Recently, for the first time, researchers used a cutting-edge technique known as whole genome sequencing (WGS) to hunt for rare genomic variants associated with Alzheimer’s disease (AD), and they successfully identified 13 previously unknown Alzheimer’s genes. In addition, the researchers discovered that the gene variants are associated with synaptic function, neural development, and neuroplasticity. Using these innovative discoveries, researchers may be able to set novel targets for the development of new drugs and therapies for AD.
Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the study involved researchers sequencing the whole genomes of 2,247 individuals from 605 families that included multiple members diagnosed with AD. The study was then replicated using WGS datasets from 1,669 unrelated individuals. Through their analysis, the researchers discovered 13 rare gene variants associated with AD. Remarkably, these gene variants were associated with the functioning of synapses, the development of neurons, and neural plasticity, while previously discovered Alzheimer’s genes have been associated with amyloid accumulation and neuroinflammation.
The study received support from the Cure Alzheimer’s Fund as well as the National Institutes of Health, and the researchers were from Massachusetts General Hospital (MGH), the Harvard T.H. Chan School of Public Health, and Beth Israel Deaconess Medical Center.
Why Is It Important to Identify Rare Gene Variants?
Prior research used genome-wide association studies (GWASs) to identify Alzheimer’s genes. During a GWAS, researchers scan the genome of participants, searching for common gene variants that occur more frequently in people with a specified disease, such as AD. The issue with this form of research is that, thus far, common genomic variations associated with AD account for less than half of the heritability of AD. A standard GWAS fails to identify rare gene variants, which are described as those variants occurring in less than 1 percent of the population. Because this new study employed WGS, which scans the entirety of a genome’s DNA sequence, the researchers were able to discover novel rare genomic mutations.
Why is it important to identify uncommon gene variants associated with AD? According to one of the authors of the study, Rudolph Tanzi, PhD, vice chair of Neurology and director of MGH’s Genetics and Aging Research Unit, rare gene variants may provide crucial information about the biology of AD. Plus, they’re plentiful: Every human has 50 to 60 million genomic variations, and 77 percent of those variants are rare.
How Might These Newly Discovered Alzheimer’s Genes Impact Future Research?
What does the future hold? Tanzi stated, “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.” Over the past decade, Tanzi and his colleagues have created 3D cell culture models and brain organoids, and they plan to use these tools to discover what happens when they insert the 13 newly discovered genetic mutations into neurons.
How else might scientists use these discoveries? They could begin studying the prevalence of these 13 novel rare gene variants in the general population. They could also study these gene variants in animal models, evaluating how they impact brain function. In addition, other researchers may be inspired to use WGS to study other neurological conditions.
AD is not caused by one specific gene, and through this research, scientists are learning more about the genetic variations that increase a person’s risk of developing AD. The discovery of these 13 new gene variants could help guide and support the development of new therapies for AD.
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