Abstract Body (Do not enter title and authors here): Background: Lipid metabolism in older adults is affected by various factors including biological ageing, functional decline, reduced physiological reserve, and nutrient intake. The dysregulation of lipid metabolism has been suggested to adversely impact brain health. This study aims to investigate the association between year-to-year lipid variability and subsequent risk of cognitive decline and dementia in older adults.
Methods: ASPREE was a randomized trial of aspirin and extended into an observational study, ASPREE-XT with a maximum follow-up of 11 years. Included in this study were participants who had cholesterol values measured at baseline, and first three-year annual visits. Only those who initiated or discontinued lipid-lowering therapy during the measurement period were excluded as this study aims to explore change in lipid levels unrelated to changes in treatment. Year-to-year variability in total cholesterol (TC), Low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglycerides was quantified using variability independent of the mean (VIM). Associations with incident dementia and cognitive impairment-no dementia (CIND) were analysed using multivariable Cox proportional-hazards models. Linear mixed model was used for assessing the association with changes in different cognitive function domains including global, memory, processing speed, verbal fluency, and a composite over 11 years.
Results: The analysis included 9,846 individuals. Baseline characteristics are shown in Table 1. 509 incident dementia and 1,760 CIND events were recorded over a median follow-up of 5.8- and 5.4-years post-variability assessment. The HRs (95%CI) comparing the highest vs. lowest quartiles of TC and LDL-C variability, were 1.60 (1.23-2.08) and 1.48 (1.15-1.91) for dementia, and 1.23 (1.08-1.41) and 1.27 (1.11-1.46) for CIND. Restricted cubic splines revealed a monotonic increased risk of dementia with higher TC and LDL-c variability (Fig 1). TC and LDL-C variability were also associated with a faster decline in global cognition, episodic memory, psychomotor speed, and the composite score (all p<0.001). No strong evidence was found for an association between HDL-C and triglycerides variability with dementia and cognitive change.
Conclusions: Tracking the variability of TC and LDL-C measured annually may serve as a novel biomarker for higher risk of incident dementia and cognitive decline in older adults.