Sexual dimorphisms in longitudinal associations of the blood lipidome with cognitive decline in Alzheimer’s disease

Abstract

AbstractBackgroundLate‐onset Alzheimer’s disease (AD) is the leading cause of dementia with neither cure nor a clearly understood disease trajectory. Previous studies have shown cross‐sectional and longitudinal associations of the blood lipidome and AD. We previously reported on significant sex differences in the associations of lipids with AD biomarkers and it has been suggested that such sex differences may result in distinct trajectories of AD progression. We performed an association study of sex‐stratified longitudinal lipidomics data with cognitive function to further characterize sexual dimorphisms in lipidomic manifestations of AD.MethodWe used a subset of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset: 1349 individuals (745 males and 604 females) with blood samples and clinical data collected at 10 time points with intervals of 6 to12 months (4145 samples total). We analyzed 749 lipid species measured by quantitative LC‐MS lipidomics profiling (Baker Heart and Diabetes Institute, Melbourne, Australia). We calculated linear mixed models (LMMs) and generalized additive mixed models (GAMMs) to analyze time‐resolved associations between lipids and two composite cognitive scores (ADNI memory and executive function) while adjusting for age, sex (pooled analysis only), BMI, HDL‐C, total cholesterol, copies of APOE ε4, years of education as well as significant medication effects.ResultWe observed a significant difference in lipid concentrations between males and females in line with previous studies, however, these differences were not fully consistent across diagnostic groups. In longitudinal association analyses, we found a substantial fraction of lipid species to have significant sex‐specific associations with cognitive function, which were not observed in the pooled analysis. These lipids were distributed across several lipid classes with enrichment in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and triglycerides (TG). Comparisons between LMMs and GAMMs further indicated that some lipids might have a nonlinear relationship with cognitive trajectories.ConclusionOur results suggest that there are substantial sex differences in longitudinal associations of the blood lipidome with cognitive decline resulting in complex and partially nonlinear relationships. The highlighted lipid pathways can serve as a starting point to better characterize sex‐specific molecular changes linked to cognitive decline in AD.