All the Alzheimer’s research we didn’t do

By Charles Piller

What if a preposterous failed treatment for Covid-19 — the arthritis drug hydroxychloroquine — could successfully treat another dreaded disease, Alzheimer’s?

Madhav Thambisetty, a neurologist at the National Institute on Aging, thinks the drug’s suppression of inflammation, commonly associated with neurodegenerative disorders, might provide surprising benefits for dementia.

It’s an intriguing idea. Unfortunately, we won’t know for quite a while, if ever, whether Thambisetty is right. That’s because unconventional ideas that do not offer fealty to the dominant approach to study and treat Alzheimer’s — what’s known as the amyloid hypothesis — often find themselves starved for funds and scientific mind share.

Such shortsighted rigidity may have slowed progress toward a cure — a tragedy for a disease projected to affect more than 11 million people in the United States by 2040.

The amyloid hypothesis holds that sticky plaques and other so-called amyloid-beta proteins build up in the brain and prompt changes that cause Alzheimer’s disease’s cruel decline, gradually stealing a person’s mastery of everyday life, cherished memories and, finally, their sense of self.

In the early 1990s, legions of researchers began to sign on to the idea that removing amyloid from the brain could stop or reverse that process. But anti-amyloid drugs failed time and again. Then, in 2006, an animal experiment published in the journal Nature identified a specific type of amyloid protein as the first substance found in brain tissue to directly cause symptoms associated with Alzheimer’s. Top scientists called it a breakthrough that provided a key target for treatments. The paper became one of the most cited in the field, and funds to explore similar proteins skyrocketed.

In 2023, the Food and Drug Administration (FDA) approved Leqembi, a drug infusion based on work inspired in part by that research, which flushes some amyloids from the brain. Tests showed that it modestly slowed cognitive decline compared with the experience of patients given a placebo. Supporters of the amyloid hypothesis — including eminent scientists who have staked their careers on proving its accuracy — declared victory. On July 2, the FDA also approved a look-alike competitor, Kisunla.

Case closed, many scientists have argued, although drugs that prevent, arrest, or reverse symptoms of Alzheimer’s remain on the hypothetical horizon.

And there are serious concerns about the new drugs. For tens of thousands of dollars per person annually — plus costly diagnostic scans — they offer benefits so slight that many neurologists say they may be imperceptible to patients and their loved ones.

Such drugs also can cause dangerous brain swelling and bleeding. The FDA required warnings of fatal side effects on each drugs’ product label. The drugs also mysteriously shrink the brain much faster than Alzheimer’s itself, with unknown long-term effects. Despite the fanfare of Leqembi’s approval, few patients have taken it.

In 2022, my investigation in Science showed evidence that the famous 2006 experiment that helped push forward the amyloid hypothesis used falsified data. On June 24, after most of its authors conceded technical images were doctored, the paper was finally retracted. Days later, a City University of New York scientist behind a well-financed, controversial Alzheimer’s drug was indicted on charges alleging research fraud.

Such cases are extreme. Yet few of the multitude of honest Alzheimer’s papers offer much hope to patients.

In reporting for my forthcoming book about the disturbing state of play in Alzheimer’s research, I’ve spoken to many scientists pursuing alternatives. Thambisetty, for example, compares brain tissues from people who died in their 30s or 40s with and without genetic risk factors for Alzheimer’s. He then compares these findings to tissues from deceased Alzheimer’s patients and healthy people. Where changes overlap, drug targets might emerge. Rather than develop new drugs through lab and animal testing, followed by clinical trials that cost vast sums — a process that can take decades — he examines treatments already approved as reasonably safe and effective for other conditions. Patent protections have lapsed for many, making them inexpensive.

Experiments have also begun to test the weight-loss drug semaglutide (sold as Wegovy, among other brands). Researchers hope that results due in 2026 will show that its anti-inflammatory effects — like Thambisetty’s idea about hydroxychloroquine — slow cognitive decline.

Ruth Itzhaki, a research scientist at the University of Oxford, stirred curiosity in the 1990s when she shared evidence tying Alzheimer’s to herpesvirus — a scourge spread by oral or genital contact and often resulting in painful infections. For years, powerful promoters of the amyloid hypothesis ignored or dismissed the infection hypothesis for Alzheimer’s, effectively rendering it invisible, Itzhaki said with exasperation. Research suggests that viruses may hide undetected in organs, including the brain, for years, causing symptoms divergent from the original infection.

But her ideas might finally be catching on. Nearly 5,000 papers have been written about infections and Alzheimer’s since Itzhaki began her work. National Institutes of Health funding intended in part to examine such links jumped from a few million dollars to nearly $250 million annually in 2023. A clinical trial treating latent herpes among Alzheimer’s patients with an antiviral drug is underway, and results are expected as soon as next year.

None of us can stop growing older or change our genes. But risk factors such as diabetes, high blood pressure, and cholesterol, obesity, depression, hearing loss, sedentary lifestyles, poor diets and racial discrimination can be targeted. Miguel Arce Rentería, a neuropsychologist at Columbia University, argues that more accessible treatment that also addresses social issues may stave off the worst of Alzheimer’s for years. Although a vast majority of research seeks an elusive remedy, the mood is shifting. Federal funding for studying care and prevention, like some of Arce Rentería’s research, has recently risen.

Sometimes a disease stems from a single clear-cut origin, such as genetic mutations that cause deadly sickle cell disease. “But very few diseases of ageing have just one cause. It’s just not logical,” said Matthew Schrag, a neurologist at Vanderbilt University Medical Centre. Working independently of his university, he discovered the 2006 research image manipulations.

Like most amyloid sceptics, Schrag agrees that amyloid-beta proteins play a role in the complex mystery of Alzheimer’s, but they’re not the singular key to a cure that so many scientists imagine. If there was a universal source for Alzheimer’s it would show up earlier in life, and be more evident in everyone who suffers from the disease.

Ultimately, solutions to Alzheimer’s could arrive much faster if the amyloid hypothesis wasn’t reinforced with quasi-religious zeal by many of the field’s most powerful scholars.

“There is an entrenched echo chamber that involves a lot of big names,” Schrag said. “It’s time for the field to move on.”