ALMOST four decades ago a desperate woman sent John Hardy a letter.
“Dear Sir,” Carol Jennings, from Nottingham in England, wrote in her careful handwriting. “I was very interested to read of your research in the Alzheimer’s Disease Society News and think my family could be of use.” Her 63-year-old father had Alzheimer’s, she said, “as does his sister, Audrey. His brother, Arthur, also may have the disease”.
Hardy remembers reading it.
“She said, ‘My doctor keeps telling me it doesn’t run in the family, but here’s my family tree, and it clearly does’.” Throughout her family were people who developed Alzheimer’s and did so in their 50s, and she wanted answers.”
This is the letter that launched a thousand studies, the letter that, in a roundabout way, led to investments worth billions. And recently, 35 years after Carol sent it and more than a decade after she started losing her mind – as she always feared she would – came a vindication of sorts.
It arrived in a factsheet for doctors produced by the US Food and Drug Administration in June, giving information on the country’s newest drug. “ADUHELM,” it began, “is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease.”
With that mundane opening sentence an experimental drug became a clinical one. The US regulators had, at last, approved a drug to treat Alzheimer’s – the first in 20 years.
If you accept that regulator’s assessment, and we will come to that, it meant more than merely that Hardy was right – that the hypothesis he pioneered towards the start of his career has been proved towards its end. It meant the billions of pounds thrown at his idea had not been wasted after all.
It was, said Hilary Evans, chief executive of Alzheimer’s Research UK, “a pivotal moment”. Bart De Strooper, director of the UK Dementia Research Institute, called it a “major milestone”.
Yet Hardy, a professor at University College London, who works with De Strooper, is not quite as jubilant as you’d think about a development that, without hyperbole, brings him significantly closer to a Nobel. “I wouldn’t put it as strong as vindicated,” he says, on a warm summer evening in his garden in Leytonstone, London. “I guess . . . I don’t feel as depressed as I had been.”
Aduhelm, also known as aducanumab, is the result of Hardy’s work. For it to work it means, as he predicted, that Alzheimer’s is caused by a toxic protein called amyloid. And for the first time it means there’s a treatment to clear that protein: to deal with the causes, rather than the symptoms, of a disease that affects millions of people worldwide.
The drug’s existence is so much more than many dreamt possible just two years ago. It is also so much less than Hardy hoped for. “We had this magic pill dream. One ring to rule them all,” he says.
“And that’s clearly not the case.”
THE story of amyloid and aducanumab is a story of science itself. It’s a story of dogged research; occasional inspiration; years of thankless, potentially futile graft; hubris and disappointment; feuds; triumph and caveats. Lots of caveats.
It could begin in many places. It could begin with Roger Nitsch, the University of Zurich scientist who in the early Noughties identified a natural antibody that seemed to keep amyloid at bay.
It could begin in 1905 with Alois Alzheimer, a German psychiatrist whose patient lived in Frankfurt’s Irrenschloss, the “Castle of the Insane”. She was confused. She forgot her name. She forgot what to call the food on her plate. “I am lost,” she said. When she died, Alzheimer cut her open and found clumped-up plaques of protein in her brain.
But there is a date in between, in the ’80s, when Carol Jennings’ letter landed in Hardy’s academic pigeonhole. That is as good a place to start as any.
Genetics was a new field then and Hardy had been inspired by research into Huntington’s disease that had found a single gene was the cause. He put out an advert in an Alzheimer’s newsletter for people who thought the same was true in their family history of Alzheimer’s. And that was what prompted Carol’s response.
Her letter is the reason we now have the first glimmer of a hint of a glint that we can cure Alzheimer’s. Other families with genetic Alzheimer’s would be found. Other researchers, Hardy is keen to emphasise, would follow the clues down the same path he took. But he was there at the front, from the start.
Most people don’t have genetic Alzheimer’s, not in the sense that a single gene causes the condition. But in those people like the Jennings family, he thought, might lie a clue. In their mutation could be a pointer to the disease in the population at large.
These days, identifying the key gene from the family members might take a postdoctoral student a month. Back then it was very different.
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