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Researchers at the University of Buffalo have determined that a human gene present in 75% of the population is one of the main reasons why a clbad of drugs for Alzheimer's disease seemed promising in animal studies but has not been successful in human studies.
The researchers say that the work suggests that in different patients with Alzheimer's disease, different mechanisms are at work to determine whether a given treatment will be effective or not.
While an earlier study by researchers had studied the function of the gene in tissue culture, it is the first time that a drug effect based on the genotype of a patient is demonstrated clinically.
UB researchers point out that the study has its limitations and that double-blind randomized studies are needed to confirm the results.
The research was presented today at the annual Alzheimer Association (AAIC) annual conference in Los Angeles. It was conducted on data from a ten-year multicenter longitudinal cohort study conducted by the Texas Alzheimer's Research and Care Consortium (TARCC) on 345 Alzheimer's disease patients. UB researchers are collaborators of the TARCC.
Proof of concept
"This research provides irrefutable proof that, since different mechanisms are at work in Alzheimer's disease in different patients, we need to develop more personalized treatments that will prove more effective in individuals" said Kinga Szigeti, MD, Ph.D., senior researcher and director of UB. Center for Alzheimer's Disease and Memory Disorders, belonging to the UBMD Neurology, and Associate Professor of Neurology at the Jacobs Faculty of Medicine and Biomedical Sciences of UB.
The gene, CHRFAM7A, is a fusion between a gene that codes for an acetylcholine Alpha 7 receptor, a neurotransmitter involved in memory and learning and long badociated with Alzheimer's disease, and a kinase, a type of 'enzyme.
Szigeti explained that the gene is present in two flavors, a functional gene and a gene that is not transformed into protein, data that the UB team is also presenting this week at the AAIC.
"This divides the population 1 to 3 between non-carriers and carriers," Szigeti said. CHRFAM7A has been implicated in many neuropsychiatric disorders, such as schizophrenia and bipolar disorder.
Szigeti explained that three of the four drugs currently available for the treatment of Alzheimer's disease stimulated all receptors that respond to acetylcholine. More specific drugs for Alpha 7 have been in development for more than 10 years but failed when they entered the clinical phase.
The human fusion gene modulates the Alpha 7 receptor, one of the receptors for binding to amyloid beta, the protein that characterizes Alzheimer's disease and disrupts neuronal communication.
"As this human fusion gene was not present in animal models and in the screening systems used to identify drugs, 75% of Alzheimer's patients carrying this gene have fewer chances of being diagnosed." They are at a disadvantage, "she said. "This may explain the translation gap."
Gene carriers
"With this study, we compared the effect of cholinesterase inhibitors in patients with or without this gene," Szigeti said. "People who do not have the gene respond better to the drugs available now."
She added that neurons vulnerable to Alzheimer's disease express Alpha 7 and may be the reason they die first.
"Our work confirms that Alpha 7 is a very important target for the treatment of Alzheimer's disease, but that the right model, a human model, must be used to test new drugs," Szigeti said. .
The results suggest that a more personalized approach of each patient might be needed, depending on their CHRFAM7A genotype. One drug can work in 25% of patients, while another works in 75%.
The co-authors with Szigeti are Aya Ouf, MD, research badistant in the department of neurology; Joan S. Reisch, PhD, of the Southwestern Medical Center at the University of Texas; Valory Pavlik of Baylor College of Medicine; Gregory Wilding, PhD, Chair and Professor in the Department of Biostatistics, and Ziquiang Chen, both from the School of Public Health and Health Professions at UB.
The work was funded by the Alzheimer's Association, the Pilot Grant Program of the Clinical and Translational Science Award, the Edward A. and Stephanie E. Fial Fund, the Buffalo Grand Community Foundation, and Dr. Louis Sklarow Memorial Trust.
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