Approved research

Brain Aging Polygenic Risk Score Prediction of Neurological Phenotypes

Lay summary

Quality of life in old age is often compromised by dementia, mild cognitive impairment, increased depressive symptoms, and declining mobility. Having better predictive tools for identifying at risk individuals and also better therapies for slowing down brain aging would be greatly beneficial. The goal of our study over the next three years is to establish whether a genetic test we developed is useful in identifying people who are at risk for faster brain aging and neurological diseases. The test is a polygenic risk score (PRS) comprised of ~1000 brain aging risk single nucleotide polymorphisms (snps), which is the sum of small person-to-person variations in a select number of genes. The PRS was developed by identifying snps that in aggregate predict biological brain age in human postmortem brain cohorts. We determined the biological age of the postmortem brains using RNA levels of ~1000 genes that change with normal aging throughout lifespan. Some subjects had biological brain ages very close to their chronological ages and some had brain ages that were older or younger than their chronological ages. We were able to correlate the difference between biological and chronological age (delta age) with genetic variation across the genome in meta-analysis. The aggregate number of risk snps for an individual is the basis for the PRS. In the UK Biobank, we will test whether this score can predict cognitive decline and neurological disease in large living cohorts. This will shed light on whether this test will be useful for physicians to put into place screening and preventative measures for at risk individuals. This may also help identify avenues for new drugs that will slow down brain aging, treat neurological diseases such as Alzheimer's, as well as identify people who would most benefit from these treatments before they have become irreversibly impaired.