Sex- and Age-Dependent Mitochondrial Dysfunction Links Familial Hypercholesterolemia to Cognitive Impairment

Background. Familial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism caused by loss-of-function variants in the low-density lipoprotein receptor (LDLR), resulting in persistently elevated LDL-cholesterol levels in plasma. Although hypercholesterolemia, especially the high levels of LDL, has been linked to an increased risk of dementia, the underlying mechanisms remain unclear. Here, we investigated the effects of sexual dimorphism and aging on metabolic and cognitive functions in a murine model of FH. Methods. Adult and middle-aged, male and female, C57BL/6 and LDLr ^−/− mice were used in this study. Behavioral assessments included locomotor activity, spatial memory, and anxiety-like behavior. Plasma lipid profiles were measured, and mitochondrial function in the hippocampus and brown adipose tissue (BAT) was assessed using high-resolution respirometry. Results. LDLr ^⁻/⁻ mice of both sexes exhibited increased cholesterol and triglycerides levels. Male LDLr ^⁻/⁻ mice displayed hyperlocomotion in the Open Field (OF) and Elevated Plus Maze (EPM) at both ages, whereas this phenotype emerged in middle-aged female LDLr ^⁻/⁻ mice only in OF. Spatial memory impairments were observed in LDLr ^⁻/⁻ mice regardless of sex or age. Hippocampal oxygen consumption was reduced in adult males and middle-aged female mice, whereas BAT respiration was impaired in both sexes at middle-aged animals, affecting distinct respiratory parameters. Correlation analyses revealed that elevated cholesterol levels were associated with memory deficits and hyperlocomotion, along with positive correlations between hippocampal and BAT mitochondrial function. Conclusions. Collectively, these findings demonstrate that FH induces sex- and age-dependent alterations in behavior and mitochondrial metabolism, providing mechanistic insights into the link between FH and neurodegenerative disease risk.