A new large-scale genetic study provides a better understanding of Alzheimer's disease by uncovering two new risk genes.
A team of scientists jointly led by co-senior author Julie Williams, a professor at the University of Cardiff in the United Kingdom, set out to examine the DNA of more than 85,000 individuals in an attempt to identify the genetic variants associated with Alzheimer's disease.
While presenting the results in the plenary session at the AAIC conference, Prof. Williams referred to the research as a "massive undertaking," due not only to the large number of study participants, but also to the collaborative efforts of more than 450 authors who made the study possible.
As Prof. Williams and colleagues explain in the study, late-onset Alzheimer's disease (LOAD) has a strong genetic component. In LOAD, patients typically experience their first symptoms at around the age of 65, and most people who develop Alzheimer's tend to have the late-onset form of the condition.
Almost 30 genetic locations are known to raise the risk of LOAD. However, these loci offer only a partial explanation for why some people inherit the disease. So-called rare genetic variants also contribute to the risk of inheriting LOAD, and Prof. Williams and colleagues set out to identify precisely such rare variants.
Genes highly expressed in brain's microglia
To do so, Prof. Williams and team conducted a "three-stage case-control study of 85,133" research participants. First, they genotyped 34,174 samples using a "whole-exome microarray." Then, using de novo genotyping and genotype imputation, they examined 35,962 independent samples and tested the genetic variations that they had identified in patients with LOAD in the first stage.
Finally, in the third stage, the scientists examined a further 14,997 samples in an effort to find which of the associations identified in the second stage were the most significant.
In the first stage, the researchers identified more than 200,000 variants. Then, they examined these further, looking for common and rare variants. After excluding variants that were already known to be associated with Alzheimer's disease, the researchers were left with 43 candidate variants, which they further investigated in the second stage.
Finally, the researchers narrowed the candidates down to two genes that were not previously believed to have links with Alzheimer's disease. They also found a new mutation in a third gene, which was already known to be implicated in LOAD.
Dr. Doug Brown, director of Research and Development of the Alzheimer's Society in the U.K., explains what the findings mean. He says, "These genes reinforce a critical role for special cells in the brain - called microglia - that are responsible for clearing up debris including damaged cells and proteins."
"The discovery of two new risk genes for Alzheimer's is an exciting advance that could help to deepen our understanding of what happens in the brains of people with the disease."
Dr. Doug Brown
The researchers conclude that these two genes are "highly expressed in microglia," and that their "genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease."
Prof. Brown also adds that insights such as those provided by this study "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."
First study author Dr. Rebecca Sims, of Cardiff University's School of Medicine, further details the findings and explains their significance for new treatment avenues.
She says, "In addition to identifying two genes that affect the risk of developing Alzheimer's disease, our new research reveals a number of other genes and proteins that form a network likely to be important in its development."
"These particular genes, which suggest that immune cells in the brain play a causal role in the disease, are also very good targets for potential drug treatment."
Dr. Rebecca Sims