BOSTON – In the first study to discover rare genomic variants associated with Alzheimer’s disease (AD) using whole genome sequencing (WGS), researchers identified 13 such variants (or mutations). In another novel finding, this study establishes new genetic links between AD and the function of synapses, the junctions that carry information between neurons, and neuroplasticity, or the ability of neurons to reorganize the brain’s neural network. These discoveries could help develop new therapies for this devastating neurological condition. Researchers at Massachusetts General Hospital (MGH), Harvard TH Chan School of Public Health, and Beth Israel Deaconess Medical Center report these findings in Alzheimer’s & Dementia: The Journal of the Alzheimer Association.
Over the past four decades, MGH, under the direction of Dr. Rudolph Tanzi, deputy chairman of neurology and director of the hospital’s genetics and aging research department, pioneered research into the genetic origins of AD. In particular, Tanzi and colleagues jointly discovered genes that cause early-onset familial AD (before age 60) (that is, a form that occurs in families), including the amyloid protein (A4) precursor (APP) and the presenilin genes ( PSEN1 and PSEN2). Mutations in these genes lead to the accumulation of amyloid plaques in the brain, a hallmark of AD.
The next 30 AD gene variants discovered are mainly linked to chronic inflammation in the brain (or neuroinflammation), which also increases the risk of this cognitive disorder. However, the loss of synapses is the neurological change that most closely correlates with the severity of dementia in Alzheimer’s disease. So far, however, no clear genetic links have been established between the disease and these vital links.
It was always surprising that the entire genome had not identified any Alzheimer’s genes that were directly related to synapses and neuroplasticity.
Rudolph Tanzi, PhD
Prior to this work, the genome-wide association study (GWAS) was the main tool used to identify AD genes. In a GWAS, the genomes of many individuals are scanned in search of common gene variants that are more common in people with a specific disease, such as AD. So far, however, common Alzheimer’s-associated gene variants have accounted for less than half of the heritability of AD. A standard GWAS measures the rare gene variants (found in less than 1% of the population), a problem solved by the WGS, which scans every bit of DNA in a genome.
This paper takes us to the next stage in disease genes discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants that we couldn’t before.
Dmitry Prokopenko, PhD, of the MGH’s McCance Center for Brain Health, is the lead author of the study.
Identifying less common gene mutations that increase your risk for AD is important, as they may contain important information about the biology of the disease, Tanzi says. “Rare gene variants are the dark matter of the human genome,” he says, and there are many of them: Of the three billion pairs of nucleotide bases that make up a complete set of DNA, each person has 50 to 60 million gene variants – and 77% are Rare.
In search of rare AD gene variants, Tanzi, Prokopenko, and their colleagues performed WGS analyzes on the genomes of 2,247 people from 605 families, including multiple members diagnosed with AD. They also analyzed WGS records from 1,669 unrelated people. The study identified 13 previously unknown rare gene variants associated with AD. Strikingly, these gene variants were linked to the function of synapses, the development of neurons, and neuroplasticity.
We believe that with this study we have created a new template that goes beyond the standard GWAS and association of diseases with common genome variants and in which you miss much of the genetic landscape of the disease. There is potential for our methods to be used to study the genetics of many other diseases. In addition, we plan to use Alzheimer’s in a bowl – three-dimensional cell culture models and brain organoids that we have developed over the past decade – to study what happens when the rare mutations identified in this article are introduced into neurons. That could help us discover novel drugs
Rudolph Tanzi, PhD
Tanzi is Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School (HMS) and Co-Director of the McCance Center for Brain Health at MGH. Prokopenko is a lecturer in neurology at the HMS.
This study was supported by the Cure Alzheimer Fund and grants from the National Institutes of Health.
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Via the Massachusetts General Hospital
Founded in 1811, Massachusetts General Hospital is the original and largest teaching hospital for Harvard Medical School. The Mass General Research Institute runs the largest hospital research program in the country, with more than $ 1 billion in annual research activities and more than 9,500 researchers working in more than 30 institutes, centers, and departments. In August 2020, Mass General was named # 6 on the US News & World Report list of America’s Best Hospitals.