Rare Alzheimer's gene ten times more common in Icelanders

People from Iceland are more likely to inherit a rare gene mutation which increases the risk of developing Alzheimer's disease, scientists have said. This newly identified mutation is located on the TM2D3 gene and could play a role in the accumulation of amyloid plaques in the brain.

In the UK, 850,000 people are affected by Alzheimer's disease, which is the most common form of dementia. Years of research have allowed scientists to identify common genetic variants associated with the illness but rare genetic mutations can also have an impact in the population. The problem is that they are much harder to pinpoint, so they are much less documented.

The aim of the study, published in PLOS Genetics, was to learn more about these rare variants, by conducting a large-scale exome-wide association study – the scientists sequenced all the expressed genes in the genome.

10 times more in Icelanders

In total, they analysed more than 11,000 genes in 1,393 late-onset Alzheimer's disease patients and 8141 controls, taken from the CHARGE consortium, a cohort designed for heart and ageing research.

Examining all this data, the international team, constituted of researchers from both Europe and the US, identified a variant in the TM2D3 gene, which appeared associated with both a higher risk and earlier age of onset of Alzheimer's disease.

Looking at people's nationalities, they discovered that this specific variant - called P155L - was about 10 times more common in Icelanders than in the general European population. However, it can still be described as a rare variant there as it is present in fewer than 1% of the Icelandic population. Furthermore, this does not mean that the prevalence of the disease is higher in Iceland than in other countries - it is actually equivalent to the rest of the world.

Tests in fruit flies

To learn a bit more about the gene variant and why it is likely to be a factor in the development of Alzheimer's disease, the scientists worked with fruit flies. They showed that p155L causes a loss of function in TM2D3 and this disrupts the Notch signalling pathway.

In past studies, interference with the Notch signalling pathway have been shown to have a role in the generation of amyloid plaques in the brain of patients, one of the hallmarks of Alzheimer's disease.

Despite these promising results the scientists caution: "We have not proven causality [between P155L and the disease] and further study is needed, including additional experiments in the fly, DNA sequencing to identify additional variants, and RNA sequencing to study effects on gene expression."