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At the Bench: John Hardy, PhD, on Unraveling the Genetics of Alzheimer’s Disease and Attending the ‘Oscars of Science’



In November, John Hardy, PhD, head of the department of molecular neuroscience and chair of molecular biology of neurological disease at the University College London Institute of Neurology, was awarded the $3 million 2016 Breakthrough Prize in Life Sciences for his work investigating the genetic underpinnings of Alzheimer’s disease (AD). His research led to the discovery in 1991 of the first genetic mutation associated with familial AD, in the gene encoding the amyloid precursor protein. Since then, he and his colleagues have identified additional genes associated with AD and other forms of dementia. Dr. Hardy spoke with Neurology Today about his prize-winning research and what it was like to receive the Breakthrough Prize in a lavish Oscars-style ceremony in the company of Hollywood celebrities and Silicon Valley entrepreneurs.


Listen to a Neurology in the News podcast interview with Dr. Hardy here.


Dr. Hardy was just about to tuck in to breakfast at home — a bacon sandwich, he recalled — when he received a phone call from a colleague, the renowned movement disorders specialist Mahlon DeLong, MD. Dr. DeLong asked if he was sitting down. “I’ve got news which is going to change your life. You’ve won the Breakthrough Prize,” Dr. DeLong, a previous Breakthrough Prize winner and a member of the selection committee, told him.


After the call, Dr. Hardy and his partner abandoned their breakfast and headed to a restaurant a mile down the road for a proper champagne toast.


He needed no convincing that the award would be life-changing. The prize, founded in 2012 by Sergey Brin of Google, Anne Wojcicki of 23andMe, Jack Ma of Alibaba and his wife, Cathy Zhang, Internet entrepreneur Yuri Milner and his wife, Julia Milner, and Mark Zuckerberg of Facebook and his wife, Priscilla Chan, proffers large sums — in Dr. Hardy’s case, $3 million of a total of $21.9 million awarded in 2015 — to physicists, mathematicians, and life scientists at the top of their fields, as well as one lucky high school student. The award was founded to give scientists the “rock star” treatment and the funding to match, Milner told the press when the prize was first announced.


Dr. Hardy soon found himself breakfasting with Zuckerberg, Brin, Wojicki, and his fellow Breakthrough Prize winners at Zuckerberg’s California home, fielding questions about their research. “They don’t need me to say it,” Dr. Hardy said, “but they were very smart people and they asked very interesting questions.”


The awards ceremony was no less exciting. It has been dubbed the “Oscars of science,” an elaborate soirée attended not only by top-tier scientists but by Silicon Valley entrepreneurs and Hollywood stars. The event was held at NASA’s Ames Research Center in Mountain View, CA, emceed by comedian Seth MacFarlane, and included presentations by Russell Crowe and Hillary Swank and entertainment by musician Pharrell Williams.


“It was an astonishing event. It was great fun, but I was relieved when it was all over, too,” Dr. Hardy confessed. “Being in the public eye so much was stressful. Being in a tuxedo I found stressful.” The normally casual Dr. Hardy said he is excited to return for next year’s award ceremony as a spectator. “It’ll be nice to be a little further in the background.”



In 1985, Dr. Hardy accepted a position as an assistant professor of biochemistry at St. Mary’s Hospital at Imperial College London under the leadership of Robert Williamson, PhD, then chair of St. Mary’s Hospital Medical School. There, for the first time, Dr. Hardy began to study the genetics of Alzheimer’s. His first hire was a postdoctoral student named Alison M. Goate, DPhil, with whom Dr. Hardy would share author credit on many papers, and who would forge a reputation as a renowned AD researcher in her own right.


That year, Dr. Hardy and Dr. Goate received a letter from a woman in Nottingham detailing her unique family history of Alzheimer’s disease. Her father and four of his nine siblings, all in their mid-50s, had Alzheimer’s, as did one of her three cousins, all siblings.


By then the gene on chromosome 21 that encodes the amyloid precursor protein had been described by Colin L. Masters, MD, and Konrad Beyreuther, PhD, and researchers were already aware of the link between amyloid pathology and Alzheimer’s. So when Dr. Hardy and his colleagues collected blood samples from the entire family in Nottingham, they immediately set about sequencing the APP gene.


Their painstaking work — which, without the next-generation sequencing tools available today, took four years — revealed that all of the affected family members had inherited the same mutation in the APP gene from their grandfather. The mutation caused the overproduction of amyloid, and every person who inherited it eventually developed AD. They reported the finding in Nature in 1991.


“That mutation was the first known cause of Alzheimer’s disease,” Dr. Hardy said. “The mutation told us that amyloid is in the pathology of the disease — we knew that already — but also that amyloid could cause the disease. That was the breakthrough.”


Continuing this line of investigation, “we then made other findings that supported the idea that in Alzheimer’s disease, amyloid pathology came first, tau pathology came second, and cell loss and dementia came third,” he said. “Because of these genetic findings, we were able to put things in order.”


Look for the full article in the January 7 issue of Neurology Today, and listen to a podcast interview with Dr. Hardy here. To read more At the Bench profiles, browse our archives here.


Image: Dr. John Hardy poses with the 2016 Breakthrough Prize in Life Sciences at the 2016 Breakthrough Prize Ceremony on November 8, 2015, in Mountain View, CA. Photo by Kimberly White/Getty Images for Breakthrough Prize.