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

Area of Science:

• Neuroscience
• Metabolic Disorders
• Epidemiology

Background:

• Cognitive dysfunction, including mild cognitive impairment (MCI) and Alzheimer's disease (AD), poses a significant public health challenge.
• Understanding the role of lipid metabolism in the pre-symptomatic phase of cognitive decline is crucial for early intervention.

Purpose of the Study:

• To investigate the association between longitudinal blood lipid trajectories and variability with the risk of developing stable MCI and AD.
• To assess if lipid profiles improve cognitive dysfunction risk prediction models.

Main Methods:

• Retrospective case-control cohort study analyzing blood lipid levels up to a decade before cognitive symptoms.
• Participants grouped by longitudinal lipid trajectories and variability independent of the mean (VIM) for cholesterol and triglycerides.
• Risk models incorporated lipid groups, APOE genotype, polygenic risk scores (PRS), age, and comorbidities.

Main Results:

• Lower HDL-C trajectories were associated with increased risk for both MCI (OR=3.8) and AD (OR=3.0).
• Lowest VIM quintile of non-HDL-C linked to higher MCI risk (OR=2.2), and lowest VIM quintile of total cholesterol to higher AD risk (OR=2.4).
• Incorporating lipid trajectory and VIM improved risk prediction models beyond APOE and PRS.

Conclusions:

• Specific patterns of blood lipid levels, particularly lower HDL-C and higher non-HDL-C/total cholesterol variability, precede and are associated with the development of MCI and AD.
• Lipid metabolism plays a critical role in the pathogenesis of cognitive decline, offering potential targets for risk assessment and prevention.