Experts Discover Five New Risk Genes for Alzheimer's

By Jane Farrell

Researchers report that they have discovered five new risk genes for AlzheimerΓÇÖs disease, while confirming others that are already known.

The international team of researchers, who analyzed results from more than 94,000 people, also reported for the first time that mutations in genes specific to the protein tau, a hallmark of AlzheimerΓÇÖs disease, may play an earlier role in the development of the disease than originally thought.

These new findings support growing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are ΓÇ£genetic hubsΓÇ¥ that are an important part of the disease process. The study, which was funded in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health (NIH), was published February 28, 2019 in the journal Nature Genetics.

ΓÇ£This continuing collaborative research into the genetic underpinnings of AlzheimerΓÇÖs is allowing us to dig deeper into the complexities of this devastating disease,ΓÇ¥ said Richard J. Hodes, M.D., director of the NIA. ΓÇ£The size of this study provides additional clarity on the genes to prioritize as we continue to better understand and target ways to treat and prevent AlzheimerΓÇÖs.ΓÇ¥

A key to these discoveries was the sample size, the largest to date for this kind of AlzheimerΓÇÖs study.

The researchers, members of the International Genomic AlzheimerΓÇÖs Project (IGAP), analyzed both rare and common gene variants in 94,437 individuals with late-onset AlzheimerΓÇÖs disease, the most common form of dementia in older adults. IGAP is made up of four consortia in the United States and Europe that have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting variations in the genome that are associated with AlzheimerΓÇÖs. Understanding genetic variants is helping researchers define the molecular mechanisms that influence disease onset and progression.

In addition to confirming the known association of 20 genes with risk of AlzheimerΓÇÖs and identifying five additional AlzheimerΓÇÖs-associated genes, investigators analyzed these genes to see what cellular pathways might be implicated in the disease process. The pathway analysis implicated the immune system, lipid metabolism and amyloid precursor protein (APP) metabolism. Mutations in the APP gene have been shown to be directly related to early onset AlzheimerΓÇÖs. The present study, done in late onset AlzheimerΓÇÖs subjects, suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant AlzheimerΓÇÖs and with late-onset AlzheimerΓÇÖs. In addition, for the first time, the study implicated a genetic link to tau binding proteins. Taken together, data suggest that therapies developed by studying subjects with early-onset disease could also be applied to the late-onset form of AlzheimerΓÇÖs.

Once the functions of the five genes newly associated with AlzheimerΓÇÖsΓÇöIQCK, ACE, ADAM10, ADAMTS1 and WWOXΓÇöare understood and examined in conjunction with the functions of the 20 known genes, researchers will be in a better position to identify where the genetic hubs of AlzheimerΓÇÖs are clustering. Armed with these findings, researchers can look more deeply into these genetic hubs to reveal disease mechanisms and potential drug targets.

A key to these discoveries was the sample size, the largest to date for this kind of AlzheimerΓÇÖs study. A large sample is especially important to find rare genes that might be involved with a disease.

ΓÇ£Having more and more samples in GWAS data sets is like adding more and more pixels to a photographΓÇöit helps researchers see details that they otherwise wouldnΓÇÖt and helps them decide where to focus further study,ΓÇ¥ explained Marilyn Miller, Ph.D., director of the Genetics of AlzheimerΓÇÖs Disease program in the Division of Neuroscience at NIA.

The research was led by a team of experts including Brian Kunkle, Ph.D. and Margaret Pericak-Vance, Ph.D., from the Miller School of MedicineΓÇÖs John P. Hussman Institute for Human Genomics at the University of Miami, and Benjamin Grenier-Boley, Ph.D. and Jean-Charles Lambert, Ph.D., from INSERM, Lille, France.