Cholesterol Regulation in the Brain: a Clinical and Genetic Link to Neuropsychiatric Disorders

Abstract

Epidemiological studies have reported associations between blood cholesterol levels and the risk of psychiatric and neurodegenerative disorders, with suggestions that pharmacological modulation of cholesterol may benefit brain health. This study aimed to investigate the biological basis of these associations by applying an integrative analytical framework that combined clinical and genetic data with methodological approaches of Mendelian randomization (MR) and genetic colocalization. Specifically, we investigated statistically supported causal and pleiotropic relationships between blood cholesterol levels and neuropsychiatric disorders, while also examining associations with grey and white matter phenotypes derived from MRI data. Our findings indicate that genetic alterations in cholesterol metabolism may influence the risk of both psychiatric and neurodegenerative conditions. We also found evidence for a causal relationship between blood levels of high-density cholesterol (HDL) and region-specific structural brain phenotypes, including grey matter volume and white matter microstructure. Notably, a proatherogenic lipid profile may increase the risk of attention-deficit disorders by modulating grey matter volume in the right caudate nucleus. Additionally, we observed that structural brain changes and disease status may, in turn, influence peripheral lipid levels. Specifically, increased grey matter volume in the putamen has demonstrated causal association with elevated HDL levels, while Alzheimer's disease showed a direct reverse causal relationship with both high- and low-density cholesterol (LDL) levels. In addition, our analyses reveal a genetic basis for the association between peripheral cholesterol levels and susceptibility to neuropsychiatric disorders, identifying multiple pleiotropic loci that influence both traits. Genetic variants associated with blood cholesterol levels may impact brain function through brain cell type-specific regulatory effects on gene expression, implicating molecular pathways involved in lipid metabolism, neural signaling, and neuroinflammation in the etiology of psychiatric and neurodegenerative disorders.