Researchers find new links to Alzheimer's

U.S. scientists find 13 new mutations that provide clues to the development of devastating neurological diseases.

Nick Beare 3 minute read April 2, 2021
Asian doctor looking at brain xray

Researchers have uncovered new mutations that suggest link to Alzheimer's disease. GETTY

Researchers in Boston have made potentially ground-breaking discoveries that could lead to the development of new therapies for Alzheimer’s disease (AD).

In a first-of-its-kind study, researchers at Massachusetts General Hospital, the Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center used whole genome sequencing (WGS) to try and find rare genomic variants associated with AD and found 13 such variants (or mutations).

The study also established new genetic links between AD and synapses, which are the structures that transmit information between neurons, and neuroplasticity, or the ability of neurons to reorganize the brain’s neural network.

The genetic origins of AD have been studied for years and previous studies have uncovered the genes that cause early onset familial AD (the form that runs in families), and the genes that cause the buildup of amyloid plaques in the brain, a distinctive feature of AD. Dozens of other AD genes have been identified as well, most of those relating to inflammation in the brain, which increases the risk of developing the devastating neurological condition. But what sets this study apart is the discovery of a genetic link between the loss of synapses and the development of AD which had not been previously identified.

“It was always kind of surprising that whole-genome screens had not identified Alzheimer’s genes that are directly involved with synapses and neuroplasticity,” said Rudolph Tanzi, PhD, vice chair of Neurology and director of Massachusetts General Hospital’s Genetics and Aging Research Unit.

Before this study, the genome-wide association study (GWAS) was the primary tool used for identifying AD genes. In that method, researchers study a large group of people with a given disease (such as AD) and try to find genes that are common among the group. The problem with that method is it misses the rare genetic differences that are picked up by a WGS. Identifying those rare mutations is increasingly important not only because they may uncover new information about the biology of the disease, but because of the sheer volume of genetic variants each person has. Of the three billion pairs of nucleotide bases that form a complete set of DNA, each person has 50 to 60 million gene variants —and 77 per cent are rare.

“This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn’t do before,” said Dmitry Prokopenko, PhD, the study’s lead author.

To find those 13 new variants, Prokopenko, Tanzi and their colleagues analyzed the genomes of 2,247 individuals from 605 families, including multiple members who have been diagnosed with AD. They also analyzed WGS datasets on 1,669 unrelated individuals. All 13 variants were associated with the functioning of synapses, development of neurons, and neuroplasticity.

“With this study, we believe we have created a new template for going beyond standard GWAS and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease,” said Tanzi. He added that these new methods could also be used to discover new information about other diseases. The researchers also plan to take this study a step further and see what happens when they insert the newly discovered mutations into neurons. “That could help guide us in novel drug discovery,” said Tanzi.

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