Multi-Omic Analysis Reveals Possible Treatment for Late-Onset Alzheimer’s Disease

investigators discover a rare genetic variant shown to protect people who carry known genetic risk factors for Alzheimer's disease

Results from a multi-omic analysis led by Icahn School of Medicine at Mount Sinai suggest that a gene that plays a role in neuronal signaling in the brain, ATP6V1A, is under expressed in many cases of late-onset Alzheimer’s disease.

The researchers also identified a drug compound they think could be used to boost levels of expression of the gene and target the neurodegenerative symptoms seen in Alzheimer’s disease.

“Our study advances the understanding of late-onset Alzheimer’s disease pathogenesis by revealing not only its global structures, but detailed circuits of complex molecular interactions and regulations in key brain regions affected,” said the lead researcher Bin Zhang, Ph.D., a professor at the Icahn School of Medicine at Mount Sinai and Director of the Center for Transformative Disease Modeling.

“The network models we created serve as a blueprint for identifying novel therapeutic targets that respond directly to the urgent need for new ways to prevent, treat, and delay the onset of late-onset Alzheimer’s disease.”

Sporadic late-onset Alzheimer’s is the most common form of the neurodegenerative disease, affecting more than 5 million people in the U.S. alone. However, despite being the sixth leading cause of death and accruing annual treatment costs of more than $200 billion, an effective treatment has yet to be discovered.

Some genetic associations have been revealed before, but have failed to detect true causative variants. Multi-omic analyses are a relatively new tool in the fight against this disease and have the potential to uncover new variants, as well as new therapy targets, and perhaps also reveal methods to slow disease progression.

As reported in the journal Neuron, Zhang and colleagues first carried out multi-omic profiling—DNA and RNA sequencing—of four areas of the brain in samples taken from 364 people who donated their brains to the Mount Sinai Brain Bank after death. The people included had a range of cognitive and neurological symptoms associated with late-onset Alzheimer’s disease and the cohort also included brains from those without Alzheimer’s for control purposes.

The analysis showed that expression of the ATP6V1A gene was reduced by 35% to 42% at the mRNA and protein level in brains from those with late-onset Alzheimer’s.

The connection with low expression of this gene and neurodegenerative symptoms of Alzheimer’s was validated in a brain neuronal cell line in the lab and also in a Drosophila model. This additional research also showed that repression of the ATP6V1A protein had a worse neurological impact when combined with β-amyloid and tau protein, build-up of which is commonly seen in the brains of people with Alzheimer’s disease.

Notably, the team predicted that a drug compound, NCH-51, could help raise levels of the ATP6V1A protein and when they tested this in the cell line and the Drosophila models their theory was proved correct.

“This finding suggests that ATP6V1A may have broad neuroprotective effects and serve as a potential therapeutic target for other tau-related neurodegenerative diseases,” says Koichi Iijima, Ph.D., Head of the Department of Alzheimer’s Disease Research at the National Center for Geriatrics and Gerontology in Japan, and a senior author of the study.

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