Predictive Analytics Models Detect Alzheimer’s-Protecting Protein

August 20, 2020 - A team from the Icahn School of Medicine at Mount Sinai, Emory University, and other collaborating institutions used predictive analytics models to discover a protein known as VGF, which protects the brain against Alzheimer’s disease, according to a study published in Nature Communications.

Researchers have yet to fully characterize the molecular underpinnings of Alzheimer’s disease, the team noted. While genome-wide association studies have implicated more than two dozen genetic regions associated with the disease risk, this information has proven difficult to translate into clinical use.

To better understand how genetic factors impact Alzheimer’s disease risk and development, the group built predictive network models of late-onset Alzheimer’s disease by mining DNA, RNA, protein, and clinical data.

“By integrating DNA variation with additional types of molecular and clinical data, more complex, holistic models of disease can be constructed and mined to elucidate regulatory and mechanistic drivers of disease and points of therapeutic intervention,” researchers said.

These predictive analytics models enabled them to identify key regulators of Alzheimer’s disease and spotlight VGF, the only key driver of a suppressed response across all datasets. VGF is a neuronal protein that regulates memory, and levels of it are reduced in the brains and cerebrospinal fluid of patients with Alzheimer’s disease.

“Our results support previous studies in demonstrating that the biology of Alzheimer’s disease is highly complex, and that there is no single genetic cause of the disease,” said Noam Beckmann, PhD, a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai and a lead author of the paper.

“However, our sophisticated model and follow-up validation studies offer convincing evidence that the protein VGF, previously associated with fear and spatial memories in mice, plays an important role in protecting the brain against the onset and progression of Alzheimer’s disease.”

While lower levels of VGF have been noted in previous Alzheimer’s disease studies, this is the first time that reduced levels of the protein have been shown to have a causal role in the disease. Researchers replicated the VGF findings in other datasets and then used multiple mouse models to study overexpression of VGF.

By ramping up levels of the gene or protein in mice, scientists were able to significantly reduce pathogenesis and progression of Alzheimer’s disease, with clear molecular and behavioral effects.

The research team stated that their findings could have important implications for Alzheimer’s disease treatment and prevention.

“Our combined big data analysis of gene expression in patients with Alzheimer’s disease and validation studies carried out in mouse models provide novel insights into disease mechanisms,” said Stephen R. J. Salton, MD, PhD, Professor of Neuroscience, and Geriatrics, at the Icahn School of Medicine at Mount Sinai.

“These studies have identified molecular networks and new gene products including VGF that impact Alzheimer’s disease, for future pharmacotherapeutic manipulation, which we anticipate will lead to a reduction in the pathogenesis and progression of this and potentially other neurodegenerative diseases.”

Researchers have made significant progress in understanding Alzheimer’s disease. A team from Stanford University recently found that a significant fraction of Americans carrying a genetic variant that puts people at high risk for Alzheimer’s disease are protected to some degree by a variant of a different gene. This finding could help drug developers identify more precise treatments for the condition.

“While 15 percent of healthy people have the ApoE4 gene variant, it's present in more than 50 percent of Alzheimer's patients,” said Michael Greicius, MD, MPH, associate professor of neurology and director of the Stanford Center for Memory Disorders. “One copy of ApoE4 triples or quadruples your risk, compared with no copies. If you're carrying two copies, your risk goes up tenfold.”

“Having one or two copies of ApoE moves the age at which you get sick earlier by five to ten years. But it turns out, not all ApoE4 carriers are destined to develop the disease. The gene variant we studied protects you from getting Alzheimer's.”