University College London | fAD_8-the_DIAN_TU_trial-SD

The devastating aspect of familial Alzheimer's disease is that you know it's coming. And even if you don't know it's
coming, you know you've got a 50-50 chance of it coming.

That's devastating for the individual. It's incredibly useful in terms of trying to conduct a trial that's early. Because

the difficulty is that in order to conduct an early trial you need to know that that person at some point is going to
develop problems. And in the world of sporadic Alzheimer's disease, it's very difficult to know that.

In the genetic forms of Alzheimer's disease and familial Alzheimer's disease, we know that that problem is coming,

it's just a matter of time. We can even predict when it's going to happen. And that means that in trials we can have

a really good idea of where the pathology is, what stage it's at, and therefore what effects the drugs are going to

have over time.

DIAN-TU trail is really exciting. This is the first in the world study trying to prevent people developing Alzheimer's in
patients that are at risk of having Alzheimer's. It started with an international network called DIAN, which is the

Dominantly Inherited Alzheimer's Network.

And they set up an observational study in 2009 looking to see if they could work out what showed you in people

before they got symptoms, that they were going to get symptoms. So, we knew these people had a mutation that
was going to, at some point, cause them to have disease. We knew when their parents had disease, and so we

could guess how far before the onset of their disease they were.

And then you start to do tests looking at their brain using imaging, using spinal fluid examinations, to find out when
things start to get abnormal. And what we found was that you could see changes up to 25 years before people get
symptoms. Which is incredible.

So, we used that information to then set up a trial where you take people that are at risk, we know that they've got
a mutation. So what you do is, if people are at risk of having mutation, you say you can enter the trial. And you

find out centrally, not on site, but the central team internationally, find out whether they've got a mutation or not.

And then use that to, when they randomise people into treatment or not treatment, they use it to make sure they

don't get treatment. But the patient never finds out whether they've got a mutation or not. So they can go in

without having to know that they're going to get Alzheimer's disease, which is great.

In the trial we have two treatment arms. So there are two types of an immunotherapy, which is basically trying to

mop up amyloid, it's an antibody trying to mop up amyloid in the system. And they get randomised into one or the
other of the treatment arms. And then in those arms, 3/4 of them get treatment, and 1/4 get placebo.
other of the treatment arms. And then in those arms, 3/4 of them get treatment, and 1/4 get placebo.

And basically what we do is we follow these people that have no symptoms, the majority of them, over four years.
And we do the studies that we found in the observational study to see if we can prevent progression in the way

that we've seen it already in those patients that didn't get treatment. So, the idea is that we show that one of these

treatments works to prevent symptoms.

The unique thing about the DIAN-TU is that this is a prevention trial. These patients do not have symptoms, so

we're treating them really early. And we're hoping that we stop them getting symptoms. That's the idea.

Previous trials - we've had 15 years of Alzheimer's trials without finding a breakthrough. And one of the reasons

may well be that we've been treating too little, too late. By the time you've got disease that we all diagnose as
dementia, then these people have too much volume loss in their brain, too much damage in their brains. You can't

reverse it. So this is a new approach.

The DIAN-TU trial is being done at the Dementia Research Centre, and also at the Leonard Wolfson Experimental

Neurology Centre. Which is really exciting because it's a new opened unit, which is cutting edge, does first in-man

trials, and novel therapeutics in neurodegenative disease. And it's built specifically for these sorts of trials.

It's the first time we've had something like that that we can use. The patients love it. It's a really good environment,
but importantly it's a very high level safe environment to be able to do new types of trials.

The trial is now one year in and we've been doing really well. We now have 17 recruits in place, we're supposed to

have 10. And people are so keen to get involved that we've actually over recruited. And there are many more

people that want to come in.

The end goal is defined in the DIAN-TU trial is to find a treatment that will make a significant difference to these

individuals. Hopefully in this population we'll find a treatment, whether it's one of these two, or whether it's

something further along the line, that delays the symptom onset significantly. Ideally forever, but realistically 5 to

10 years would make a huge difference. And if we can find it in them, then the aim is to then use that in the

sporadic Alzheimer's population.