MIT researchers have made significant strides in Alzheimer’s disease research by leveraging extensive datasets to uncover new potential treatment targets. This groundbreaking study identifies previously unlinked genes and cellular pathways, including one associated with DNA repair, signifying a crucial step in the ongoing quest for effective therapies.
Despite the development of several drugs aimed at Alzheimer’s, many have fallen short of expectations. The collaborative effort with Harvard Medical School utilized data from both humans and fruit flies to shed light on cellular pathways related to neurodegeneration, indicating further avenues for exploration.
“Current evidence suggests multiple pathways contribute to the progression of Alzheimer’s disease,” explains Ernest Fraenkel, Grover M. Hermann Professor in Health Sciences and Technology at MIT and senior author of the study. “This multifactorial nature could explain the challenges in creating effective treatments. A combination of therapies targeting different aspects of the disease may be necessary.”
Matthew Leventhal PhD ’25 is the lead author of the paper published today in Nature Communications.
Exploring Alternative Pathways
For decades, much of the focus on Alzheimer’s has centered around amyloid plaque accumulation in the brain, initiating a chain of events that leads to neurodegeneration. Although several drugs have been developed to address these plaques, they often exhibit limited effects on disease progression. Consequently, researchers are actively seeking alternative mechanisms that could contribute to the onset of Alzheimer’s.
“It’s possible that Alzheimer’s has more than one underlying cause, with various factors influencing an individual’s condition,” Fraenkel adds. “Even if the amyloid hypothesis holds true, understanding and targeting these other factors could enhance treatment outcomes.”
To investigate these additional factors, Fraenkel’s team partnered with Mel Feany, a Harvard Medical School pathology professor specializing in fruit fly genetics. By evaluating nearly every conserved gene in fruit fly neurons, they discovered around 200 genes that accelerate neurodegeneration.
Some of these genes were already known to be linked with neurodegeneration, including those related to amyloid precursor proteins and presenilins, which are integral in the formation of amyloid proteins.
The team employed advanced network algorithms developed in Fraenkel’s lab to correlate the identified genes with specific cellular pathways and functions linked to neurodegeneration. By combining findings from the fruit fly experiments with genomic data from Alzheimer’s patients’ postmortem tissues, they highlighted the relevance of these pathways.
Network Analysis
The subsequent phase of analysis incorporated various data related to Alzheimer’s disease, including eQTL (expression quantitative trait locus) data that measures how gene variants affect protein expression levels. Utilizing their network optimization algorithms, the researchers pinpointed pathways connecting genes to their potential roles in Alzheimer’s development, ultimately narrowing focus to two specific pathways.
The first pathway, previously unlinked to Alzheimer’s, pertains to RNA modification. The researchers found that the absence of genes MEPCE and HNRNPA2B1 rendered neurons more susceptible to Tau tangles, a hallmark of Alzheimer’s. They confirmed these findings through gene knockdown studies in both fruit flies and human neurons derived from induced pluripotent stem cells (iPSCs).
The second pathway, involved in DNA damage repair, includes NOTCH1 and CSNK2A1—genes recognized for cell growth regulation but not previously connected to DNA repair in Alzheimer’s context. The study indicated that missing these genes results in DNA damage accumulation, correlating with neurodegeneration.
With these promising targets identified, the researchers aim to collaborate with other laboratories to explore potential drugs aimed at enhancing neuron health. Fraenkel and his colleagues are pursuing IPSCs from Alzheimer’s patients to develop neurons for testing these novel drugs.
“The pursuit of Alzheimer’s medications will accelerate significantly with robust experimental systems in place,” Fraenkel remarks. “We are nearing a crucial point where innovative experimental models and computational approaches harmonize, setting the stage for potential breakthroughs.”
This research was funded by the National Institutes of Health.
Photo credit & article inspired by: Massachusetts Institute of Technology
