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Genes point to immune role in Alzheimer's disease

New frontier The discovery of a link between Alzheimer's disease and changes in several genes associated with inflammation opens a new frontier for investigation into the cause of the disease.

Two independent studies, published today in Nature Neuroscience, support an emerging theory that inflammation may play a key role in Alzheimer's disease.

Researchers in the first study collected post-mortem brain tissue from 708 individuals who were enrolled in studies of ageing. The second study took post-mortem brain samples from four individuals.

Both groups examined the tissue for well-known pathological signs of Alzheimer's disease, known as neurofibrillary tangles, then analysed the DNA in the brains for 'epigenetic' changes.

Epigenetic changes switch particular genes on or off . One of the ways this can occur is by altering the biochemistry of the DNA — a process called DNA methylation.

"The epigenome is modifiable by human experience and exposure. We're interested in seeing whether different life experiences or other exposures actually affect Alzheimer's disease through the epigenome," says co-author Dr David M. Bennett, professor of neurology and head of the Rush Alzheimer's Disease Center, Chicago.

"There's a lot of interest in both the genomic and environmental risk factors for Alzheimer's disease, and by environmental, we're not talking about the high wires or pollution, we're really talking about the experiential, like cognitive activities, or psychological like depression, or medical like diabetes."

Complex disease

Both teams of researchers independently identified several genes where DNA methylation was much more common in the individuals who had Alzheimer's disease, and in the regions of the brain specifically affected by the disease.

These methylations were also present in those who had not shown symptoms of the disease before they died but whose brains showed evidence of Alzheimer's disease.

"This would suggest that somehow these genes are part of the network of genes that are involved in a complex disease like Alzheimer's disease," says Bennett.

One particular gene, called ANK1, is known to play a role in inflammation and immune activation.

"So there's a whole immune system and inflammation, both peripheral and central, that's now becoming a very high target for understanding, that we never would have gone after before," Bennett says.

Co-author of the second paper, Dr Jonathan Mill says the ANK1 gene is also associated with type 2 diabetes.

"That's interesting because we know that individuals with type 2 diabetes have an increased risk of developing Alzheimer's disease and dementia," says Mill, from the Institute of Psychiatry at King's College London.

"It may mean nothing but that's certainly a lead that's worth investigating."

Mill says the next step is to work out the biological significance of these genes, and why they are altered in individuals with Alzheimer's disease.

"It could be something about these individuals' lifestyles, something else could trigger a change here that brings about the disease, or it could actually result from the disease itself," Mill says.

"This is really the first step in probably a long pathway of trying to work out what's going on."