Beyond Amyloid: MIT Uncovers Alternative Alzheimer’s Pathways Using AI and Fruit Flies

MIT researchers have identified several promising new targets for Alzheimer’s disease treatment by integrating data from fruit flies, human brain tissue, and cell studies. Their computational approach revealed previously overlooked cellular pathways that could contribute to neurodegeneration, potentially opening new avenues for developing more effective treatments.

The study, published today in Nature Communications, reveals how genes involved in DNA repair and RNA modification might play critical roles in the development of Alzheimer’s disease. This discovery comes at a time when researchers are increasingly looking beyond the traditional amyloid plaque hypothesis to explain why the disease is so difficult to treat.

“All the evidence that we have indicates that there are many different pathways involved in the progression of Alzheimer’s. It is multifactorial, and that may be why it’s been so hard to develop effective drugs,” says Ernest Fraenkel, the Grover M. Hermann Professor in Health Sciences and Technology in MIT’s Department of Biological Engineering and the senior author of the study.

Why Current Alzheimer’s Treatments Fall Short

Despite decades of research focusing on amyloid plaques as the primary culprit in Alzheimer’s disease, drugs targeting these protein buildups have shown limited success in slowing cognitive decline. This has prompted scientists to search for alternative mechanisms that might contribute to neurodegeneration.

“One possibility is that maybe there’s more than one cause of Alzheimer’s, and that even in a single person, there could be multiple contributing factors,” Fraenkel explains. “So, even if the amyloid hypothesis is correct — and there are some people who don’t think it is — you need to know what those other factors are.”

The insight that Alzheimer’s likely has multiple causes suggests that combination therapies targeting several pathways simultaneously might be necessary for effective treatment. This approach would mirror treatment strategies used for other complex diseases like cancer and HIV.

Key Cellular Pathways Identified

• DNA damage repair mechanisms that, when disrupted, lead to neurodegeneration
• RNA modification processes that increase vulnerability to tau tangles
• Specific genes (NOTCH1 and CSNK2A1) that protect neurons from DNA damage
• Genes (MEPCE and HNRNPA2B1) that when missing make neurons more vulnerable to tau pathology
• Cell cycle regulation processes that become dysregulated in aging neurons

From Fruit Flies to Human Brain Cells

The research team, which included scientists from Harvard Medical School, began with an extensive genetic screen in fruit flies. They systematically knocked out nearly every gene expressed in fly neurons and observed which knockdowns accelerated neurodegeneration as the flies aged.

This approach identified approximately 200 genes that, when missing, led to earlier neurodegeneration. The researchers then applied advanced network analysis algorithms to connect these findings with human genomic data from postmortem brain tissue of Alzheimer’s patients.

Their analysis revealed that many of the genes identified in fruit flies also decline with age in human brains, suggesting a conserved role in protecting against neurodegeneration across species. The team focused on two particularly promising pathways for further investigation.

Unexpected Role of DNA Repair

Perhaps the most intriguing discovery was the connection between DNA damage repair and Alzheimer’s disease. The researchers found that two genes – NOTCH1 and CSNK2A1 – appear to protect neurons from DNA damage through different mechanisms.

When these genes were knocked down in both fruit fly neurons and human neural cells, the researchers observed significant increases in DNA damage. This finding connects to previous research showing that accumulated DNA damage can lead to neurodegeneration.

What makes this discovery particularly notable is that while both genes had previously been linked to Alzheimer’s, their specific role in DNA repair hadn’t been identified. They were primarily known for regulating cell growth rather than protecting DNA integrity.

The Power of Computational Integration

The study showcases how computational approaches can help make sense of the vast amounts of data being generated in Alzheimer’s research. By combining information from genetic screens, protein measurements, and human genomic data, the researchers could identify patterns and connections that might otherwise remain hidden.

“The search for Alzheimer’s drugs will get dramatically accelerated when there are very good, robust experimental systems,” Fraenkel says. “We’re coming to a point where a couple of really innovative systems are coming together. One is better experimental models based on IPSCs, and the other one is computational models that allow us to integrate huge amounts of data. When those two mature at the same time, which is what we’re about to see, then I think we’ll have some breakthroughs.”

From Discovery to Treatment

With these new targets identified, the researchers are looking to collaborate with other laboratories to explore whether drugs targeting these pathways could improve neuron health. One promising approach involves using neurons derived from induced pluripotent stem cells (IPSCs) from Alzheimer’s patients to test potential therapeutics.

While still in early stages, the discovery of these alternative pathways offers hope for developing more effective treatments for a disease that affects millions worldwide. By addressing multiple causes simultaneously, future therapies might finally be able to significantly slow or even reverse the progression of Alzheimer’s disease.

The research, led by Matthew Leventhal, was funded by the National Institutes of Health and represents a collaboration between computational biologists and geneticists working across institutional boundaries to tackle one of medicine’s most challenging diseases.