Researchers Identify New Genes That Could Play Key Role in Development of Alzheimer’s

Research into developing a treatment for Alzheimer’s disease has proven to be incredibly difficult, with multiple companies reporting failure after failure of therapies in the clinic, particularly those focused on amyloid plaques.

A new study, though, could help lead to the potential development of a treatment for the dreaded neurological disease. An analysis of the genetics of nearly 95,000 people across the United States and Europe who have been diagnosed with Alzheimer’s disease has led to the discovery of four new genetic variants in the body that can increase the risk of developing the form of dementia. According to the study, which was published in Nature Genetics, the risk for late-onset Alzheimer’s disease (LOAD) is partially driven by genetics. Researchers said these four new genes work in tandem with 20 previously-known genome-wide significant common variant signals. That is in addition to signals from the ApoE4 gene, which is involved with the transportation of cholesterol and is considered one of the most significant risk factors for Alzheimer’s.

“We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s,” the researchers said in Nature Genetics.

With these new genome-wide loci having been identified, the work now begins to understand how those function and related to the development of Alzheimer’s disease.

“The enrichment of rare variants in pathways associated with Alzheimer’s disease indicates that additional rare variants remain to be identified, and larger samples and better imputation panels will facilitate identifying them. While these rare variants may not contribute substantially to the predictive value of genetic findings, they will enhance the understanding of disease mechanisms and potential drug targets. Discovery of the risk genes at genome-wide loci remains challenging, but we demonstrate that converging evidence from existing and new analyses can prioritize risk genes,” the researchers wrote in the conclusion of the article.

Richard Isaacson, who directs the Alzheimer's Prevention Clinic at Weill Cornell Medicine, told CNN that the data presented in the study is another step forward in the understanding of Alzheimer’s disease. He told CNN that the discovery of these four new genes will allow clinicians to target those genes as they continue to attempt treatment options. Also, Isaacson said the new genetic discoveries provide researchers “a greater insight to potential causes of Alzheimer’s.”

The study, which was led by researchers from the University of Miami's Hussman Institute for Human Genomics, is a follow up to a 2013 genome-wide association study that identified 11 gene locations that had not previously been known to be associated with the development of Alzheimer’s, CNN said.

Margaret Pericak-Vance, director of the Hussman Institute, noted the complexity of Alzheimer’s. In an interview with CNN, she noted that it’s not like some other genetic-associated diseases like Huntington’s or Parkinson’s, “where one gene is altered and you get the disease.”

"With Alzheimer's, it's multiple genes acting together. We were trying to get at the very rare gene variants that could contribute to Alzheimer's. And we couldn't do that before. We just didn't have the sample size to do it,” she noted.

Harvard professor of neurology Rudy Tanzi, director of the Alzheimer's Genome Project and a member of the research team also told CNN that this study validated the role of amyloid and immune system genes in the development of Alzheimer’s. The study could renew interest in that area, despite some of the failures to target it.

In January, Tanzi told BioSpace that he did not believe the amyloid theory had been invalidated.

“I think amyloid and tangles trigger the disease, but they’re not sufficient to cause dementia. In a nutshell, what we’ve learned is that amyloid comes very early, 15 years before symptoms. And all the genetics tells us this disease begins with amyloid,” Tanzi said.

He added that the tangles and amyloid plaque are the precursors, which lead to neuroinflammation, which he said is what kills the neurons and leads to dementia.