Researchers Identify New Risk Factor for Alzheimer’s Disease, ALS

April 28, 2020 - Researchers at the HudsonAlpha Institute for Biotechnology, the University of California, San Francisco (UCSF), and the University of Alabama at Birmingham (UAB) have uncovered a new genetic risk factor for multiple neurodegenerative conditions, including Alzheimer's disease.

For the study, published in the American Journal of Human Genetics, researchers sequenced and analyzed whole genomes of more than 1,100 people. The team collected the majority of the samples used in the project from the UCSF Memory and Aging Center and sequenced and analyzed the samples at HudsonAlpha.

Once the group had the sequencing results, they analyzed the genomes of 493 people with either Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), or frontotemporal dementia (FTD) and 671 healthy people. Many of the patients had early-onset versions of neurodegenerative disease, suggesting that it’s more likely that there would be a genetic component of their illness.

During genome analysis, researchers examined both coding and non-coding regions of the genome for DNA sequence variants. The team found that a rare variation in the gene TET2 nearly doubled the risk of developing conditions like Alzheimer’s disease, ALS, and FTD.

“We didn’t go in with any suspicions about what we might [get], so we’re excited that we did find a new genetic association here,” said first author Nicholas Cochran, PhD.

TET2 encodes a protein that catalyzes DNA demethylation. Previous work has demonstrated that changes in DNA methylation happen during aging, so the team hypothesized that mutations in the gene could lead to a faulty TET2 protein that disrupts how the brain ages and contributes to the development of neurodegenerative diseases.

“Sometimes we get a hit, and it’s hard to understand what it might be doing, but TET2 already has established roles in the brain. So this finding really made sense,” Cochran explained.

After identifying TET2, the team looked at previously generated genetic data from more than 32,000 healthy people and people with neurodegenerative diseases. The data confirmed that variants in TET2, in both protein-coding and non-coding regions, were more likely to be present in the genomes of people with ALS, Alzheimer’s, or FTD than in people without these diseases.

"Finding evidence for a risk factor that contributes to multiple neurodegenerative diseases is exciting," said Richard M. Myers, PhD, HudsonAlpha president and science director. "We already know that these diseases share some pathologies. This work shows that the underlying causes of those pathologies may also be shared."

The researchers acknowledged that the organizations’ partnerships were what propelled the study forward. Next, the team plans to focus on how changes in TET2 levels or function could contribute to aging and neurodegenerative disease.

“The project wouldn’t have been possible without extensive collaboration between institutions,” said Cochran, who is a senior scientist in the Myers Lab. “You end up being able to find things that you can’t find working alone.”

Recently, researchers have increasingly focused on the impact of genetic variants in disease development. A team from the University of Chapel Hill (UNC) School of Medicine just discovered that rare structural variants could play a role in the development of schizophrenia. The finding could accelerate precision medicine therapies and improve outcomes for patients with schizophrenia.

“Our results suggest that ultra-rare structural variants that affect the boundaries of a specific genome structure increase risk for schizophrenia,” said Jin Szatkiewicz, PhD, associate professor in the UNC Department of Genetics.

“Alterations in these boundaries may lead to dysregulation of gene expression, and we think future mechanistic studies could determine the precise functional effects these variants have on biology.” 

These studies reflect the potential for genetics and genomic research in healthcare. Patients are on board with these innovative areas as well: A survey from the American Society of Human Genetics (ASHG) in partnership with Research!America showed that 77 percent of Americans are optimistic about human genetic research, with individuals expressing interest in what genetics can tell them about human history and heritage.

“When it comes to human genetics, the US public is supportive of research, believes more research is needed, and believes it’s important to national health and their families’ health,” said ASHG President Anthony Wynshaw-Boris, MD, PhD. “It’s exciting how curious and hopeful Americans are about this fast-paced area of research.”