UCL's Professor Sir John Hardy was the first to identify the role of amyloid in Alzheimer's disease - now, three decades later, that finding has resulted in a drug that may help patients.
In newly published trial results, a drug has for the first time been shown to slow the rate of cognitive decline in people with Alzheimer's disease. The drug, lecanemab, was found to have a modest effect in treating the disease, but its implications have been hailed as momentous - marking a turning point in Alzheimer's research and giving hope to millions across the globe.
The news is particularly poignant for Professor Sir John Hardy (UCL Queen Square Institute of Neurology), as it represents a lifetime of work, by supporting a hypothesis that he first developed 30 years ago.
Lecanemab works by targeting beta amyloid - a plaque that builds up in the brains of people with Alzheimer's disease.
This was an idea pioneered by Professor Hardy when he began working with Carol Jennings and her family.
Carol reached out to Professor Hardy in the mid-1980s, after her father, his sister and brother all developed symptoms and were diagnosed with Alzheimer's in their 50s.
Professor Hardy said: "Throughout her family were people who developed Alzheimer's and did so in their 50s, and she wanted answers. She's a very determined woman, a remarkable woman."
Genetic Alzheimer's is rare and only accounts for around 1% of Alzheimer's cases. However, Professor Hardy believed that Carol's family could unlock clues as to the cause of the condition in the wider population.
Intrigued, he and his team took blood samples from members of the Jennings family to identify if there were any genetic differences between those who had Alzheimer's and those who didn't.
After five years of research, the team discovered a mutation to the amyloid precursor protein (APP) gene, which creates the amyloid plaques that form in the brain during Alzheimer's disease.
Amyloid affects brain cells by causing them to become overactive and signalling for ongoing inflammation, which can disrupt normal processes in the brain.
Blood flow can also be affected and other proteins in the brain can become involved. For example, when too much amyloid is deposited, it can react with another toxic protein called tau, which causes neuronal death.
In those with genetic Alzheimer's this happens early because the patient makes too much APP. However, it also happens in those with non-genetic Alzheimer's but at a slower rate.
As a result of these findings, in 1992, Professor Hardy and his colleague Professor David Allsop published the amyloid cascade hypothesis, which they hoped would "facilitate rational design of drugs to intervene in this process."
The theory helped to explain the three key features seen in the brains of people with Alzheimer's disease, including the brain appearing smaller due to the death of brain cells, the build-up of amyloid protein and tangles with tau.
From that point, there was a drive to understand more about Alzheimer's and other dementias, with Professor Hardy winning the $3million Breakthrough prize in life sciences in 2015.
Professor Hardy was also knighted in the 2022 New Year Honours for services to "human health in improving our understanding of dementia and neurodegenerative diseases".
