The man on the other end of the phone was distraught. At times, it was as if he couldn’t quite believe the story he was reliving. His wife, Jean Terrien, he explained, had been diagnosed with Alzheimer’s, the most common type of dementia, aged 65.
And, looking for some kind of hope, she had volunteered for a drug trial. More than a year into that trial, things went horribly wrong. Jean suffered a stroke. In a panic, her husband rode with her in an ambulance to the local hospital.
Doctors attempted to treat her with blood-clot busting medicine, but the effect was catastrophic. ‘As soon as they put it in her, it was like her body was on fire,’ the man told me. ‘She was screaming, and it took eight people to hold her down. It was horrific.’
Jean suffered from seizures and, as her condition worsened, she was placed on a ventilator. A few days later, she died. The doctors who treated her said they had never before seen such massive bleeding in the brain – and believed the Alzheimer’s drug she had been given, called lecanemab, may have been the cause.
I’d received the tip-off about this shocking case via a confidential source in the medical world. This is how I get many of my stories, as an investigative journalist for the American magazine Science.
Many drugs are trialled to help with Alzheimer’s and dementia, but scientists already know with certainty that there are steps people can take early in life to reduce their risk of developing the conditions
Charles Piller has uncovered a series of Alzheimer’s research scandals, and has been looking into the safety of Alzheimer’s ‘wonder drugs’ lecanemab and donanemab
Over the years, I have uncovered a series of Alzheimer’s research scandals. At the time, I’d recently published a story which described how studies behind another new dementia drug, called simufilam, had apparently been doctored.
A New York researcher who collaborated with the company behind the drug looked to have manipulated his findings in the laboratory to make it seem as though the drug could be effective against Alzheimer’s when, in fact, it was a dud. Thousands of patients signed up for a simufilam trial in the vain hope it would cure them.
My stories, which exposed elements of the scandal, appeared prior to the conclusion of a federal investigation that led to the criminal indictment of the New York scientist.
The drug later failed in human testing and was pulled from use – and the company that made it, Cassava Sciences, paid $40 million to settle charges by US authorities related to allegations of securities-law violations. The company did not admit any wrongdoing. The case against the New York scientist is still ongoing.
Now, a new source had contacted me because a growing number of scientists were concerned about the safety of lecanemab – as well as donanemab, a similar Alzheimer’s drug undergoing clinical trials at the time.
Less than a month after I published Jean’s story, I was contacted by another family. This time it was the daughter of a 79-year-old woman who had died after taking lecanemab, now sold under the brand name Leqembi. Genevieve Lane, a retiree from Florida, died after she developed brain swelling and bleeding, and violent seizures.
Genevieve Lane, a retiree from Florida, died after she developed brain swelling and bleeding, and violent seizures after taking lecanemab
Other than early symptoms of Alzheimer’s, Genevieve was in good health for her age and had no medical issues that could have triggered this catastrophic event. An autopsy concluded that, while it was impossible to know for certain, lecanemab was the most likely cause of Genevieve’s death.
Some scientists believed that lecanemab (and later, donanemab) did not slow the progression of Alzheimer’s as effectively as described by their makers.
Despite those concerns, in the last two years both received the green light from regulators in the US and Britain. That was a big moment. They were among the first medicines ever to be shown in trials to slow the progression of Alzheimer’s. Some experts even heralded their arrival as the ‘beginning of the end’ for what was assumed to be an incurable disease.
But there was a catch for British patients. The NHS ruled that these drugs did not benefit patients enough to justify their price tag. Despite this, last month the drugs went on sale at a private clinic in the UK, which reportedly charged over £60,000 a year for treatment. The firms behind lecanemab alone hope to make about $10billion by 2031 from this roll-out. And they don’t intend to stop there.
Pharma companies and some of their scientific collaborators have suggested that the earlier patients receive these medicines, the better they may work. Those companies hope to offer these drugs to millions of patients who do not even have Alzheimer’s symptoms.
In 2022, a study partly funded by drug maker Roche and Biogen concluded that as many as 315 million people worldwide had ‘pre-clinical Alzheimer’s’. The paper argues that these patients have no symptoms of the disease but have build-ups of Alzheimer’s-related proteins in their brains. Would giving them lecanemab or donanemab prevent them from getting Alzheimer’s?
It’s an exciting theory – and a drug-maker’s dream: the potential for millions of people to take a costly medicine for years, perhaps even decades.
It’s no surprise that the pharma giant Eisai is funding a trial that will involve giving its drug, lecanemab, to patients deemed at risk of developing Alzheimer’s.
And a US trial is currently investigating the benefits of giving a new drug, called gantenerumab, to patients who carry a rare genetic mutation that increases the chance of the disease at an early age. The drug, developed by Roche, is being offered to patients as young as 18.
Ms Lane died after taking her third dose of lecanemab in September 2022. An autopsy concluded the drug led to her death
But some scientists find these moves terrifying. In principle, they believe that millions of people would be given a treatment with – at best – modest benefits and potentially lethal side effects, for a disease that they might never fall victim to.
So how have we got to this stage?
While the cause of Alzheimer’s remains a mystery, over the past three decades one theory gained prominence. Researchers believe the disease is triggered by a toxic protein called amyloid, which can clump together in the brain and form sticky deposits called plaques. The hypothesis says that those proteins begin a cascade of biochemical effects that can kill brain cells and lead to dementia.
The theory was proposed in the early 1990s and, since then, drug companies have raced to develop a medicine that can remove the toxic protein from the brain.
Some experts say that the amyloid theory is flawed – arguing the plaques and proteins are linked to the disease but not its cause, meaning that removing amyloid is unlikely to slow the disease.
Many anti-amyloid drugs that were tested in clinical trials very effectively remove the plaques from the brain, but failed to slow the progression of Alzheimer’s.
But in 2022, Biogen and Eisai published data that showed lecanemab was the first dementia medicine ultimately approved in the UK to slow decline in patients – by as much as 27 per cent, compared to people in human trials who received a dummy treatment. Just months later, another drug, donanemab, developed by US firm Eli Lilly, was shown to be slightly more effective.
At the time, the results made headlines around the world. But, having reported on these trials, I was troubled by this response.
Many reports seemed to downplay side effects. One in eight patients taking lecanemab experienced swelling in the brain and one in seven had brain bleeds, according to a study published in the New England Journal of Medicine. And, as I’ve mentioned, I spoke to the grieving families of those who didn’t survive these.
Donanemab, according to the trial results, had even higher rates of side effects.
The drug companies claim that most of that swelling and bleeding is minor and rarely leads to severe symptoms. But scans also appeared to show that the brains of patients taking lecanemab and donanemab shrank rapidly – more so than the brains of patients not taking the drugs.
While it is still unclear what the impact of this will be, it is hard to imagine it will be positive. Perhaps just as worrying were the claims from some top researchers that, if the drugs were beneficial, the effects were so subtle as to be imperceptible to doctors and patients.
Scan of brain bleed that killed Genevieve Lane, 79
Genevieve Lane learned about the experimental Alzheimer’s drug lecanemab from other dementia patients in her retirement village.
The former car-hire manager from Florida had been diagnosed with the disease two years earlier, in 2019.
She asked her doctor if she could sign up for the lecanemab trial, and after months of tests, was enrolled.
The scan shows where an amyloid vessel ruptured and bled
Lecanemab is given via intravenous infusion every few weeks, and in August 2022 Genevieve began treatment. Her family, who are now trying to raise awareness of the potential side effects, say that after the first dose she began to experience headaches.
Then, a week after her third dose, she collapsed. Five days after she was admitted to hospital, she died. An autopsy concluded she had suffered a catastrophic seizure triggered by a burst blood vessel in her brain, left.
The team involved believe that lecanemab was the most likely cause of death.
Those on the trials were asked to take a brain function test every six months, which analysed memory and brain performance. This test had a score out of 144 points.
On average, the group who had been given the drug declined by ten points and the placebo group declined by 13 points. It is this difference that allows the drug companies to claim the treatments can slow dementia by nearly a third.
These results are the reason why the NHS – along with some health insurance firms in the US – decided not to fund patients to undergo treatment with lecanemab or donanemab.
But this hasn’t stopped the drug firms pressing on, hoping to find new groups of patients to treat – possibly including this new group with ‘pre-dementia’. Using blood tests designed to identify build-ups of amyloid and tau, another toxic protein, in the brain, drug firms hope to identify the patients who they say are most at risk of Alzheimer’s. In plans set out by the US-based Alzheimer’s Association, which has taken funding from both Eisai and Eli Lilly, patients with these build-ups but no symptoms would be diagnosed with ‘stage one’ of the disease.
As Maria Carrillo, chief scientific officer at the association, told the Los Angeles Times: ‘In order to prevent dementia we need to detect and treat the disease before symptoms appear.’
The Alzheimer’s Association said it does not, at present, advocate ‘routine diagnostic testing’ for the disease and was open about its partnerships with the industry. However, other scientists see a serious flaw in this approach.
Research shows that a 60-year-old who tests positive for amyloid in their brain has a less than one-in-four lifetime risk of developing dementia. Even those with the highest genetic risk – those who carry two pairs of a gene passed down through families called APOE4 – have at most a six-in-ten chance of developing the condition by aged 85.
How will doctors know which patients with these protein build-ups will go on to develop Alzheimer’s? They cannot.
A spokesman for Eisai said that lecanemab had been granted marketing authorisation in ten countries and regions based on high-quality clinical trials.
They added that the company has an ‘established, rigorous safety monitoring process’ and was ‘working with the regulatory authorities’ to ensure they have all the required safety data.
An Eli Lilly spokesman said donanemab had been approved by various regulators in countries including the UK based on clinical trial data which concluded the drug was safe and effective, adding: ‘As with any prescription medicine, patients taking donanemab may experience adverse reactions, sometimes severe. Lilly remains committed to monitoring, evaluating, and reporting safety data.’
The obsession among researchers and drug companies with these treatments could also be distracting them from exploring other routes to preventing or treating Alzheimer’s.
Last month, an Oxford University study suggested many cases of Alzheimer’s could be triggered by viruses in the brain. Researchers said that it was possible that the herpes simplex virus type 1, also known as the cold-sore virus, as well as the varicella zoster virus (responsible for chickenpox and shingles) could lie dormant in the brain. They could then be reawakened, the scientists say, by a blow to the head, for example, and trigger Alzheimer’s.
It’s just a theory at this point, but if it’s substantiated by further studies then surely developing effective treatments or vaccines against these viruses could be more effective and safer than using these potent anti-amyloid drugs.
Moreover, scientists already know with certainty that there are steps people can take early in life to reduce their risk of developing Alzheimer’s.
Last year, The Lancet Commission published 14 lifestyle changes to lower the chances of developing dementia. These included taking a daily statin, losing weight, exercising regularly, cutting down on alcohol and even getting a hearing aid.
There is no magic bullet to stop Alzheimer’s. But this obsession with using potentially dangerous and at-best minimally effective drugs to treat the disease is distracting us all from exploring other possible treatments, and emphasising the importance of more common sense lifestyle measures.
I hope the medical world – and the public – realise this soon for everyone’s benefit.
- Adapted from Doctored by Charles Piller (Icon Books, £20), to be published on February 13. To order a copy for £18 (offer valid to 15/02/25; UK P&P free on orders over £25) go to www.mailshop.co.uk/books or call 020 3176 2937.
