NEW FINDINGS — NEUROLOGY
Neurodevelopmental gene discovered
Age of onset and Alzheimer’s disease
New hope in the search for Alzheimer's disease treatment Since Alzheimer’s disease was first formally defined in 1901, there have been virtually no effective treatments. Most existing drugs may temporarily improve symptoms, but none target the underlying mechanism of the disease. One hallmark of Alzhei- mer's is the abnormal build-up of protein fragments within and between neurons, which causes irreversible damage. Studies show that lower levels of two proteins, beta-amyloid and tau, may slow disease progression. Newer therapies focus on remov- ing these proteins by various mechanisms, including antibodies. Antibodies are a natural part of our immune systems and bind to harmful proteins to destroy them. In January 2023, researchers and physicians presented findings from an 18-month phase 3 trial of the beta-amyloid REFERENCE: Hiatt, S.M., et al. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype. The American Journal of Human Genetics (2023) 110:(2), 215 - 227. doi: 10.1038/s41586-023-06254-7 The laboratory of HudsonAlpha faculty researcher Greg Cooper, PhD contributed to this work. More details can be heard at the Tiny Expedition podcast at this link https://www.hudsonalpha.org/an-exploration-of- neurodegenerative-diseases/ Approximately 1-3% of children are affected with neurodevelop- mental disorders (NDDs), including developmental delays and intellectual disability. A majority of these conditions are thought to be genetic in origin. Over the past decade, advances in genetic and genomic testing have led to increased rates of diagnosis for children with NDDs, but over 50% of affected children and their families still do not have an answer. A recent project, hinging on data-sharing between 48 different research groups and clinical institutions, described a new NDD caused by genetic changes in the ZMYM3 gene. This work started with a submission to the online GeneMatcher ® database in 2018. Over the next four years, the team collected information on 27 individuals with NDDs who had potentially disease-causing variations in the ZMYM3 gene. What emerged was a consistent set of symptoms that defined a new X-linked neurodevelopmental disorder. Males with disease-causing variants in ZMYM3 were found to have developmental delays and/or intellectual disabilities, autism or autistic features, and atypical facial features. A small- er number also had genitourinary anomalies, short stature, and small head size. A smaller number of affected females were also described with developmental delays and atypical facial features. All variants identified were rare and predicted by protein modeling to be deleterious. Electronic databases, like GeneMatcher, are accelerating genetic discovery, providing an avenue for collaboration and information sharing between scientists across the globe. n
About one in every ten people over the age of 65 is diag- nosed with Alzheimer’s disease (AD). For one large family in Antioquia, Colombia, in South America, the number is far higher; thousands of individuals are affected with rare autosomal dominant early-onset AD. They carry the same variant in the PSEN1 gene. This genetic change, called E280A, dates to the time of the conquistadors and was likely introduced by a single European individual. Family members who inherit the variant have a nearly 100% chance of developing dementia, with an average age of onset of 49 years old. A new study sought to identify other genetic factors in these individuals that could contribute to differences in the age of onset of AD within this large family. The team used DNA samples from 340 affected people whose age of onset was documented in their medical records. Genetic data from this group was compared to other groups with autosomal dominant AD and groups with more typical AD. Scientists identified 13 genetic variants that appear to contribute to differences in age of onset, even among indi- viduals with the same E280A variant. The identified variants are in or near genes associated with how the brain pro- cesses proteins involved in Alzheimer’s disease symptoms, like tau and amyloid-beta. In Alzheimer’s, abnormal levels of these proteins build up, causing damaging plaques and tangles that are hallmarks of the disease. This study identified new genetic factors associated with differences in age-of-onset of dementia. These factors provide a starting point for additional studies on the genetic mechanisms of AD and potential avenues for treatment. n REFERENCE: J. Nicholas Cochran, et.al., Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred. Alzheimer's and Dementia (2023) 19(9): 3835-3847. doi.org/10.1002/alz.13021
The laboratory of HudsonAlpha faculty researcher Nick Cochran, PhD, contributed to this work.
antibody Lecanemab in individuals in the early stages of Alzheimer’s disease. The antibody can bind to beta-amyloid before and after it forms plaques and helps remove it from the body. Data showed that the drug significantly reduced levels of beta-amyloid in the brains of those on treatment compared to placebo. There was a moderate but measurable effect on the decline of cognition and function. However, some of the treated individuals had adverse side effects. In July 2023, the FDA approved Lecanumab based on the results of this trial, making it the first new AD drug to be granted traditional approval in over 20 years. This research and approval pave the way for similar treatments for AD, which may change the course of disease for millions of people. n
REFERENCE: van Dyck, C.H., et al., Lecanemab in early Alzheimer’s disease. N Engl J Med (2023) 388:9-21. doi: 10.1056/NEJMoa2212948
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