Beyond Aduhelm: Why experts have never felt more optimistic about Alzheimer's treatments

PHILADELPHIA – Katrín Björk Guðjónsdóttir had her first stroke at 21, followed by a blood clot. Several months later, she had a second massive stroke. There was little doubt about what the rest of her short life would look like.

Her tight-knit Icelandic family harbors a fatal genetic fluke. It causes a protein called beta-amyloid to build up and form clumps in their cells, triggering repeated strokes. Across generations of her extended family, people withthis condition, calledhereditary intracerebral hemorrhage, developed dementia in their 30s, 40s and 50s and died prematurely.

But Guðjónsdóttir got lucky.

Her uncle, a prominent lung and genetics expert at the University of Pennsylvania, was called in to consult on her care.

In the process of saving Guðjónsdóttir, now 28, Dr. Hakon Hakonarson may have provided evidence for a new treatment for Alzheimer's, which now affects nearly 6 million Americans.

His idea, though still very preliminary, is part of a burgeoning effort to approach Alzheimer's in new ways, including repurposing therapies for problems like stroke, breathing issues and erectile dysfunction – or even using light and sound to help the brain heal itself.

As improbable as some of the efforts may sound, experts in the field say they've never felt more optimistic.

"There's a lot of excitement going on," said Rebecca Edelmayer, senior director of scientific engagement for the Alzheimer’s Association. "A lot of hope on the horizon for patients."

For decades, drug companies have been trying in vain to develop treatments for the degenerative brain disease, mostly targeting clumps of beta-amyloid and tangles of another protein called tau.

The one treatment to ever show any effectiveness against these disease-defining proteins, Aduhelm, was approved last year. But the approval was considered controversial because the drug didn't appear to make much difference in outcomes and carries potentially serious side effects.

Its manufacturer, Biogen, recently cut its price in half to encourage more people to take it, but last week, the Centers for Medicare & Medicaid Services agreed to cover the cost of the drug only for those participating in clinical trials, which will dramatically limit its use.

Now, instead of looking just for a new blockbuster drug to remove amyloid, the Alzheimer's Association's Part the Cloud research program is supporting 59 treatments in early-stage human trials, many of them repurposing drugs that target inflammation, metabolism, growth factors, and other biological functions believed to underlie Alzheimer's.

The Alzheimer's Drug Discovery Foundation is supporting about two dozen of the more than 120 drugs in clinical development, three-quarters of which are not going after the long-time targets of Alzheimer's drugs.

Dr. Howard Fillit, the foundation's co-founder, said he thinks Alzheimer's will need to be attacked from several directions at once, just as cancer usually needs to be treated with more than one approach.

Drugs like Aduhelm will become one of many strategies used to tackle the disease, said Fillit, also the organization's chief science officer.

A diabetes drug that reverses insulin resistance might also be part of the solution to Alzheimer's, he said, along with something that reduces inflammation, another that gets rid of toxic proteins and a fourth that clears out dead cells. "Multiple pathways go wrong with aging," he said.

Diagnostics are also on the verge of transforming the field, Fillit said. Beta-amyloid clumps can now be detected with a blood test and tau will soon follow, which will "change the way early diagnosis is done and the way clinical trials are being done."

Blood tests should help inexpensively match patients with appropriate treatments, both for clinical trials and eventually for care, he said.

"We're just opening the door right now to this new era," Fillit said. "This and the efforts worldwide in finally moving our science into clinical drug development should give great hope to patients and their loved ones and their doctors that there should be many drugs on the market in the relatively near future."

Promising new approaches

Berislav Zlokovic believes preventing problems in the circulatory system, particularly the brain's tiny blood vessels, will help prevent Alzheimer's as well as vascular dementia.

"What's good for the heart is good for the brain," said Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of the University of Southern California.

In several studies, he's shown that leaks in the brain's capillaries cause damage that can lead to cognitive impairment independent of amyloid buildup. People who carry the APOE4 gene, which is known to increase the risk for Alzheimer's, are more likely to have leaking capillaries as they age, he found. Slowing or reducing brain capillary damage, he believes, may slow down or arrest cognitive impairment.

In his latest research, published in November, Zlokovic showed that medication being developed to treat strokes called 3K3A-APC also protected mice from injury to the brain’s white matter – the second leading cause of dementia in people.

Zlokovic is a scientific founder and heads the advisory board of a company that is developing 3K3A-APC for stroke. The company, ZZ Biotech of Houston and Sydney will start a pivotal Phase 3 trial for stroke in early 2022, and also is testing the drug in ALS and for wound healing.

Feixiong Cheng, who runs a lab at the Cleveland Clinic’s Genomic Medicine Institute, recently screened 1,600 already-approved drugs to see if any could block the formation of beta-amyloid clumps as well as tau tangles.

The drug that looked the best was sildenafil, the generic form of the erectile dysfunction drug Viagra.

Using patient data, Cheng's team showed that people taking sildenafil had a 69% reduced likelihood of developing Alzheimer's.

Now, he and his colleagues are planning a clinical trial to verify whether sildenafil can have a benefit in people with early Alzheimer’s disease. They will test a variety of dosages of sildenafil.

Foundations and the federal government are essential for funding such work, he and others said because drug companies can't afford to pay for hugely expensive clinical trials on a drug whose patent protection has expired.

Stumbling across a possible breakthrough

While Cheng's search for an Alzheimer's treatment was very deliberate, Hakonarson's was purely accidental.

Hospitalized after her second stroke, his niece Guðjónsdóttir was struggling to breathe.

Hakonarson would normally have prescribed her a drug called Pulmozyme, used to help cystic fibrosis patients. But in Iceland, where she lives, that inherited lung disease is rare and the drug wasn't readily available.

Instead, he put her on N-acetylcysteine or NAC, which the FDA has considered banning as a supplement because it is already approved as a drug.In addition to thinning clumps of mucus in the chest, NAC also helps the body produce more glutathione, a protective antioxidant.

A few months later, as Guðjónsdóttir recovered, her doctors in Iceland wanted to take her off the NAC, but she asked to stay on it, saying she felt it was helping. Around the same time, Hakonarson, who was studying her cells in a lab dish, discovered that NAC seemed to break up the clumps of beta-amyloid that collected in them.

What if the NAC were actually treating her underlying disease? he wondered. That hypothesis became more convincing as Guðjónsdóttir continued her recovery and avoided further strokes. Hakonarson launched a formal clinical trial, testing NAC on her and 16 of her family members and distant relatives who had the same genetic condition. He showed that levels of amyloid in their cells fell. None had strokes.

He is currently working on expanding the study to include all Icelanders with the condition – virtually everyone on Earth known to be at risk for the same genetic condition. He's now using an altered version of NAC that gets into the brain and cells more easily, which he has patented and created a company, Arctic Therapeutics, to market.

If Hakonarson's studies in Icelandic people continue to look strong, he plans to test his altered NAC in people with Alzheimer's, to see if their levels of beta-amyloid fall, too, and if that makes a difference in their symptoms.

Others are already exploring NAC to prevent dementia. In one study, researchers at Baylor College of Medicine in Houston are looking to see if it has an effect on cognition, glutathione levels, brain cell energy use, and brain inflammation.

NAC has previously been shown to increase levels of the brain's major antioxidant, glutathione, which can reverse cell damage caused by oxidative stress, said Krista Lanctôt, a senior scientist and director of the neuropsychopharmacology research group at the Sunnybrook Health Sciences Centre in Toronto.

One small study a decade ago showed that NAC provided small improvements in cognition among people with Alzheimer's.

Lanctôt found that a certain type cell damage is common in people at risk for developing vascular dementia. She and her colleagues are now studying whether giving people NAC to protect cells from this damage and then increasing their exercise will reduce their risk for cognitive decline.

NAC can act on several processes at once and can be safely given before disease develops, she said. "Giving a natural health supplement in combination with exercise is highly feasible," she said. "If successful, it may allow us to move earlier into the disease (process) and work on prevention."

Flashing lights and low notes

Perhaps the most unusual approach to preventing Alzheimer's comes from a research lab at the Massachusetts Institute of Technology.

There, Li-Huei Tsai, director of the Picower Institute for Learning and Memory, has been studying whether certain tones of sound and frequencies of light can help regulate brain waves and help clear out cellular trash, including toxic proteins.

First discovered in mice, Tsai has since tested the approach in eight patients with early Alzheimer's, exposing them to LED light flashes and sound frequencies for an hour a day, while seven others received white noise and constant light.

For an hour a day, her team subjected volunteers to a twinkling LED light that flashes so quickly it's imperceptible and sounds in the range of 30-50 hertz, played 40 times per second. "Like clicking," Tsai said. "It's far from music." People can watch videos during the treatment.

That study was very small and needs to be repeated in many more people, Tsai said, but participants stuck with the treatment and their brain atrophy seemed to slow.

She and her team are working to launch a much larger study and already have the support of the Alzheimer's Association and Gates Foundation.

Tsai said it's too early to know when this kind of treatment should be started or how well it will work if damage has already occurred, but it doesn't have any obvious side effects or risks.

"I can imagine people can start exposure when they're still relatively young to keep their brain healthy," said Tsai, who exposes herself to the 2-foot-by-2-foot light and soundbox most days.

"Alzheimer's is extremely complex," Tsai said. "It's difficult to imagine any single medication can take care of it."

Scientists need to better understand whether there are different subtypes of Alzheimer’s, perhaps generated by genetics, lifestyle, or even gender. Women, who are more likely than men to develop Alzheimer's, show differences from men at the cellular level, she said.

While treatment may eventually need to be personalized, she hopes that using light and sound will help address a wide range of problems.

"The major difference between this approach and all other approaches," she said, "is that this approach doesn't just target one molecule or one pathway or one cell type. This is a holistic approach to take care of the whole system."

Leaning into lifestyle

Of course, the best way to prevent Alzheimer's is to keep it from occurring in the first place.

Lifestyle changes have been shown to have a major impact on Alzheimer's risk, Fillit said, including getting good sleep, eating a mostly Mediterranean diet, keeping blood pressure under control and avoiding diabetes, smoking and excessive drinking.

"We do know the factors that reduce the risk of Alzheimer's," he said. "The real challenge is not so much about the knowledge of what works, but more about the compliance and implementation side, of helping people be compliant and live their best lives."

For her part, Guðjónsdóttir said she's feeling upbeat about her long-range prospects. She's less burdened by the lingering symptoms of that second stroke, which left her unable to walk without assistance and with throat muscles too weak to allow her to speak.

A recumbent bicycle she received during the pandemic gave her back a sense of freedom and helps her burn off energy. She can communicate by spelling out words on a letter board.

Plus, COVID-19 has slowed the rest of the world down to her post-stroke pace, Guðjónsdóttir wrote in a recent blog post, and helped her realize that she's not missing out on as much as she thought. Instead, she's grown to better appreciate the life she has with her parents in her small Icelandic town.

Contact Karen Weintraub at kweintraub@usatoday.com.

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

This article originally appeared on USA TODAY: New Alzheimer's treatments beyond Aduhelm are bringing 'a lot of hope'