Scientists believe that Alzheimer’s disease is caused by sticky clumps of protein (amyloid plaques) that build up in the brain and lead to nerve cell damage. Some drugs have been created to remove these plaques, but they haven’t slowed the disease.
Researchers are now investigating other possible causes of Alzheimer’s to find better treatments. By analyzing large amounts of data, MIT scientists have discovered new potential ways to treat or prevent the disease.
Researchers have discovered new genes and biological pathways related to Alzheimer’s, including one tied to DNA repair—something not previously linked to the disease. Since existing Alzheimer’s drugs haven’t worked as well as hoped, finding new treatment targets is crucial.
The MIT and Harvard team analyzed data from humans and fruit flies, helping them uncover additional pathways that may contribute to neurodegeneration. Because Alzheimer’s involves multiple biological processes, developing effective drugs has been a challenge, requiring scientists to take a broader approach.
To explore other factors in Alzheimer’s, researchers collaborated with geneticist Mel Feany, using fruit flies as a model. They systematically turned off nearly every conserved gene in fly neurons and observed how it affected neurodegeneration. This led to identifying about 200 genes that speed up the process.
Some of these genes were already known to be linked to neurodegeneration, including those involved in forming amyloid proteins, which are associated with Alzheimer’s disease.
The researchers used advanced network algorithms to find connections between genes that might be involved in the same biological processes. They combined data from fruit flies with genetic information from Alzheimer’s patients to see how these genes are linked to neurodegeneration.
Their first analysis showed that many of the genes found in fruit flies also decline in humans as they age, suggesting they could play a role in Alzheimer’s.
In the next part of their study, researchers analyzed more Alzheimer ‘s-related data, including eQTL data, which shows how different gene variants affect protein production. Using advanced algorithms, they identified pathways connecting specific genes to Alzheimer’s.
They focused on two pathways, one involving RNA modification—something not previously linked to the disease. The study found that when specific genes in this pathway (MEPCE and HNRNPA2B1) are missing, neurons become more vulnerable to the harmful Tau tangles seen in Alzheimer’s patients. This was confirmed through experiments in fruit flies and human neurons grown from stem cells.
The study also highlighted a second pathway tied to DNA repair. It involves two genes, NOTCH1 and CSNK2A1, which were previously linked to Alzheimer’s but not in terms of fixing DNA damage. These genes are mainly known for controlling cell growth.
Researchers found that damaged DNA accumulates in cells when these genes are missing, leading to neurodegeneration. Now that these genes have been identified as possible drug targets, scientists hope to collaborate on new treatments that could help protect neurons.
To test potential drugs, researchers are using neurons derived from Alzheimer’s patients’ stem cells.
Journal Reference:
- Leventhal, M.J., Zanella, C.A., Kang, B. et al. An integrative systems-biology approach defines the mechanisms of Alzheimer’s disease neurodegeneration. Nat Commun 16, 4441 (2025). DOI: 10.1038/s41467-025-59654-w
