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Carol’s story: there’s something in the family

Watch the story of discovering a gene for Alzheimer’s disease told by Carol who has fAD, and Professors John Hardy and Martin Rossor.
When my father was in his mid 50s, he started to have problems. He was finding it difficult to remember things, he was making mistakes with his work, and he was needing to be prompted with most things. And so that we knew it was something wrong. He went to the doctors, he was sent to the hospital for tests, and he was diagnosed with Alzheimer’s disease, which we’d never heard of. It wasn’t really long after that that one of his sisters, who was younger than my father– she was only in her early 50s– and she started developing the same sort of symptoms.
And she had a brother, and the next thing we knew was that her brother had also started to develop these symptoms. I remembered that my grandfather, when he was younger, had had similar problems. He had been looked after by my grandmother for many years, up to the end of his life. And I put two and two together, and thought, there’s something funny going on here. This is the same family, developing the same symptoms, at a similar age. There must be something that is going on here. I made a family tree. I found out lots of names, and I thought, this was interesting to someone who could do something about it. That was the main thing.
And so that was sent to Martin Rossor and to John Hardy, and they started to work on it. I think I have the original letter here. Martin Rossor picked it up, and John Hardy, and Mike Mullan. There was a team of them here. And they actually applied to get to grant, to explore the family, which they got. And in 1991, they turned up to take blood samples, and Carol coordinated across the family, to get all the family giving blood. And she was– I mean, she’s always been quite a motivated, social person.
She got the whole family: cousins, second cousins, all of the family on the paternal side, where the problem was. It wasn’t maternal; it was the paternal side. She got them all involved, and they came up and took blood tests from them all. The early hunt for the Alzheimer gene, or the gene that was causing familial Alzheimer’s disease, was– very much depended, actually, on being contacted by Carol. And she’d been aware that there was Alzheimer’s disease in her family, and it was affecting individuals at a young age, in their 40s and early 50s, and she was trying to interest scientists.
And she became aware that John Hardy and I, John Hardy being the scientist, and myself being the clinician, who were working at St. Mary’s, had very recently got a grant from the Medical Research Council, to look in families, see if we could identify the gene. And I’d come across one or two relatively small families where there might be an affected individual, and perhaps an aunt or cousin or a brother, but they were very small. And this is back in the late 1980s, when the technology for looking at genes was much, much less advanced.
And so the only way you could try and track down the abnormal gene was to get very large numbers of individuals, some of whom are affected and some weren’t, and comparing markers on their chromosomes, and to try and narrow it down, which gene is the culprit. And it so happened that Carol’s family was very large. And so there were a number of cousins and distant cousins, and she introduced us to many family members. And we were able to take blood and extract the DNA, and look at that. From the blood samples, we made DNA. And in those days, we used a technique called Southern blotting, for assessing inheritance of DNA.
Nowadays, we wouldn’t do that; we’d use much more fast methods. And we started to look at the inheritance of genes on chromosome 21, because people with three copies of chromosome 21 always got Alzheimer’s disease. So that was a big clue, really, that we should start on chromosome 21. So we started to look at markers on chromosome 21. We made a false start– I won’t say a false– a false start, because we assumed that all familial Alzheimer’s disease have mutations in the same gene. And that assumption turned out to be wrong, and that assumption cost us a couple of years of work, as we tried to pool data from other families.
But when we realised the we should analyse families one at a time, we immediately, or fairly immediately, realised that the amyloid gene was inherited with the disease in Carol’s family. And then we sequenced the amyloid gene in the family, and found a mutation. And that was the first known cause of Alzheimer’s disease. Within a very short time, really, a couple of years, they actually got back to us, and said that they had discovered the fault for our family, and it was a fault on chromosome 21. And John Hardy was able to identify that in the amyloid precursor protein gene, the APP gene, there was indeed a mutation that was causing the disease in that family.
Now following that, of course, that meant there were a number of families that didn’t have an APP mutation, but it was found that they had mutations in two other genes, and they were called PSEN1 gene and PSEN2. But it ties together very nicely, because those genes are involved in how you process the amyloid precursor protein, to form the amyloid that gets deposited in the brain. So it makes a nice story. And from that discovery was the so-called amyloid hypothesis, the amyloid cascade hypothesis. When you look at the brains of somebody with Alzheimer’s disease, anybody with Alzheimer’s disease, you see, really, three features. The first thing you feature, when you see when you just get the brain, is that it’s shrunken.
And you get– so there’s clearly nerve cell loss, neurodegeneration. So that’s the first feature. The second feature, under a microscope, you see plaques. And these are about 0.1 millimetre across, and they stain black in a silver stain, and they’re just horrible lumps in the brain, tiny lumps in the brain. And we now know, from work by other scientists, Glenn and Masters and Bayreuther, that these lump are made of the amyloid protein. And then also, under the microscope, inside nerve cells, we see damaged proteins called– it’s the tau protein, and these are called tangles, inside nerve cells.
So you’ve got these three features: the nerve cell loss, the plaques, and the tangles. And really, we had no way of knowing which came first, what was the order of this pathology. And everybody had a different opinion on the relative importance, of the relative primacy, of each of these features. And really, the finding of amyloid mutations, in my view, settled that primacy. It said, these people have got Alzheimer’s disease because they’ve got mutations in amyloid, and that mutated amyloid is deposited in their brain. So amyloid comes first. And that’s really been the underlying idea that most people working on Alzheimer’s disease have had, ever since we made that finding.
So one might ask, did it make any difference, discovering a gene in a particular family? And I think it made quite a big difference. And particularly, it did give rise to the amyloid cascade hypothesis, that you’ve got a very real handle on what might be the proximate cause, i.e. what actually starts the disease process. And one of the advantages of studying familial Alzheimer’s disease is that if you know that somebody carries the abnormal gene, you can study them before they develop symptoms. And we know now that you can see changes in brain imaging, or by examining the cerebrospinal fluid. You see changes many years before people began to develop symptoms.
And that’s a real window of opportunity for treatment, and a lot of the treatments now are being trialled in individuals who are at risk of familial Alzheimer’s disease. And it’s– I think it’s a great tribute to all the family members who contribute to this research.

Watch Carol describe the journey from her father’s Alzheimer’s diagnosis to the discovery of a gene linked with fAD. We also hear from two of the scientists and doctors at the heart of this discovery, Professors John Hardy and Martin Rossor.

In the video Martin Rossor explains the different genes that cause this inherited form of Alzheimer’s disease and explains how, since they all have a common effect, it makes a clear scientific story implicating amyloid as a cause of the disease. In the years since these were discovered, further genes have been identified that don’t cause Alzheimer’s to be inherited but do increase people’s risk of developing the disease. We take a more in-depth look at these genes in the next step.

This video also introduces the amyloid cascade hypothesis – the idea that the first step in the cascade of changes that leads to an individual developing Alzheimer’s disease is the build up in the brain of tiny abnormal clumps of this protein called amyloid. It’s this hypothesis that has led to the idea that clearing amyloid from the brain might slow or stop Alzheimer’s disease from progressing. We hear about a trial at UCL aiming to do just that later this week.

Here’s a simplified look at the sequence of events leading up to symptoms in familial Alzheimer’s disease, according to the amyloid cascade hypothesis:

diagram showing amyloid cascade hypothesis

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