Unravelling the genetics of Alzheimer’s

Professor Julie Williams’ research has uncovered two new genetic links to Alzheimer’s disease

Julie works in the MRC Centre for Neuropsychiatric Genetics and Genomics at the University of Cardiff. Here, scientists are trying to understand the genetic basis of neurological disorders which place a burden on society – from dyslexia to multiple sclerosis.

“Genetics has really taken off in the last 20 years and I was lucky enough to begin my research career just when things were really starting to blossom,” explains Julie. “It’s a very fast-moving and exciting field with new advances in technology almost every year, so it’s quite challenging to keep up with it all.”

One of Julie’s particular research interests is trying to understand and pinpoint the biological processes that go wrong in Alzheimer’s disease. As part of an international collaboration of scientists, she has discovered two new genes, CLU and PICALM, which make people more susceptible to developing the disease.

“Over the years we’d found a few promising genetic variants, but we hadn’t been able to replicate the findings in other studies to prove there really was a link between the genes and Alzheimer’s disease,” explains Julie.

“So we bit the bullet and pulled together 16,000 cases of Alzheimer’s and a comparative group of healthy volunteers – the biggest ever genome-wide association study that had been done in this disease. And we found very strong evidence that two genes were associated with a risk of developing the disease, and that the pattern persisted across the very large sample we were looking at.”

So what was it like to make such an important discovery?

“We’re a pretty cynical lot in genetics, and having had so many disappointments in the past, you tend to disbelieve findings when you see them. So my first thought was to wonder what we’d done wrong,” says Julie. “But the penny finally dropped when we replicated the finding in other studies and also because the gene has a similar function to another Alzheimer’s-associated gene, ApoE. So the secret was, as we suspected, in having really powerful sample.”

Now that the genes have been identified, the scientists need to work out exactly how they contribute to the disease, which will eventually guide the development of treatments to slow down or prevent Alzheimer’s.

Julie explains: “One of the genes is centred on how the brain transports and processes cholesterol molecules. And since we did that study we’ve found two other Alzheimer’s disease genes associated with a process called clatherin-mediated endocytosis – which is basically a process the cell uses to bring large molecules into the cell and transport them to different parts of the cellular ‘machinery’ to be processed.”

“These findings give us a lot more focus for where we should be targeting drugs for Alzheimer’s disease in future. It also gives us the potential to reduce risk factors for the disease, so that we can reduce the number of cases of Alzheimer’s or perhaps delay its onset to give people another 10 years of healthy life.”

So what inspired Julie to take up a career in medical research?

“I’ve always wanted to do it. I remember having a bit of a nerdy moment at the age of about eight, going into WH Smith and buying a book on the jottings of Faraday and thinking wouldn’t it be great to find out something that nobody else knows – what a fantastic way to spend your time.”

“If one day I could see new understanding and knowledge coming from the genes we’ve discovered leading to a treatment that would be fantastic.”

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