A new study provides solutions to the pressing need to identify factors that influence Alzheimer’s disease (AD) risk or resistance while providing an avenue to explore potential biological markers and therapeutic targets.
Published in the American Journal of Human Genetics by researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, the paper is the work of researchers who have integrated computational and functional approaches that enabled them to identify not only specific genes whose alterations predicted increased AD risk in humans and behavioural impairments in AD fruit fly models but also show that reversing the gene changes has a neuroprotective effect in living organisms.
“Alzheimer’s disease affects more than 50 million people worldwide and although researchers have learned a great deal about it over the years, its causes are still not fully understood and effective therapies are not yet available,” said study author Dr Juan Botas, Professor of Molecular and Human Genetics and Molecular and Cellular Biology at Baylor. Botas also is the director of the High-Throughput Behavioral Screening Core at the Duncan NRI.
Although extensive genome-wide studies have uncovered hundreds of genes potentially associated with the disease, assessing the roles these genes play in AD is necessary to distinguish those that confer risk for the condition from uninvolved bystanders.
“We addressed this issue by first integrating published genome-wide association data with multiple computational approaches to identify genes likely involved in AD,” said co-author Morgan C Stephens, a graduate student in the Botas laboratory. “We then tested those computational predictions experimentally.”
The researchers systematically perturbed AD candidate genes identified from their computational analyses and assessed their potential to modulate neuronal dysfunction and hallmark AD-related cellular alterations, such as neuropathology or accumulation of tau protein, in living organisms.
The computational analyses revealed 123 candidate genes for AD risk and the team confirmed that the expression of many of them is altered in human AD and correlates with the accumulation of tau or beta-amyloid protein in brain cells affected by the condition. Evaluation of 60 of these gene candidates available in fruit fly models pointed at 46 that modulated neuronal dysfunction in one or both fly models. The altered expression of 18 of these genes predicted the increase of AD risk in humans.
Importantly, reversing the alterations in 11 of these genes protected fruit flies from damage to their nervous system.
“In the list of final candidates, MTCH2 turned up to be at the top on the functional studies,” Stephens said. “MTCH2 expression is downregulated in human AD brain samples, and reducing its function in flies aggravates motor dysfunction. It was very exciting to find that restoring MTCH2 expression in flies reversed motor dysfunction and reduced tau accumulation in human neural progenitor cells in the lab. Our findings support further exploration of MTCH2 for therapeutic purposes and highlight the value of a combined computational and experimental approach to uncover main genetic players in Alzheimer’s disease and other neurodegenerative conditions,” Botas said.
- Stephens MC, Li J, Mair M, et al. Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease. Am J Hum Genet. Published online April 7, 2025. doi:10.1016/j.ajhg.2025.03.012