Researchers have discovered a new genetic defect that increases the risk of developing late-onset Alzheimer’s, by far the most common form of the disease, by threefold or more. The mutated gene is known to play a role in the immune system and inflammation in the brain, and its discovery could open up new lines of attack in treating Alzheimer’s.
Two groups of scientists independently identified mutations in the gene, called TREM2. Their findings were reported online in the New England Journal of Medicine.
The newly identified gene mutation occurs in about one in 50 people with Alzheimer’s disease. It is far less common than the better known APOE-E4 gene, which scientists discovered in 1993 likewise increases the risk of developing Alzheimer’s. While having either gene mutation increases the likelihood of developing Alzheimer’s, it does not mean you will get the disease. Most cases of Alzheimer’s are likely caused by a complex blend of environmental and genetic factors.
Scientists previously identified several genes that are linked to Alzheimer’s onset. Variants in genes known as APP, presenilin-1 and presenilin-2, for example, cause the early-onset form of Alzheimer’s, which strikes people before age 60. Unlike the TREM2 and APOE-E4 variants, carrying one of these genes invariably leads to Alzheimer’s.
A handful of other rare genes have also been linked to an increased risk of late-onset Alzheimer’s, which typically becomes apparent after age 70. But the effects of the TREM2 gene are more pronounced, rivaling or exceeding the impact of APOE-E4.
"The risk associated with this new variant is the largest seen to date and heralds the start of a new era in Alzheimer’s disease genetic research,” said Kevin Morgan, Professor of Human Genomics and Molecular Genetics at The University of Nottingham in the U.K., where some of the research was carried out. “At long last we are beginning to witness major breakthroughs that will hopefully result in therapeutic developments to help alleviate this devastating condition."
The TREM2 variant is rare, occurring in just 0.3 percent of people. By contrast, APOE-E4 is present in up to 25 percent of the population.
TREM2 is known to play a role in the immune system’s ability to fight off infection and illness. When the mutation in TREM2 is present, immune system cells in the brain become less able to repair damage or control inflammation. Inflammation in the brain is a well-recognized feature of Alzheimer’s and may occur early in the course of the disease.
The TREM2 defect may make it difficult for brain cells to clear beta-amyloid, the toxic protein that builds up in the brains of those with Alzheimer’s, the research suggests. As beta-amyloid accumulates, it forms hard barnacle-like plaques and brain cells are killed, leading to the hallmark loss of memory and thinking skills that characterize the dementia of Alzheimer’s.
While much more study is needed to delineate the role of TREM2 in brain health and Alzheimer’s, scientists are hopeful that the new findings may lead to new and more effective strategies for treating the disease. Finding new drugs that boost the beneficial effects of TREM2 on the immune system, for example, could help to delay the onset of Alzheimer’s symptoms.
Source: Thorlakur Jonsson, Ph.D., Hreinn Stefansson, Ph.D., Stacy Steinberg Ph.D., et al: “Variant of TREM2 Associated with the Risk of Alzheimer's Disease.” Rita Guerreiro, Ph.D., Aleksandra Wojtas, M.S., Jose Bras, Ph.D., et al: “TREM2 Variants in Alzheimer's Disease.” Harald Neumann, M.D., and Mark J. Daly, Ph.D.: “Variant TREM2 as Risk Factor for Alzheimer's Disease” (editorial). New England Journal of Medicine, published online, Nov. 14, 2012.