Largest Alzheimer’s study discovers 5 new genes of risk

Brain connect the dots graphic

An international team of researchers — including faculty of UT Health San Antonio — analyzed information from more than 94,000 individuals to arrive at new findings about the underlying causes of Alzheimer’s disease, including five new genes that increase Alzheimer’s risk.

The meta-analysis, which combines and reevaluates data collected by four consortia that make up the International Genomic Alzheimer’s Project (IGAP), appeared in the journal Nature Genetics on Feb. 28.

“I am very grateful to the neurology working group in the CHARGE consortium, which is one of the four pillars of IGAP,” said Sudha Seshadri, M.D., professor of neurology at UT Health San Antonio and founding director of the university’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases. “I am the principal investigator of this group that includes large NHLBI [National Heart, Lung and Blood Institute] studies: the Framingham Heart Study, the Cardiovascular Health Study and the Atherosclerosis Risk in Communities Study, as well as large European groups such as the Rotterdam Study and Fundacio ACE in Barcelona, Spain. Colleagues from all these groups were in San Antonio this week for the South Texas Alzheimer’s Conference.”

This unprecedented project, funded in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health (NIH), scrutinized more genetic data than any other study of Alzheimer’s disease to date. Collaborative data sharing enabled the scientists to discover five novel genetic variants or changes that influence the risk for Alzheimer disease.

Common features found between early- and late-onset disease

The researchers, all IGAP members, including Dr. Seshadri and lead authors, Drs. Brian Kunkle and Margaret Pericak-Vance at the University of Miami and Drs. Benjamin Grenier-Boley and Jean-Charles Lambert from INSERM, Lille, France, also made other landmark breakthroughs. For example, they uncovered how the existence of specific changes (variants) in genes that bind to a protein called “tau” may affect disease development at an earlier stage than previously thought. They also revealed a formerly unknown common feature between early-onset and late-onset Alzheimer’s disease (i.e., how certain proteins called amyloid precursor proteins are broken down). The latter finding suggests that some therapies developed for early-onset disease may also work for late-onset disease.

Examination of genetic hubs in Alzheimer’s

The researchers examined not just what the genes convey independently, but how they build on each other and interact with the environment. The new findings from this study support the idea that groups of genes linked to specific biological processes work in tandem to control functions that affect disease development. For example, amyloid processing, tau binding, lipid transport, inflammation and immune response appear to be controlled by “genetic hubs.”

Once the functions of the five genes newly associated with Alzheimer’s disease—IQCK, ACE, ADAM10, ADAMTS1 and WWOX—are understood and examined in conjunction with the functions of other genes known to influence risk, scientists will be in a better position to identify where the genetic hubs of Alzheimer’s disease are clustering. Armed with these findings, researchers can look more deeply into these genetic hubs to reveal disease mechanisms and potential drug targets.

Study suggests rare risk variants are more impactful than previously thought

The study also revealed that rare variants, which occur at a frequency of less than 1 percent in a population, likely play an important role in Alzheimer’s disease. The researchers discovered this by showing that common risk variants (genetic variants found in more than 1 percent of a population) and rare risk variants for Alzheimer’s disease tend to be found in the same genes and hubs. While several rare variants have been previously linked to increased risk of the disease, this is the first study to show that many more rare risk variants exist, and they are most likely to be found in the same genes and hubs that contain common risk variants. Identifying and confirming these rare risk variants will be a significant step forward for the creation of personalized screening strategies and better-informed drug development for Alzheimer’s disease.

Follow-up studies at Glenn Biggs Institute, Sam and Ann Barshop Institute

“It is important to follow up on these genetic discoveries with functional work, and the Glenn Biggs Institute, partnering with the Sam and Ann Barshop Institute for Longevity and Aging Studies, also at UT Health San Antonio, is emerging as one of the strong groups in tau research, with six researchers working on various aspects of tau biology in relation to DNA regulation, tau propagation across synapses and through glia, and tau effects on blood vessels, on senescence and on mTOR pathways. [mTOR stands for mechanistic target of rapamycin.] Such follow-up studies accelerate the translation from genetic discoveries to effective therapies. We have been funded for pilot drug studies in three of these approaches.”

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