Genomic Data Analysis Uncovers 13 New Alzheimer’s Genes

A first-of-its-kind genomic data analysis revealed 13 new genetic variants associated with Alzheimer’s disease, according to a study conducted by researchers from Massachusetts General Hospital (MGH), Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center.

The research also established new genetic links between Alzheimer’s and the function of synapses, which are the junctions that send information between neurons, as well as neuroplasticity, which is the ability of neurons to reorganize the brain’s neural network.

Prior to these findings, the research team has discovered genes that cause early onset familial Alzheimer’s, including the amyloid protein precursor and the presenilin genes (PSEN1 and PSEN2). Mutations in these genes lead to accumulation of amyloid plaques in the brain, a hallmark of Alzheimer’s.

Researchers discovered 30 more gene variants that are primarily linked to chronic inflammation in the brain, which also increase the risk of Alzheimer’s. However, loss of synapses is the neurological change that is most closely correlated with the severity of dementia in Alzheimer’s disease.

Until now, no clear genetic links between the disease and these vital connections have been 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 the hospital's Genetics and Aging Research Unit at Massachusetts General Hospital.

Researchers noted that the genome-wide association study (GWAS) was the primary tool used for identifying Alzheimer’s genes. In GWAS, the genomes of many individuals are scanned in search of common gene variants that occur more frequently in people who have a given disease, like Alzheimer’s.

To date, common Alzheimer’s-associated gene variants have accounted for less than half of the heritability of Alzheimer’s. The team stated that a standard GWAS misses the rare gene variants – those occurring in less than one percent of the population – which can be solved by whole genome sequencing (WGS), a method that scans every bit of DNA in a genome.

"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, of MGH's McCance Center for Brain Health, who is lead author of the study.

It’s critical to identify less-common gene mutations that increase the risk for Alzheimer’s disease because they may hold important information about the biology of the disease, researchers noted. Of the three billion pairs of nucleotide bases that form a complete set of DNA, each person has 50 to 60 million gene variants – 77 percent of which are rare.

"Rare gene variants are the dark matter of the human genome," said Tanzi.

The team performed WGS analyses on the genomes of 2,247 individuals from 605 families that include multiple members who have been diagnosed with Alzheimer’s. Researchers also analyzed WGS datasets on 1,669 unrelated individuals.

Researchers identified 13 previously unknown rare gene variants associated with Alzheimer’s, and these gene variants were found to be associated with 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.

Researchers believe that their method could be used to study the genetics of other conditions as well. The team also plans to use three-dimensional cell culture models and brain organoids that they have developed over the past decade to discover what happens when these rare Alzheimer’s gene mutations are inserted in neurons.

"That could help guide us in novel drug discovery," said Tanzi.

The study from MGH, Harvard, and Beth Israel comes on the heels of new genetics research at UVA Health. A team from the UVA School of Medicine has conducted an analysis of the entire genetic makeup of 53,831 people of diverse backgrounds on different continents.

The study from the Trans-Omics for Precision Medicine (TOPMed) program offers a wealth of insights into heart, lung, blood, and sleep disorders. The findings could lead to the development of therapies that will better treat and prevent common causes of disabilities and death.

“The human genome project has generated a lot of promises and opportunities for applying genomics to precision medicine, and the TOPMed program is a major step in this direction,” said Stephen S. Rich, PhD, a genetics researcher at the School of Medicine who helped lead the project.

“An important feature of TOPMed is not only publishing the genomic data on 53,000 people with massive amounts of data related to heart, lung, blood and sleep disorders but also the great diversity of the participants who donated their blood and data.”