Lipid Trajectories Improve Risk Models for Alzheimer's Disease and Mild Cognitive Impairment

To assess the relationship between lipids and cognitive dysfunction, we retrospectively analyzed blood-lipid levels in clinically well-characterized individuals with stable mild cognitive impairment (MCI) or Alzheimer's disease (AD) over the decade prior to first cognitive symptoms. In this case/control cohort study, AD and MCI cases were diagnosed using DSM-IV criteria; MCI cases had not progressed to dementia for ≥5 years; and controls were propensity matched to cases at age of symptom onset (MCI: 116 cases, 435 controls; AD: 215 cases, 483 controls). Participants were grouped based on longitudinal trajectories and quintile of variability independent of the mean (VIM) for total cholesterol, HDL-C, LDL-C, non-HDL-C and ln(triglycerides). Models for the risk of cognitive dysfunction evaluated trajectory and VIM groups, APOE genotype, polygenic risk scores (PRS) for AD and lipid levels, age, comorbidities, and longitudinal correlates of blood-lipid concentrations. Lower HDL-C trajectories (OR = 3.8, 95% CI = 1.3-11.3) and the lowest VIM quintile of non-HDL-C (OR = 2.2, 95% CI = 1.3-3.0) were associated with higher MCI risk. Lower HDL-C trajectories (OR = 3.0, 95% CI = 1.6-5.7) and the lowest VIM quintile of total cholesterol (OR = 2.4, 95% CI = 1.5-3.9) were associated with higher AD risk. The inclusion of lipid-trajectory and VIM groups improved risk-model predictive performance independent of APOE genotype or PRS for AD and lipid levels. These results provide an important real-world perspective on the influence of lipid metabolism and blood-lipid levels on the development of stable MCI and AD.