produces an extra dose of amyloid that forms plaques visible on brain scans by the time people with Down syndrome are in their late 30s or early 40s. Tangles of tau, another protein implicated in Alzheimer’s, also develop.

Those genetic roots make Alzheimer’s in people with Down syndrome similar to a rare form of the disease, called familial Alzheimer’s, which is caused by inherited mutations. For the broader population, the picture is more complex. “There are a lot of risk factors at play, some genetic, some not,” said Beau Ances, a professor of neurology at Washington University in St. Louis.

Ances’s laboratory, and several others across the country, are tracking biological changes in the brain, blood and cerebrospinal fluid of adults with Down syndrome to identify biomarkers that herald the onset of Alzheimer’s disease. The efforts are part of a National Institutes of Health initiative to examine medical issues affecting people with the genetic condition.

Many of the changes in biomarkers occur at an earlier age but are similar to changes seen in adults in the broader population who develop Alzheimer’s later in life. This suggests a greater understanding of the illness in people with Down syndrome might contribute to better treatments for anyone needing them, scientists say.

About 6 million people in the United States have Alzheimer’s, a number projected to double by 2040. Age is the biggest risk: 11 percent of people 65 and older have the disease, with most at least 75. The average age of diagnosis is 80, with patients often living several more years.

Of the 210,000 people with Down syndrome, about a third have Alzheimer’s, or are at high risk because of their age, with the average age of diagnosis about 54. The illness worsens relatively quickly, with individuals dying within four years. Alzheimer’s is the No. 1 killer of people with Down syndrome.

Sonja Rasmussen, a pediatrician and medical geneticist at the University of Florida, said the improving life expectancy for people with Down syndrome will stall unless the grip of Alzheimer’s is loosened.

The disease tore at the heart of her family. For years, her brother, Mark, who had Down syndrome, lived on his own. He cheered the Minnesota Vikings, read Hardy Boys books and worked at McDonald’s. But in his 50s, Mark became increasingly confused. One day, he showed up for work at 4 a.m. When Rasmussen visited Mark, he thought she was their niece. “Dana, what are you doing here?” he asked.

Diagnosed with Alzheimer’s at 56, Mark moved into a nursing home and died of the disease four years later, in the spring of 2020. His family could not be with him because of the coronavirus pandemic.

The first steps

Carli Binek, 35, was the first person to enroll when Washington University opened a site for the biomarkers study. Every 16 months, Binek, who has Down syndrome, undergoes brain scans and cognitive testing and provides blood and other samples.

“I have to help find a cure for Alzheimer’s” to help other people with Down syndrome “and old people like my mom,” Binek said.

Many scientists say the best way to beat Alzheimer’s is to treat it before symptoms appear and the disease causes irreversible damage. People with Down syndrome may need to start taking drugs to prevent the dementia disease in their 20s, doctors say.

The biomarker study is laying the groundwork for what scientists hope will be the next step, enrolling people with Down syndrome in clinical trials for Alzheimer’s drugs. Considering how much people with Down syndrome have to overcome, “they should be at the forefront of clinical trials,” Rafii said.

Rafii and others are working to organize a group of 120 people with the genetic condition to track over time and be quickly enrolled in Alzheimer’s trials run by an international network of experts. One of the first drugs to be tested will probably be an anti-amyloid therapy designed to prevent the disease, Rafii said.

Experts say enrolling people with Down syndrome in trials poses challenges. Scientists need to use different tools, and have worked on developing them for years, to measure how an Alzheimer’s drug affects memory and cognition in people with the condition.

That means people with Down syndrome must be enrolled in trials separate from those for the general population. In addition, some families have been leery about exposing their relatives to experimental drugs. But increasingly, people with Down syndrome are eager to take part in research.

Drug companies once showed little interest in people with Down syndrome, but that is starting to change, said Brian Skotko, a medical geneticist at Massachusetts General Hospital. He pointed to AC Immune, a Swiss company that is testing an Alzheimer’s vaccine to treat people with Down syndrome. The company ran a small safety study involving people with the condition and said it plans to test an “optimized formulation” of its anti-amyloid vaccine this year.

But people with Down syndrome have not been included in trials by the pharmaceutical giants testing three new amyloid-reducing drugs headed to the FDA in the next year or so. Eli Lilly said in a statement that the company does not exclude people with Down syndrome, and hopes to include them, but that “the timing of Alzheimer’s disease onset makes identification of trial-eligible participants with Down syndrome a challenge.”

Roche said that people with Down syndrome are not specifically excluded but that its trial criteria, which excludes people with conditions that may affect cognition, “likely means people with Down syndrome were ineligible.” Eisai, which is collaborating with Biogen on its second Alzheimer’s drug after Aduhelm, said people with conditions that contribute to cognitive impairment were excluded from the trials.

Worth the fight?

Before issuing the final Medicare decision last week, Chiquita Brooks-LaSure, administrator of the Centers for Medicare and Medicaid Services, which oversees those two health programs, noted that Medicare and the FDA use different standards in scrutinizing medications.

“While the FDA reviews drugs to ensure they meet applicable safety and effectiveness standards, CMS generally evaluates whether the drug is clinically beneficial to Medicare patients,” she wrote in a letter last month to a member of Congress.

On Thursday, in issuing the final decision on Aduhelm, CMS officials said the restrictions were designed to ensure the drug helped and did not harm Medicare beneficiaries. They also said similar drugs might not be subject to the same coverage restrictions if they receive traditional approval from the FDA.

On Friday, the two agencies released an unusual statement on “ensuring access to safe and effective treatments.” In the statement, Brooks-LaSure and Robert Califf, the new FDA commissioner, acknowledged their agencies’ decisions “have an outsized impact on the U.S. health care system, as well as implications for the rest of the world.” They also explained the roles the agencies play in approving drugs and paying for them.

Califf said recently the Aduhelm approval “has temporarily impacted the trust in the FDA by people who pay attention to these things.” He made the comments at the Breakthrough Science Summit by Stat, a health and medicine news site.

Some Alzheimer’s experts said they understood the frustration of the Down syndrome community and agreed they should be included in trials but that Aduhelm was not worth fighting for.

“We don’t even know if the drug is effective” in other people with Alzheimer’s, for which it is intended, Jason Karlawish, a neurologist at the University of Pennsylvania, said.

‘30 years to fix this’

Margot and Chris Rhondeau met through Operation Smile, the medical nonprofit where they both worked. In 2017, a few years after they got married, Margot became pregnant. They learned at three months the fetus had Down syndrome.

They had long talks about the implications. Margot, who was working for Special Olympics, had met several impressive adults with Down syndrome and “could see the possibility” of their daughter “having a really good life.”

She doesn’t remember being told about Alzheimer’s when she heard about the results of her genetic tests. She learned about the link in 2020, when she went to work for the National Down Syndrome Society.

On a recent day, her daughter, Hannah, played with toy horses on the living room floor at their family home in Herndon, Va. Sporting a blond pony tail, she wore pink glasses and matching pink sneakers and brandished a book she wanted read aloud.

“It was and is difficult, but she brings us so much joy,” said her father. “Every day, I have a full-on belly laugh.”

As an advocate and mother, Margot is outspoken about her belief that doctors and patients, not Medicare, should decide whether to use Aduhelm, but she also realizes better treatments are needed.

When she talks to scientists, she says, “I’m giving you 30 years to fix this.”

Karen Gaffney does not have 30 years. She urges her peers with Down syndrome to do everything they can to stay healthy through frequent exercise, a good diet and social stimulation.

“It is my generation that is showing what is possible,” she said, noting her peers with Down syndrome have become writers, athletes and small business owners. “But it is also my generation that is marching directly into the ugly path of Alzheimer’s disease, and if that happens, there is no road back for us.”