Scientists at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital have used fruit flies to gain new insights into how genes linked to Alzheimer’s disease may affect the brain. Their study, published in the American Journal of Human Genetics, involved examining 100 fruit fly versions of human Alzheimer’s risk genes.
“We studied fruit fly versions of 100 human Alzheimer’s disease risk genes,” said Dr. Jennifer Deger, a neuroscience graduate student in Baylor’s Medical Scientist Training Program, 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 commonly used in genetic research because most human genes have counterparts in these insects. Their short lifespan allows researchers to quickly observe effects related to aging and neurodegenerative diseases.
Dr. Joshua Shulman, professor at Baylor and co-director of the Duncan NRI, said, “We were very excited about the results. 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, “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.”
“One standout example was the gene Snx6, the fly version of human SNX32,” Shulman explained. “When this gene was turned off, the flies developed holes in their brain tissue – a sign of neurodegeneration.”
The team also found that some genes were essential for normal electrical activity in neurons or for recovering from stress such as heat or mechanical shock; turning off these genes led to seizures or paralysis.
They further tested whether these genes affected how flies responded to amyloid-beta or tau proteins—both associated with Alzheimer’s pathology. Deger noted: “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.”
Researchers grouped these risk genes based on their effects—structural damage, functional impairment or poor stress recovery—and compared them with genetic data from people with Alzheimer’s disease.
Shulman stated: “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.”
To help other scientists access their findings quickly and support future research efforts on Alzheimer's genetics across species models like fruit flies and humans alike, they created an online portal called ALICE (Alzheimer's Locus Integrative Cross-species Explorer), available at https://alice.nrihub.org/.
Other contributors included researchers affiliated with Baylor College of Medicine and/or Duncan NRI: 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 , Hugo Bellen .
Funding came from several National Institutes of Health grants as well as support from organizations such as Baylor Research Advocates for Student Scientists; Robert and Janice McNair Foundation; Southern Star Medical Foundation; BrightFocus Foundation.
