Could Down's syndrome point the way to preventing Alzheimer's disease?

People with Down's are dramatically more prone to Alzheimer's than other adults. Now, scientists have united in a bid to pin down why – and to find drugs that could halt dementia

Doctors took an hour to realise Sarah Merriman had Down's syndrome after her birth in January 1992. By then, her father, Andy, had phoned friends and family to tell them his wife, Alison, had given birth to a healthy baby. His happy news was dashed. "It was a real shock," Andy recalls. "From the start, we were warned about the difficulties and troubles that lay ahead for Sarah. Then she was diagnosed as having a hole in her heart. The worry, for the first years of her life, was constant."

Sarah's heart healed. She did well at her school in Haringey, north London, and went on to pass the equivalent of four GCSEs. Today, she is studying catering and lives with other students near her college in Somerset. "Sarah is independent and copes with life in a way we could never have imagined just after she was born," says Andy.

It is a reassuring story, although one major worry still besets the Merriman family: Sarah's long-term future and her susceptibility to Alzheimer's disease, a form of dementia that leads to complete loss of memory, speech and awareness and which is closely linked to Down's syndrome. Among members of the general population, the risk of getting Alzheimer's before the age of 65 is less than 5%. For a person with Down's syndrome the figure is 50%.

In the 21st century, such rates threaten to become a major health problem, says Carol Boys, chief executive of the Down's Syndrome Association. "Thirty years ago, my son was born with Down's and I was told his life expectancy was around 30. Today, new medical treatments for heart and other conditions linked to Down's mean that life expectancy for those with the syndrome is over 60. It's good news but it does mean our children face the prospect of dementia in later life."

The nature of the problem has led to the creation of a remarkable new research group, the London Down's Syndrome Consortium (LonDown's). Made up of psychologists, geneticists, clinical psychiatrists, neuroscientists and stem cell researchers, the consortium has been given £2.5m of Wellcome Trust funding to explore the links between Down's syndrome and Alzheimer's disease over the next five years.

"Our prime, long-term goal is to develop drugs to halt the onset of Alzheimer's disease in Down's individuals," says geneticist and consortium member Professor John Hardy, of University College London. "Then we can work on medicines to ward off Alzheimer's in the general population."

A starting point for the group will be the protein beta-amyloid. Autopsies of Alzheimer's patients invariably reveal clumps – or plaques as researchers term them – of beta-amyloid that have become wrapped round their brain's nerve cells and which have extended in filaments into their neurones.

"There are more than 300,000 people in Britain with Alzheimer's and all have beta-amyloid plaques," says Hardy. "They are the defining feature of the disease, although we still do not know if they are the actual cause of the condition." It is also uncertain when these plaques first start in patients but most scientists suspect they develop many years before the appearance of Alzheimer's first symptoms of apathy and loss of memory and attentiveness.

But what sets off the coalescing of these amyloid plaques and the subsequent destruction of patients' brain tissue? Scientists point to one key factor, a chemical called amyloid precursor protein or APP. In Alzheimer's patients, APP appears to break down into smaller proteins, including beta-amyloid, and these fragments accrete into plaques. Crucially, the gene responsible for making APP is found on chromosome 21, a bundle of genetic material that is directly implicated as the cause of Down's syndrome.

Down's is caused when a person acquires an extra copy of chromosome 21 (see below). As a result, each person with the syndrome has extra copies of the gene that makes APP and that, in turn, means their bodies make excess amounts of the protein – with dramatic consequences. By the time people with Down's have reached young adulthood, their brains are invariably filled with amyloid plaques that usually only appear in later life in the general population. Hence their susceptibility to Alzheimer's.

"The correlation may sound simple but it is actually complex," adds LonDown's consortium leader, André Strydom, a consultant psychiatrist based at University College London. "Yes, 50% of Down's patients get Alzheimer's by the time they are 65, so there is a link. By the same token, however, the other 50% do not. And that observation is just as important, if not more important, for our work. It shows there are other factors involved in the causation of the disease other than the plaques that appear in their brains. Other influences are modifying or accentuating the condition. And it is the hunt for these modifiers that will dominate our work for the next five years."

The consortium's task is to pinpoint the factor or group of factors that suppress the onset of Alzheimer's in some Down's individuals and target them using drugs that could then delay the onset of dementia, not just in individuals with the syndrome but ultimately in the general population.

It will not be an easy task, as psychologist and consortium member Professor Annette Karmiloff-Smith, of Birkbeck College, points out. "We will be trying to find some feature in the behaviour or the make-up of an individual with Down's syndrome that predicts whether he or she will go on to get Alzheimer's in later life or avoid it. At present, we haven't got a clue what that predictive trait will be and it will take a great deal of co-operation between all the consortium groups to track it down."

For Karmiloff-Smith's group, that work will focus on Down's infants between six and 40 months old and will involve the use of tests that will measure their attention span, memory, their eye movements and other variables. Brain wave patterns will also be administered, along with event-related potential (ERP) tests, another non-invasive method for measuring brain activity during cognitive processing.

"We are seeking a test that divides our group of Down's children in a way that hopefully will reflect the differences between those who will get Alzheimer's disease and those who do not," adds Karmiloff-Smith. "Such a test might involve children's attentiveness or their eye movements, for example."

A similar approach will be taken a team led by Strydom who will use a battery of cognitive tests, though his group will target adolescents and young adults rather than infants. "We will be in continual discussions with the other groups in the consortium, including those who are testing Down's children and will be exchanging ideas all the time," adds Strydom.

On top of this research, another group, led by Professor Elizabeth Fisher, professor of neurogenetics at UCL, and Victor Tybulewicz, at the National Institute for Medical Research, London, will carry out tests on mice that have had their chromosomes engineered so they develop the rodent equivalent of Down's. "We have also put a human chromosome 21 into mice. So we have very good animal models to test out our ideas. Mouse models are perfect for working out basic biology and then developing treatments before you carry out full trials on humans."

Guided by the work of Karmiloff-Smith, Strydom and other members of the consortium, Fisher and Tybulewicz aim to hunt through the genomes of their engineered rodents until they pinpoint the genes responsible for the traits that provide protection against Alzheimer's, while also identifying one that make individuals particularly vulnerable. At the same time, other groups will carry out similar searches using cell cultures.

The final task will be to pinpoint drugs that can interfere with the factors that make individuals susceptible to dementia, thus protecting them from cognitive degeneration in the future.

Just what these treatments might be is a tricky issue, however. At present, there are no drugs that can halt the effects of Alzheimer's once the disease has been diagnosed, despite pharmaceutical companies' efforts. Two drugs, one developed by Johnson and Johnson and Pfizer and the other by Eli Lilly, were recently developed to try to block the growth of beta-amyloid plaques in Alzheimer's patients. However, after lengthy trials, these failed to produce convincing results.

And this continued failure poses a problem. If a test is developed that shows a person is liable to get Alzheimer's in later life but no prospect of a treatment is offered, then doctors will face a major ethical headache whether to inform them or not when there is no treatment available.

"It is a real problem," Fisher admits. "However, those recently failed drugs were given to people who already had plaques in their brains. By contrast, they could easily prove to be effective – not in getting rid of plaques once they have become established, but in preventing them from building up in the first place. The Down's population is terribly at risk of Alzheimer's and they have the most to gain from trying out approaches like this."

Certainly, the development of a treatment to ward off dementia would be warmly welcomed by families such as the Merrimans. "My daughter is lucky in one sense," says Andy. "She has an elder brother, Daniel, and a younger one, Joel. Both are devoted to her and it is comfort for my wife and I to know they will be there for her," says Andy. "However, it is perhaps unfair to expect too much from them. What we really need is a treatment to offset the worst that lies ahead."

Professor Karmiloff-Smith would welcome volunteer families who have a
baby between 6 and 40 months with Down's syndrome and would like to be included in the research to contact her for further details at:

• This article was amended on 15 October 2012. The original referred to Professor Lizzie Fisher rather than Elizabeth Fisher. This has been corrected.


Robin McKie

The GuardianTramp

Related Content

Article image
Alzheimer's study reveals new genes implicated in disease

Largest study yet into genetics of Alzheimer's disease identifies double the previous number of genes associated with disorder

Ian Sample, science correspondent

27, Oct, 2013 @6:05 PM

Article image
GM worm study provides 'powerful first step' towards preventing Alzheimer's
Research is at a very early stage, but scientists are hopeful that a ‘neurostatin’ preventative drug for neurological conditions will become a reality

Alan Yuhas in Washington DC

12, Feb, 2016 @7:08 PM

Article image
Could arthritis drug combat Alzheimer's?

It affects 35 million people and billions have been spent on research – to little avail. But an unconventional approach might provide a way forward. Dara Mohammadi reports

Dara Mohammadi

17, Nov, 2013 @12:05 AM

Researchers devise safer Down's syndrome test

If successful it would eliminate the small risk to the foetus posed by invasive testing methods

David Pallister

06, Oct, 2008 @11:01 PM

Article image
Down's syndrome cells 'fixed' in first step towards chromosome therapy

Researchers shut down the extra chromosome responsible for Down's syndrome, paving the way for future treatments

Ian Sample, science correspondent

17, Jul, 2013 @5:00 PM

Article image
Annette Karmiloff-Smith obituary
Neuroscientist who provided fresh insights into our development as individuals

Jeffrey Elman and Lorraine Tyler

26, Jan, 2017 @3:40 PM

Article image
This may be a turning point in treating neurodegenerative diseases
Success in trials for Huntington’s and Spinal Muscular Atrophy, raises hopes that diseases such as Alzheimer’s and ALS could be tackled using a new class of drugs

Hannah Devlin Science correspondent

15, Dec, 2017 @5:37 PM

Article image
In praise of the humble fruit fly
Drosophila, the hard-working fruit fly widely used in genetics research, is a lot more like us than we might care to think. Time we got to know the little pest

Andrew Anthony

25, Sep, 2016 @7:45 AM

Article image
Gene linked to long life also protects against mental decline in old age
Discovery gives scientists hope of developing a therapy that could slowdown the progression of Alzheimer’s disease and other forms of dementia

Ian Sample, science editor

27, Jan, 2015 @5:00 PM

Article image
Alzheimer's genetic link raises hopes of earlier tests

New research brings to 10 the known number of genes associated with the disease

Ian Sample, science correspondent

03, Apr, 2011 @5:00 PM