Abstract
INTRODUCTION: The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships. METHODS: We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication. RESULTS: We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes. DISCUSSION: Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings.