Fruit Flies Offer New Insights into How Human Alzheimer’s Disease Risk Genes Affect the Brain

HOUSTON (Oct. 30, 2025) – Scientists have identified hundreds of genes that may increase the risk of developing Alzheimer’s disease but the roles these genes play in the brain are poorly understood. This lack of understanding poses a barrier to developing new therapies, but in a recent study published in the American Journal of Human Genetics, researchers at Texas Children’s Duncan Neurological Research Institute (NRI) and Baylor College of Medicine offer new insights into how Alzheimer’s disease risk genes affect the brain. 

In the study, researchers examined fruit fly versions of 100 human Alzheimer’s disease risk genes to determine how these genes influence brain structure, function and stress resilience during aging. By selectively “turning off” each gene in the flies, the team was able to observe how the loss of these genes impacted brain health over time.

These tiny insects, known scientifically as Drosophila melanogaster, have long been used in genetic research and are invaluable for studying brain function. Fruit flies might seem far removed from humans, but scientists have found that most human genes have counterparts in fruit flies, allowing researchers to explore how these genes work in a living organism. In addition, the fly’s short lifespan (only 10 weeks) makes it an ideal model to study human conditions of old age like Alzheimer’s disease. 

“We were very excited about the results,” said Dr. Joshua Shulman, co-director of the Duncan NRI at Texas Children’s. He also is co-corresponding author of the work. “We found that most of the genes are expressed in the adult fly brain, including 24 specifically expressed in neurons and 13 in glia, another type of brain cell.”

Overall, the research identified 50 candidate Alzheimer’s disease risk genes in flies that were involved in both brain structure and function, including 18 that caused possible neurodegeneration when turned off.

“One standout example was the gene Snx6, the fly version of human SNX32,” Shulman said. “When this gene was turned off, the flies developed holes in their brain tissue – a sign of neurodegeneration.”

In addition, the team found that 35 genes were required for proper electrical activity of neurons and eight for the ability of the flies to recover from stress. When these genes were turned off, the flies showed signs of seizures or paralysis after being exposed to heat or mechanical shock.

The researchers also tested whether the genes influenced the toxic effects of two proteins – amyloid-beta and tau – which build up in the brains of people with Alzheimer’s. They found that 28 of the genes changed how the flies responded to amyloid-beta or tau, either making the damage worse or helping protect against it.

Beyond identifying individual genes, the researchers looked for patterns. They grouped the genes according to the type of brain problem they caused – structural damage, functional impairment or poor stress recovery. Then, they compared these groups to genetic data from actual patients with Alzheimer’s disease.

“Different people seemed to carry risk genes from different groups. Some had genetic changes linked to brain structure problems, while others had genetic variations tied to stress resilience,” Shulman said. “This suggests that different individuals may develop Alzheimer’s disease through distinct biological pathways. This idea – called ‘causal heterogeneity’ – could help explain why Alzheimer’s looks different from person to person and why some treatments work for some people but not others.”

To accelerate the study of Alzheimer’s risk genes, the team created a portal called ALICE, or Alzheimer’s Locus Integrative Cross-species Explorer, at https://alice.nrihub.org/, where users can access the functional data generated in this study for their own investigations.

Other contributors to this work include Jennifer M. Deger, Shabab B. Hannan, Mingxue Gu, Colleen E. Strohlein, Lindsey D. Goodman, Sasidhar Pasupuleti, Zahid Shaik, Liwen Ma, Yarong Li, Jiayang Li, Morgan C. Stephens, Michal Tyrlík, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Chad A. Shaw, Oguz Kanca and Hugo Bellen. The authors are associated with the Duncan NRI and/or Baylor College of Medicine.

This work was supported by National Institutes of Health grants (T32GM136611, F31NS129062, R01AG074009, R01AG073260, R24OD031447, U01AG072439, T32NS043124, P50HD103555 and U54HD083092). Additional support was provided by Baylor Research Advocates for Student Scientists, the Robert and Janice McNair Foundation, Southern Star Medical Foundation and the BrightFocus Foundation (Postdoctoral Fellowship Program in Alzheimer’s Disease Research, A2021008F). 

About Texas Children’s 

Texas Children's, a nonprofit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children's hospital in Texas and among the top in the nation, Texas Children's has garnered widespread recognition for its expertise and breakthroughs in pediatric and women's health. The system includes the Texas Children's Duncan NRI; the Feigin Tower for pediatric research; Texas Children's Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children's Hospital West Campus, a community hospital in suburban West Houston; Texas Children's Hospital The Woodlands, the first hospital devoted to children's care for communities north of Houston and Texas Children's Hospital North Austin, the new state-of-the-art facility providing world-class pediatric and maternal care to Austin families. The organization also created Texas Children's Health Plan, the nation's first HMO focused on children; Texas Children's Pediatrics, the largest pediatric primary care network in the country; Texas Children's Urgent Care clinics that specialize in after-hours care tailored specifically for children; and a global health program that is channeling care to children and women all over the world. Texas Children's Hospital is affiliated with Baylor College of Medicine. For more information, visit www.texaschildrens.org.