Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have used fruit flies to study the effects of human Alzheimer’s disease risk genes on brain function. Their findings, published in the American Journal of Human Genetics, shed light on how these genes may contribute to Alzheimer’s disease.
“We studied fruit fly versions of 100 human Alzheimer’s disease risk genes,” said Dr. Jennifer Deger, a neuroscience graduate in Baylor’s Medical Scientist Training Program (M.D./Ph.D.), mentored by Drs. Joshua Shulman and Hugo Bellen. “We developed fruit flies with mutations that ‘turned off’ each gene and determined how this affected the fly’s brain structure, function and stress resilience as the flies aged.”
Fruit flies are often used in genetic research because most human genes have counterparts in these insects, allowing for the study of gene functions within a living organism. Their short lifespan also makes them suitable for aging studies relevant to diseases like Alzheimer’s.
Dr. Joshua Shulman, professor at Baylor and co-director of the Duncan NRI, noted that their results showed many risk genes are active in adult fly brains: “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.”
Deger added that they identified numerous candidate risk genes affecting both brain structure and function: “Overall, we 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.”
Shulman pointed out one example from their findings: “One standout example was the gene Snx6, the fly version of human SNX32. When this gene was turned off, the flies developed holes in their brain tissue – a sign of neurodegeneration.”
The team also observed changes related to neural activity and stress response. Thirty-five genes were necessary for proper neuron electrical activity while eight were important for stress recovery; disabling these resulted in symptoms like seizures or paralysis after heat or mechanical shock exposure.
To further understand these effects, researchers tested whether any of these genes influenced damage caused by amyloid-beta or tau proteins—both linked to Alzheimer’s pathology. “Twenty-eight of the genes changed how the flies responded to amyloid-beta or tau, either making the damage worse or helping protect against it,” Deger said.
Patterns emerged when grouping these genes based on their impact—such as structural damage or impaired stress recovery—and comparing them with genetic data from patients with Alzheimer’s disease. Shulman explained: “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... 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.”
The team has launched an online portal called ALICE (Alzheimer’s Locus Integrative Cross-species Explorer) at https://alice.nrihub.org/ where researchers can access functional data generated from this study.
This project involved contributions from several scientists affiliated with Baylor College of Medicine and/or Duncan NRI. Funding came from multiple National Institutes of Health grants as well as support from organizations such as Baylor Research Advocates for Student Scientists and BrightFocus Foundation.
