Researchers from Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have developed an innovative machine-learning method called Evolutionary Action Machine Learning (EAML), which discovers sex-specific genes and molecular pathways that could contribute to Alzheimer’s Disease (AD) development and progression. The breakthrough study was published in Nature Communications.
EAML is an ensemble computational approach that includes nine machine learning algorithms to analyze functional impacts of non-synonymous coding variants on biological processes, with the EA score as a feature to identify genetic elements that might influence AD differently between men and women.
Analysis of 2,729 AD patients and 2,441 control subjects led to the identification of 98 genes that seemed related to AD. After verifying their findings by testing the homologs of these genes with two fruit fly models of AD, the team was able to unearth 36 genes that could modulate tau-induced degeneration and 29 that could modulate Aβ42-induced neurodegeneration. Furthermore, when EAML was applied separately to males and females, 157 AD-associated genes were identified in males and 127 in females.
The Baylor team’s study also showed that certain biological pathways may have a greater impact on AD for one sex than another. For instance, female-specific EAML candidates were associated with cell cycle control and DNA quality control, possibly connecting AD and breast cancer, two diseases more common among women.
Most impressively, the team was able to find valuable conclusions even when their sample size was reduced, proving the efficiency of machine learning and the EA score to identify genetic factors in complex diseases.
The findings of the Baylor College of Medicine team suggest that sex-specific analyses are a crucial factor in determining the causes of complex diseases and for designing stratified clinical trials.
The main figures behind this important study include Olivier Lichtarge, MD, Ph.D., professor of biochemistry and molecular biology at Baylor College of Medicine, Ismael Al-Ramahi, Juan Botas and their teams at the Center for Alzheimer’s and Neurodegenerative Diseases and Duncan NRI. The study was funded by grants from the National Institutes of Health. By leveraging cutting-edge scientific innovations, the study was able to provide a detailed assessment of the genetic influences of AD with the potential to revolutionize the understanding and treatment of this debilitating disease.
