Genetic ‘hotspots’ that speed and slow brain aging could provide new targets for Alzheimer’s drugs

Researchers from a USC-led consortium have discovered 15 ‘hot spots’ in the genome that speed up or slow down brain aging – a discovery that could provide new drug targets to resist Alzheimer’s disease and other diseases. other degenerative brain disorders, as well as developmental delays.

The research appears online today in Natural neuroscience.

“What’s game-changing here is the discovery of locations on the chromosome that accelerate or slow brain aging in populations around the world. These can quickly become new drug targets,” said Paul Thompson of USC. , one of the lead authors of the study and the co-founder and director of the ENIGMA Consortium. “Through our AI4AD (artificial intelligence for Alzheimer’s disease) initiative, we even have a genome-guided drug repurposing program to target them and find new and existing drugs that help us age better.”

ENIGMA is a USC-based task force that explores a vast wealth of brain data and has published some of the largest neuroimaging studies ever conducted on schizophrenia, major depression, bipolar disorder, epilepsy, Parkinson’s disease and even HIV infection.

To discover the hotspots, or genomic loci, more than 200 ENIGMA member scientists around the world searched for people whose brains were scanned twice by MRI. The scans provided a measure of how fast their brains were gaining or losing tissue in regions that control memory, emotions and analytical thinking.

A million markers sifted through

After calculating the rates of brain tissue change in 15,000 people of all ages, the researchers sifted through a million markers in their genomes to detect 15 genomic loci – specific physical locations of genes or other DNA sequences on a chromosome – which accelerated changes in brain tissue.

These loci included some well-known Alzheimer’s risk genes, such as APOE, and some new ones, Thompson said. The researchers also found an overlap with genes involved in depression, schizophrenia and cognitive functioning.

“Some of these genetic variants affect growth rates of brain substructures during childhood, while others affect the rate of brain tissue loss in adulthood,” said co-author Neda Jahanshad, associate professor of neurology at USC’s Keck School of Medicine. . “Different parts of the brain have specific genes associated with their rates of change.”

Thompson added: “You can see that APOE – the famous Alzheimer’s disease gene – negatively affects a few brain structures – the hippocampus and the amygdala – which also makes sense because these are the most more vulnerable to Alzheimer’s disease and it seems to accelerate tissue loss there specifically.

ENIGMA also has international projects studying childhood brain disorders – from Tourette syndrome and autism to epilepsy. The new list of genes that slow or speed up brain growth in children also provides new leads to pursue in these disorders, the researchers said.

About this study

Besides Thompson and Jahanshad, other USC scientists involved in the study included Sophia Thomopoulos, Joanna Bright, Leila Nabulsi, Linda Ding and Alyssa Zhu, all of the USC Mark and Mary Stevens Neuroimaging and Informatics Institute. For a full list of authors, see the published study.

The study was funded by the National Institutes of Health, including the National Institute on Aging (U01AG068057, R01AG058854, R01AG059874), the National Institute of Mental Health (R01MH117601), the National Institute of Biomedical Imaging and Bioengineering (P41 EB015922), and a Zenith grant (ZEN-20-644609) from the Alzheimer’s Association.

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Material provided by University of Southern California. Original written by Leigh Hopper. Note: Content may be edited for style and length.