New Potential Drug Targets for Alzheimer Disease Identified
A recently published study in Nature Communications identified new potential drug targets for the treatment and prevention of Alzheimer disease (AD).
“All the evidence that we have indicates that there are many different pathways involved in the progression of Alzheimer,” said senior author Ernest Fraenkel, PhD, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, in a news release. “It is multifactorial, and that may be why it’s been so hard to develop effective drugs.”
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The first portion of the study involved a genome-scale forward genetic screen in fruit flies; researchers knocked out 5261 conserved genes to measure the effect of each gene on the age of neurodegeneration onset. After identifying 198 genes that promoted age-associated neurodegeneration, the researchers used a network integration model to combine the fruit fly data with additional data sets, including human genomic data from post-mortem AD patients, to determine the particular cellular pathways and processes associated with neurodegeneration.
An initial analysis revealed that several of the genes identified in the flies also declined with age in humans (p=1.14 ×10−5), which indicated that the genes may be involved in human neurodegeneration.
The researchers then used network optimization algorithms to identify pathways that connected each gene to a possible role in the development of AD. The first identified pathway was linked to the modification of ribonucleic acid (RNA); researchers found that when either the HNRNPA2B1 or MEPCE genes are missing from this pathway, neurons become more vulnerable to the Tau tangles which form in AD patients’ brains (1-way analysis of variance [ANOVA] with Tukey’s post-hoc correction p<0.05).
The second identified pathway was related to the repair of damaged deoxyribonucleic acid (DNA). In this pathway, missing NOTCH1 and CSNK2A1 genes were found to lead to a buildup of unrepaired DNA, which is also associated with neurodegeneration (1-Way Binomial Test p < 0.01).
In future studies, researchers aim to explore drugs that target these identified pathways in hopes of discovering treatment that can improve neuron health.
“The search for Alzheimer drugs will get dramatically accelerated when there are very good, robust experimental systems,” Fraenkel said. “We’re coming to a point where a couple of really innovative systems are coming together.”
The researchers also pointed out that similarly structured future studies could benefit treatment development for neurodegenerative diseases beyond AD. “The framework presented in this paper could be used to combine the screen hits with appropriate disease-specific data to search for disease-universal or disease-specific regulators across neurodegenerative diseases,” they concluded.
Reference
Scientists discover potential new targets for Alzheimer’s drugs. News release. EurekaAlert. May 20, 2025. Accessed May 20, 2025.
