Understanding Alzheimer's disease by investigating the disease in people with Down's syndrome

Read about a research project we funded on finding new molecular pathways in Alzheimer's disease.

Lead Investigator: Professor Elizabeth Fisher

  • Institution: University College London
  • Grant type: PhD studentship
  • Amount: £84,990
  • Start date: October 2014
  • End date: September 2017

The background

People who have Down’s syndrome have a greatly increased risk of developing Alzheimer’s disease compared to the rest of the population. By studying the Alzheimer’s dementia in Down’s syndrome researchers hope to understand more about the condition.

Chromosomes are very large molecules in the centre of our cells that carry the genes. Most people inherit 23 chromosomes from both their mother and their father.

People with Down’s syndrome have an extra chromosome number 21. Down’s syndrome arises because people have three, not two, copies of all the genetic information on chromosome 21.

This project aims to understand more about the genes on chromosome 21 that seem to increase the risk of early-onset Alzheimer’s disease.

A gene called the ‘APP’ gene sits in the middle of human chromosome 21. People with Down’s syndrome have three copies of APP. That is almost certainly enough to explain the Alzheimer’s disease many of them develop. However, the research team have shown this is not the whole story. There are other genes on human chromosome 21 that change the effects of APP.

What did the researchers do?

The research team have a mouse model of Alzheimer’s disease that forms plaques that we see in humans with the condition and a model of Down’s syndrome that carries an extra copy of human chromosome 21. They have already shown that the extra chromosome 21 caused a change in the model of Alzheimer’s.

For example, many more of the amyloid plaques develop and the mice also had more problems with learning and memory. 

The key question for this PhD studentship was to establish which gene(s) on human chromosome 21 were important for causing these changes the Alzheimer’s disease mouse model. 

The team crossed their mouse model of Alzheimer’s disease with another two different mouse model that carried just some of the genes present on human chromosome 21 and observed the impact this had. 

What were the key results?

The research team found when crossed with the first mouse model, the mice had a greater chance of suddenly dying compared to the model of Alzheimer’s disease. This experiment was immediately stopped. Although this isn’t a feature of Alzheimer’s disease, they believe it was caused by seizures which are more common in people with the condition.

When the research team crossed the Alzheimer’s mouse model with the second model with genes from chromosome 21 they found an increase in the amount of amyloid that builds up around the nerve cells. This suggests that a gene or genes within this region causes this hallmark of Alzheimer’s disease. 

One gene found in this region is DYRK1A which has previously been linked to amyloid and tau another hallmark of Alzheimer’s disease and the team would like to explore its effect on APP.

How will this benefit people with dementia?

This work is laboratory research that is fundamental for providing insight into the biochemistry of cells affected by Alzheimer’s disease. 

Ultimately, although translation from ‘bench to bedside’ takes many years, new treatments and therapies depend on findings from investigations like this. This type of research offers long-term hope for reducing the effects of Alzheimer’s disease and improving the quality of life for people affected.

Next steps

The PhD carrying out this work aims to continue this area of work and will apply for funding to support it. They hope to understand more about the region of genes that caused an increase in the build up of amyloid in their mouse models and why that might be. They will be applying to the MRC to explore these genes. 

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