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NIH Funds Two Computational Approaches to Unravel Alzheimer's Mechanisms, Improve Treatment

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Two research studies recently funded by the National Institutes of Health will develop computational methods to analyze and model the activities of genes and pathways that are complicit in cognitive decline in Alzheimer's disease with the hope of finding molecular targets for new and existing drugs.

These methods will help both groups adopt system-wide approaches to studying the molecular disruptions that lead to the development of the disease, taking advantage of different kinds of molecular and clinical information gleaned from brain tissue samples collected from hundreds of Alzheimer's patients over time. Ultimately, the groups are hoping to find previously unknown drug targets for Alzheimer's and test the ability of a variety of drugs to reverse or delay the condition.

The first group, comprising researchers from Mount Sinai's Icahn School of Medicine, the New York Stem Cell Foundation, and elsewhere, has been awarded $1.6 million of a possible $8.2 million grant over five years to create mathematical models that mimic Alzheimer's gene networks and pathways using molecular, cellular, and clinical data collected from patients enrolled in Mount Sinai's Disease Research Center Brain Bank.

The researchers will then use the models to explore the genetic mechanisms of the disease and test whether existing drugs can treat or prevent the disease, validating their findings in animal models and induced pluripotent stem cell lines generated from Alzheimer's patients.

Samuel Gandy, the director of Mount Sinai's Center for Cognitive Health and a principal investigator in the study, said that, among other targets, the team will look at a pathway that involves TYROBP (TYRO protein tyrosine kinase-binding protein), encoded by the TYROBP gene, as well as TREM2 (triggering receptor expressed on myeloid cells 2 protein), encoded by theTREM2 gene. An earlier study by scientists from Mount Sinai and other institutions and published in Cell identified the TREM2-TYROBP pathway in brain microglial cells as one of the causal mechanisms of late onset Alzheimer's — one of the most common forms of the disease.

"This was the first genetic evidence that clearly pointed to the possibility [that] a defect in microglial function would underlie Alzheimer's," Gandy told BioInform. "That was suspected for many years [but] we never had genetic evidence to really nail that down." In their new study, Gandy and colleagues will further flesh out the TREM2-TYROBP pathway's mechanism, exploring its behavior in silico and in living models, gauging its response to therapies, and identifying new pathways that could serve as treatment targets.

While the Cell study focused on patients with moderate to severe cases of Alzheimer's, in the current project Gandy's team will analyze data in Mount Sinai's brain bank from 300 patients that have mild disease or are in pre-clinical stages of the disease to try to discover early changes occurring in the brain. "We want to be able to develop compounds or interventions that will delay or prevent the disease altogether … not just arrest progression," Gandy explained.

Under the second grant, researchers at Brigham and Women's Hospital, the Broad Institute, and Harvard and Rush Universities will develop methods to integrate and analyze clinical, pathological, genomic, and other sorts of molecular data collected from over 1,000 volunteers in two studies of aging and dementia — the Religious Order Study and the Rush Memory and Aging Project, both run by Rush University Medical Center. They'll then use this data to identify disrupted cellular functions in Alzheimer's patients and to screen for chemical compounds that can correct the abnormal activity. The group received $1.7 million from the NIH with the potential of $7.9 million over five years.

"The goal of the project is to take an unbiased approach to understand the molecular networks that are working in the brain … that are basically affected by Alzheimer's disease in the brain," Philip De Jager, an associate professor of neurology at Brigham and Women's and one of the study's co-PIs, explained to BioInform. "One big challenge for Alzheimer's is there are no therapies currently for the disease and most of the energies are focused on a small number of targets that have been known for decades. So there is really a need to understand better what other targets there may be and that’s why we do this unbiased approach."

Specifically, De Jager and his colleagues will work on methods to integrate and analyze clinical, neuropathologic, genomic, epigenomic, and transcriptomic data from frozen brain tissue from patients enrolled in both studies before mining it to identify potential drug targets. He explained that the team will be looking for key "nodes" in the networks that can serve as drug targets. "We'll be leveraging existing methods but adapting and enhancing them to address the problem at hand," he said. They'll also develop data reduction methods to make information more manageable for analysis, he said.

Other parts of the project will include using proteomic profiling and RNA interference to validate targets identified during the analysis process, and screening possible treatments using the most promising targets from the validation step in iPSC-derived neurons and glial cells.

Both projects were funded under a $45 million research grant from the NIH to support Alzheimer's prevention and therapy development studies as part of its National Plan to Address Alzheimer's Disease. In addition to the aforementioned projects, the NIH also funded three clinical trials, two of which will test anti-amyloid beta drugs, and a third that will evaluate the effect of increasing doses of allopregnanolone, a natural brain steroid, in treating mild cognitive impairment and Alzheimer’s disease. A fourth project will study data from patients and mouse models to identify therapeutic targets in the immune system.

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