Specific Mutation May Impact Alzheimer’s by Triggering Other Genes

Selonterra researchers have discovered that the APOE4 gene impacts Alzheimer’s disease (AD) mechanisms in an entirely different way than previously believed. The mutation does not change the behavior of the protein itself, but triggers the activation of nearby genes, which may contribute to Alzheimer’s.

The study, “Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer’s Disease,” was published in the journal Scientific Reports.

“The importance of APOE4 for AD has been recognized for decades, but this has not translated to approved therapies,” Anne Urfer-Buchwalder, PhD, co-founder and CSO of Selonterra, said in a press release.

Using a computer assisted approach, researchers discovered that the mutation in the APOE gene, which is present in many sporadic Alzheimer’s patients, changes the DNA sequence so that it becomes identical to another known sequence — one that makes up the binding site of a transcription factor known as NRF1.

Transcription factors are molecules that bind to specific stretches in the DNA to activate genes that are downstream of their binding site. NRF1 is known to control key metabolic and mitochondrial genes.

The discovery can also account for the impact of environmental factors in the development of Alzheimer’s, according to Selonterra.

“In contrast to an involvement of the APOE4 protein in Alzheimer’s disease, our discovery suggests that it is the DNA sequence of the APOE4 variant itself that controls the expression of genes located in close vicinity to the APOE gene,” she said. “The APOE4 /NRF1-mediated expression of these genes may lead to the known hallmarks of Alzheimer’s disease.”

Selonterra, a biotech company focusing on developing new therapies for Alzheimer’s and Parkinson’s diseases, will now work to identify compounds that target the newly identified mechanism — with the goal of developing a new type of Alzheimer’s treatment.

“AD is one of the defining health challenges of our time,” said Roman Urfer, PhD, co-founder and CEO of Selonterra. “Therapies targeted at this novel mechanism have the potential for disease-modification because they will address the genetic root cause of Alzheimer’s disease. We hope that our discovery will serve as a stimulus for further research toward an effective treatment of this disease.”