Polygenic scores for longevity and cognitive performance are associated with predicted brain age in 70-year-olds from the general population.

Introduction: Genome-wide association studies (GWASs) have shown that several genes, beside the “high-effect” APOE gene, are involved in modulating the risk of dementia and longevity, and some of these genes overlap between the traits. Considering longevity, there are also associations with genes related to other age-related disorders, such as diabetes and cancer. Previous studies have shown associations between genetics of dementia and longevity and measures reflecting brain age, but the vast majority of these studies were performed in age heterogeneous samples. The aim of our study is to investigate how polygenic scores for dementia, general cognitive function, and longevity, associate with predicted biological brain age in 70-year-olds from the general population. Methods: The study sample included 710 individuals from the Gothenburg H70 1944 cohort with data on genetics and MRI (after QC). Polygenic scores (for longevity, general cognitive function, and Alzheimer's disease) were constructed based on genetic data derived by genome-wide genotyping and summary statistics from previous GWASs. A deep learning model, developed in- house using minimally processed T1-w MRI from ∼17000 neurologically intact individuals from UK Biobank, ADNI, AIBL, and GENIC and validated via hold-out and cross-validation approaches, was applied to generate the predicted brain ages. Statistical analyses were performed using linear regression, in the total sample and after stratification by sex. Results: Higher polygenic score for longevity was associated with lower biological brain age in men (β = -0.24; SD = 0.10; p = 0.02), and higher polygenic score for general cognitive performance was associated with lower biological brain age in women (β = -0.25; SD = 0.10; p = 0.02). No associations were seen with polygenic score for Alzheimer's disease. Discussion: The results of our study indicate that genetic variation related to longevity and general cognitive performance is associated with biological brain age in 70-year-olds, but the identified associations appear to differ between the sexes. A possible explanation might be divergent pathways involved in biological aging of the brain in men and women.