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Genes Point to Immunity, Inflammation as Alzheimer's Triggers

Pam Harrison
August 01, 2017

Three new susceptibility mutations in one known and two new Alzheimer's disease (AD) genes have been isolated and point to involvement of immunity and inflammation as a causal trigger in the development of the disease, a large consortium of researchers report.

"There's a lot of evidence of an elevated immune response, including inflammation in the Alzheimer's brain, but historically, it's been thought that that they were the result of the disease itself," lead researcher, Rebecca Sims, PhD, research fellow, Cardiff University School of Medicine, United Kingdom, told Medscape Medical News.

"But our work, as well as work of others, is now showing that immunity and inflammation are causative in the disease so they're part of the underlying mechanism of disease," she added.

"And one of these genes, which is an enzyme, may be a good target for potential drug treatment," Dr Sims said.

The research was published online July 17 in Nature Genetics.

Enormous Effort

Researchers pursued a three-stage case-control study design using participants from the International Genomics of Alzheimer's Project.

In stage 1, investigators genotyped 16,097 cases of late-onset AD and 18,077 cognitively normal elderly controls.

In stage 2, researchers tested associated variants in 35,962 independent samples using de novo genotyping and imputed genotypes.

In stage 3, they used an additional 14,997 samples to test the most significant stage 2 associations using imputed genotypes.

This enormous effort isolated three new genome-wide significant variants that are associated with AD.

The first, PLCG2, is actually a protective variant; PLCG2 carriers are more than 30% less likely to develop AD at an odds ratio (OR) of 0.68. Being an enzyme, PLCG2 should, at least in theory, be a fairly easy target for development of a drug targeting it, said Dr Sims. However, researchers need to understand what the enzyme is doing first in order to target it.

The second variant, ABI3, increases the risk of a carrier developing AD by 43%, with an OR of 1.43. The third variant is a new mutation in TREM2, a known susceptibility gene for AD.

Importantly, the immune response has long been considered a response to AD.

"Our work provides further strong evidence against this and specifically implicated the action of microglia — immune cells in the brain — suggesting that these [cells] are much more pivotal in Alzheimer's disease than previously thought," she said.

Dr Sims also noted that the mutations they have now identified are actually a protein coding so they change the proteins themselves.

This is in contrast to previous research, which showed that most risk factors for the disease were related to changes in the expression of proteins or gene products.

"So it's much more exciting for us from a research perspective in that we can actually see a change in the protein and work out what that change does," said Dr Sims.

"This will mean it'll be a lot quicker to go from the bench into the clinic compared to a number of other genes that we have previously identified," she added.

"The fact that the immune response is a contributory factor and not just a secondary consequence of Alzheimer's disease is a pivotal message from this research," Dr Sims concluded.

New Pieces of the Puzzle

Commenting on the study for Medscape Medical News, Rosa Sancho, MD, head of research at Alzheimer's Research UK, who in part funded the research, the discovery of new genes is like finding pieces in a puzzle that biologists can start to fit together to build a complete picture of the disease.

"There are currently no treatments to slow the progression of Alzheimer's, and increased investment in research is vital so that we can capitalise on new findings and drive progress for people with the condition and their families," she said in a statement.

Doug Brown, MD, director of research and development at the Alzheimer's Society, United Kingdom, who also funded the research, added in the same statement that the discovery of two new risk genes for AD is an "exciting advance" that could help deepen medical science's understanding of what happens in the brains of people with AD.

"These genes reinforce a critical role for special cells in the brain, the microglia, that are responsible for clearing up debris, including damaged cells and proteins," Dr Brown said.

"Insights like this are vital to help unravel the complexities of Alzheimer's disease and show researchers where to focus their efforts in the search for new effective treatments," he added.

Commenting further on the research, Andrew Saykin, PsyD, professor of genetics, Indiana University School of Medicine, Indianapolis, noted that this research clearly highlights the importance of immune pathways in AD, contributing to the evolving understanding of the role that the immune system plays in the pathogenesis of this disease.

"The newly identified variants in PLCG2, ABI3, and TREM2 are intriguing and add to the panel of genome-wide association studies and sequencing hits in immune genes, including other variants in TREM2, many of which are related to microglial signaling," Dr Saykin told Medscape Medical News.

The next step, he said, is to understand the key drivers of this gene network in AD, including their role at various stages of disease, and to look for the best place or places to intervene with drug targeting and lifestyle interventions, he observed.

"Further mechanistic studies of these genes, alone and in combination, are needed to clarify their specific contributions to normal function and pathology," Dr Saykin noted.

"But this study is a great illustration of the importance of international collaborative efforts that enable very large and well-powered association analyses," he concluded.

SOURCE: Medscape, August 01, 2017. Nature Genet. Published online July 17, 2017.





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