Newly discovered genetic marker could pave the way for future treatments for Alzheimer’s disease

Indiana University School of Medicine researchers have identified a new genetic marker that may play a role in the development of Alzheimer’s disease, characterized by two main pathologies: beta-amyloid plaques and tangles. Tau neurofibrillary cells. Their findings, recently published in Natural communicationscould pave the way for new therapeutic targets and new diagnostic tools for the disease.

The study involved an international team of researchers who analyzed genetic and advanced Tau imaging data from more than 3,000 people, making it the largest effort to date to explore the genetics of detected cortical tau by PET. She identified a genetic locus – the specific location of a gene on a chromosome – that accounts for a significant proportion of tau deposits in older people with or at risk of developing Alzheimer’s disease.

“The identification of this novel genetic marker opens a new avenue for research and potential therapeutic development by targeting an abnormal form of tau protein that comprises the tangles seen in the brain in Alzheimer’s disease,” said Andrew J. Saykin, PsyD, principal investigator of the study. and Raymond C. Beeler Professor of Radiology at the IU School of Medicine.

“While many previous genome-wide association studies compared the genetic profiles of Alzheimer’s disease patients to those of cognitively healthy older adults, this study used tau PET as the phenotype continued to detect a genetic locus that accounts for a significant portion of tau deposition in study participants.”

Saykin, who also directs the Indiana Alzheimer’s Disease Research Center and the IU Neuroimaging Center, said that while previous studies have made progress in identifying genetic variants associated with amyloid deposits, understanding the genetic drivers of tau deposition has been more difficult due to the lack of large datasets containing both Tau and genetic information.

This study fills this gap, demonstrating that the rs2113389 variant located on chromosome 2p22.2, between the CYP1B1 and RMDN2 genes, is strongly associated with increased tau load in several brain regions. This variant alone explains approximately 4.3% of the variation in tau deposition, even exceeding the contribution of the well-known APOE4 gene, which accounts for 3.6%.

“More research is needed to dig deeper and determine exactly what drives this association,” Saykin said. “We now have a new locus at the intersection of these genes to study as potential targets for diagnostic and therapeutic approaches.”

The 3,000 participants studied came from 12 different sites around the world. Some people had no cognitive deficits, while others had mild or severe cognitive impairment.

“We need to replicate the findings in larger samples,” said Shannon L. Risacher, Ph.D., co-principal investigator of the study and associate professor of radiology at the IU School of Medicine. “Most patient cohorts studied are based in the United States, Canada, and Australia, but PET scans are performed in many other regions around the world. A future goal would be to expand the sample size to replicate our results.”

The team also plans to continue studying the locus and its behavior in mouse models.

“A very important step following the human findings is more functional validation in model systems including mice and cell cultures or organoids,” said Kwangsik Nho, Ph.D., co-principal investigator of the study and professor of radiology at the IU School of Medicine. “We want to see if this effect can be modeled in the laboratory, which could greatly facilitate drug development efforts.”

Saykin said the combination of advanced neuroimaging and genetics is something the research team has been pursuing for many years.

“It is exciting to see this approach generate a potential new target,” Saykin said. “To ultimately prevent Alzheimer’s disease, we need to better understand what causes plaques and tangles. Genetic research combined with biomarkers and cognitive studies will enable earlier detection and more precise interventions in people affected or at increased risk.”