Patient Genotyping May Turn Failed Alzheimer’s Drugs Into Successful Ones

Oct 17, 2020 | Alzheimer’s Disease, CNS, News, UBMD, University of Buffalo

Patient Genotyping May Turn Failed Alzheimer’s Drugs Into Successful Ones

On October 6, UBMD Medical Group published “Patient Genotyping: Potential Key to Treating Alzheimer’s,” arguing that prior trials that found no benefit for Alzheimer’s medicines need to be re-examined in light of new discoveries in genotyping and a recent study on gene CHRFAM7A. Previous research had shown that the gene, unique to humans but not active in everyone, can determine if someone will respond to “three out of the four Alzheimer’s disease treatments approved by the Food and Drug Administration that increase acetylcholine, a neurotransmitter involved in learning and memory.” This prior work suggested why drugs targeting the alpha 7 nicotinic receptor, which looked positive in mice studies, failed to benefit human trials. 

Gene Turned Off in 25% Who May Benefit

“This uniquely human gene modifies the alpha 7 nicotinic receptor, and as a consequence, drugs that are optimized in mice are insufficient for 75 percent of the population that has the active CHRFAM7A gene and the humanized receptor,” according to Dr. Kinga Szigeti, who practices at UBMD Neurology and is one of the study authors. “This underlying, previously unknown genetic heterogeneity, especially with this ratio, undermined drug development efforts,” she said. “Our data indicate that drugs that target the nerve cells in which acetylcholine acts as a neurotransmitter, known as the cholinergic system, may benefit 25 percent of the individuals, and now we can identify who they are.” Dr. Szigeti continued, “For Alzheimer’s, if we can treat 25 percent of patients, that is 1.5 million people,” says Szigeti. “That would be a major advance.”

Different Drug for Different Alzheimer’s 

In the CHRFAM7A study, researchers took skin cells from Alzheimer’s patients and created pluripotent stem cells. “This system that we created models the 25 percent of patients who could respond to the cholinergic drugs that supposedly failed in clinical trials,” reports Szigeti. “This is the best evidence so far that those clinical trials should be reanalyzed,” she said. Quoting UBMD, “The research also provides evidence that individualizing treatment to patients’ genotypes will be key to attacking Alzheimer’s disease. The paper reports that this is the first proof of concept study that genotype and mechanism-specific treatment is feasible in Alzheimer’s disease.” The scientists think that, like cancer, Alzheimer’s may “represent a number of diseases, each of which will require its own targeted treatment.” And a simple blood test will be able to determine whether a patient will respond to a given drug. Szigeti noted that the findings can be validated inexpensively by reanalyzing completed trials.

UBMD is the biggest medical group in Western New York, with more than 500 doctors in 18 specialties. All UBMD’s doctors teach at the Jacobs School of Medicine and Biomedical Sciences at the University at BuffaloDr. Szigeti uses genetic tools to find new risk factors and possible pathways that can be targeted to prevent or stop Alzheimer’s. Her focus “is translating discoveries made in the laboratory into improved methods of disease prevention, diagnosis, and treatment.”


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