Comparison of Single Polygenic, Multiple Polygenic Risk, and Lifestyle for Brain Health Index in Explaining Cognitive Function Among Middle-aged and Older Adults in The Maastricht Study

Cognitive function is shaped by both genetic and environmental factors. The Lifestyle for Brain Health (LIBRA) index, based on epidemiological evidence, targets modifiable risk and protective factors during midlife and early old age. This study compares the explanatory power of polygenic risk scores (PGSs) and the LIBRA score in relation to cognitive function among middle-aged and older adults in the Maastricht Study. We analyzed 17 cognition-related PGSs individually and combined significant PGSs into a multi-PGS model. The performance of the LIBRA model, individual PGS models, the multi-PGS model, and integrated LIBRA-genotype models was evaluated. The intelligence PGS exhibited the strongest association with cognitive function ({beta} = 0.109, 95% CI: 0.094-0.124). Five PGSs remained significant and were incorporated into the multi-PGS model. Compared to the LIBRA-only model, genetic models, including either the top single-PGS or multi-PGS, showed improved performance, with Adjusted R{superscript 2} increasing by 2.5% to 3.1%. The LIBRA + multi-PGS model provided the highest explanatory power, with a 4% increase in Adjusted R{superscript 2}, validated by 10-fold cross-validation. These results underscore the value of integrating PGSs, particularly multi-PGS models, with the LIBRA score to enhance the prediction of cognitive outcomes. This genetic-environmental approach offers potential for better understanding and predicting cognitive function in middle-aged to early old-aged populations, with implications for clinical and public health applications.