Neurology

More gene changes have role in Alzheimer's disease

BBC News reports that there has been "Alzheimer's insight from DNA study". The BBC says that a clearer picture of what causes Alzheimer's disease is emerging after the largest-ever analysis of patients' DNA.

Despite being the most common type of dementia the causes of Alzheimer’s disease are unclear.

Increasing age and genetics are the most established risk factors for Alzheimer’s.

The current study combined the results of various studies that have compared the DNA of over 17,000 European people with Alzheimer’s with DNA from over 37,000 healthy people. The researchers then confirmed the genetic links that they had identified in a separate group of Europeans, and finally pooled all the data together. Overall they found genetic variants in 11 new locations on the DNA sequence that were associated with Alzheimer’s.

Some of the variants are associated with immune function. This has led to some speculation in the media that a possible cause of Alzheimer’s is a failure of the immune system to remove abnormal clumps of proteins from the brain.

The researchers estimated that the proportion of people in the population with Alzheimer’s disease would be changed by between 1 and 8% if the risk associated with these genetic variants was removed.

However, before thinking of possible gene therapies, the researchers still need to confirm which genes within the identified DNA regions are having an effect. Then there is the problem that, even if the genes are identified, they may not be the only genetic cause for Alzheimer’s disease. With other non-genetic risk factors also likely to be involved, finding a gene therapy that could completely prevent or treat Alzheimer’s may be difficult.

Currently we can't say whether this finding will contribute to the development of new genetic therapies to treat or prevent Alzheimer’s disease.

Where did the story come from?

This multinational study was conducted by researchers from various institutions worldwide and was published in the peer-reviewed scientific journal Nature Genetics.

The work received numerous international sources of funding including the Wellcome Trust, the Medical Research Council, Alzheimer’s Research UK and the Welsh government. 

There is variable news coverage of this story from the purely factual to the wildly optimistic.

The Independent’s suggestion that Alzheimer’s may be related to a "malfunctioning" immune system, while intriguing, is speculation. As is the Daily Mail’s headline suggesting that Alzheimer’s will be treated by replacing faulty genes.

What kind of research was this?

This was a type of case-control study called a genome-wide association study (GWAS) looking into the genetics of Alzheimer’s disease.

GWAS studies involve analysing the DNA of a large number of people with a specific condition and comparing these with healthy controls to see what genetic variations may be involved in the development of a disease. The researchers say that 11 genetic variants or genes have been found to be associated with Alzheimer’s in previous research. This includes the most well established – the APOE gene.

However, much of the genetic risk remains unexplained. In order to search for possible new genetic links, the researchers have combined the findings of several GWAS studies conducted worldwide. This increases the number of people being analysed and allows identification of variants that are having a smaller effect than would have been detectable by the individual studies.

What did the research involve?

In the first part of the study the researchers looked at the data from four European GWAS studies including 17,008 people with Alzheimer’s disease and 37,154 healthy controls. They looked at over 7 million single “letter” variations in the DNA sequence, called single nucleotide polymorphisms (SNPs). They only looked at SNPs that were assessed for at least 40% of cases and 40% of controls.

In the second stage of the study, over 11,000 single letter variations in the DNA sequence that had been significantly associated with Alzheimer’s in the first part of the study were studied in a separate sample of 11,312 controls and 8,572 European people with Alzheimer’s disease.

Finally, any SNPs that were significantly associated with Alzheimer’s disease in both stages of the study were analysed by pooling all of the data from stages one and two together. The researchers also looked at where on the DNA sequence these genetic variants were found, and what genes were nearby and therefore might be causing the association seen.

What were the basic results?

As well as the variants in and near the APOE gene, genetic variants in 19 different places in the DNA sequence were significantly associated with Alzheimer’s in the different stages of the study.

Eleven of these 19 had not previously been associated with Alzheimer’s disease. Some of the variants were associated with increased risk, and some with reduced risk.

The researchers looked at what genes were nearest to the genetic variants and discussed what was known about what they did in the cells and how that might fit into what happens in Alzheimer’s disease.

The researchers reported that these genetic variants may be associated with between 1 and 8% of cases of Alzheimer’s disease.

How did the researchers interpret the results?

The researchers conclude that their GWAS meta-analysis has identified genetic variants in 11 places in the DNA sequence associated with Alzheimer’s disease, that have not previously been linked to the condition. In addition the findings have reinforced the associations already known. They say that “strong efforts” will now be needed to look more closely at the DNA in these regions to identify exactly which genes and variations are causing this link.

Conclusion

This is valuable research using genetic information from a very large set of people worldwide. It increases our knowledge about where in the DNA sequence genes that contribute to our risk of Alzheimer’s may lie.

The genetic variants identified are usually not themselves affecting risk; instead they lie near the genes that are affecting risk. The next step will be for the researchers to look more closely at the genes in these regions to confirm which are playing a role.

Each variant is associated with a small change in risk. Having these variants does not guarantee that a person will or will not definitely go on to develop dementia. The researchers calculated that the proportion of people in the population with Alzheimer’s disease would be changed by between 1 and 8% if everyone in the population did not have these genetic variants. To put this into context, this figure was calculated to be about 27% for the form of the APOE gene that is already known to be associated with Alzheimer’s disease (suggesting that there is a much firmer link with this already recognised gene).

It is likely that these new variants do not provide the whole answer for risk of Alzheimer’s disease. Other genetic and non-genetic factors (such as lifestyle habits and environmental factors) are likely to be involved.

Currently we can't say whether this finding may aid the development of new genetic therapies to treat or prevent Alzheimer’s disease.

However, hopefully the results provided by this comprehensive study will provide another clue to help us to solve the puzzle of Alzheimer’s disease.


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