Pioneering studies of post-mortem brain tissues have yielded the first evidence of a potential association between Alzheimer's disease and the epigenetic alteration of gene function. The researchers stress, however, that more research is needed to find out if the changes play a causal role in the disease or occur as a result of it.
We already have some evidence that the risk of developing Alzheimer's might be elevated by poor diet, lack of exercise, and inflammatory conditions such as diabetes, obesity and clogging of blood vessels with fatty deposits. The new research hints that the lifestyle changes that raise Alzheimer's risk may be taking effect through epigenetic changes.
The idea is strengthened by the fact that the brain tissue samples studied in the new work came from hundreds of people, many of whom had Alzheimer's when they died, and that a number of genes identified were found by two teams working independently, one in the UK and one in the US.
"The results are compelling and consistent across four cohorts of patients taken across the two studies," says Jonathan Mill at the University of Exeter, who led the UK-based team. "It's illuminated new genetic pathways affecting the disease and, given the lack of success tackling Alzheimer's so far, new leads are going to be vital."
"We can now focus our efforts on understanding how these genes are associated with the disease," says Philip De Jager of the Brigham and Women's Hospital in Boston, who headed the US team.
That might not be easy. Because the samples came from the brains of people who had died, the researchers cannot say yet whether the gene changes help cause the disease, or occur as a result of it. One Alzheimer's researcher not involved in the study even wonders whether the epigenetic changes are simply a natural part of ageing.
Both teams screened DNA from the brain samples for chemical changes that switch genes off through methylation – the addition of chemical methyl groups to DNA. These epigenetic changes don't alter the underlying sequence of DNA that someone has inherited, but they can change dramatically the pattern of genes that are expressed in a way that can encourage the development of
De Jager's team looked at methylation patterns in samples from the prefrontal cortex of 708 people, about 60 per cent of whom had Alzheimer's when they died. The prefrontal cortex is vital for higher cognitive thinking and invariably damaged in people with Alzheimer's.
Mill's team screened tissue from the same region, and from two other brain areas that also suffer disproportionate damage in Alzheimer's: the entorhinal cortex and the temporal gyrus. As control tissue, Mill's team also screened tissue from the cerebellum – which is usually not damaged by the disease – and blood. They initially screened for methylation changes in samples from 122 people who had Alzheimer's when they died, then to validate the initial results they repeated the procedure in further post-mortem samples, taken from about 220 people who had also died with the condition.
The most dramatic methylation differences between tissue affected by Alzheimer's and control tissue samples, especially in the entorhinal cortex, were in a gene called ANK1, which has not previously been linked with Alzheimer's. That gene produces ankyrin 1, an essential ingredient of the outer membranes of cells that is vital for keeping cell structure intact.
"There's not been any evidence linking it to dementia previously," says Mill. "But genetic studies have linked it to type 2 diabetes, which, in turn, has links to dementia, so there could be some common pathway linking the two diseases," he says.
In all, De Jager's research highlighted 11 genes, while Mill's research identified seven – four of which were also among De Jager's 11, including ANK1.
"This innovative research has discovered a potential new mechanism involved in Alzheimer's by linking the ANK1 gene to the disease," says Simon Ridley, Head of Research at Alzheimer's Research UK, which also provided funding for the study. "We will be interested to see further research into the role of ANK1 in Alzheimer's and whether other epigenetic changes may be involved in the disease," he says.
Cause or effect?
The key challenge now for both teams is to establish whether these epigenetic changes can accelerate the progression of the disease. That is important because some of the epigenetic effects were as pronounced in people who died with the disease as in those who had classic signs of the disease in their brains at death but had shown no symptoms of Alzheimer's.
This point drew criticism from some researchers, who said it reduced the case for causation. "Is it Alzheimer's or simply ageing causing these changes?" asks Ewan McNay of the State University of New York in Albany, who is exploring links between diabetes and Alzheimer's. "It's very preliminary work, and more is needed to further explore the associations."
Mill and De Jager say that the changes seen occur very early in the disease, and so at the very least they might be useful for predicting whether people are at raised risk of developing symptoms later on. De Jager also points out that methylation is a reversible process, so with the right drugs it might be possible to treat the epigenetic changes.
Journal references: Nature Neuroscience, DOI: 10.1038/nn.3782 (UK team) and DOI: 10.1038/nn.3786 (US team)
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