Modulatory Effect of Blood LDL Cholesterol on the Association between Cerebral Aβ and Tau Deposition in Older Adults

Abstract

Background: This study investigates the synergistic relationship between blood low-density lipoprotein cholesterol (LDL-C) and cerebral beta-amyloid (Aβ) in relation to tau deposition, a key factor in the pathology of Alzheimer's disease (AD), in older adults across a diverse cognitive spectrum.

Objectives: To examine whether higher levels of LDL-C in the blood moderate the association of cerebral Aβ with tau deposition in older adults, including those with normal cognition, mild cognitive impairment, and Alzheimer's disease dementia.

Design: Cross-sectional design.

Setting: The study was conducted as a part of a prospective cohort study. All assessments were done at the Seoul National University Hospital, Seoul, South Korea.

Participants: A total of 136 older adults (aged 60-85 years) with normal cognition, mild cognitive impairment or Alzheimer's disease (AD) dementia were included.

Measurements: Serum lipid measurements, [11C] Pittsburgh Compound B-positron emission tomography (PET), [18F] AV-1451 PET, and magnetic resonance imaging were performed on all participants.

Results: There was a significant Aβ x LDL-C interaction effect on tau deposition indicating a synergistic moderation effect of LDL-C on the relationship between Aβ and tau deposition. Subsequent subgroup analysis showed that the positive association between Aβ and tau deposition was stronger in higher LDL-C group than in lower LDL-C group. In contrast, other lipids, such as total cholesterol, high-density lipoprotein cholesterol, and triglycerides, did not show a similar moderation effect on the relationship between Aβ deposition and tau deposition.

Conclusion: Our findings suggest that blood LDL-C synergistically enhances the influence of Aβ deposition on tau pathology, emphasizing the need for greater attention to the role of LDL-C in AD progression.

Keywords: Alzheimer’s disease; Low-density lipoprotein cholesterol; beta-amyloid, tau; neurodegeneration.

Figure 1

Multiple linear regression plots showing moderating effects of LDL-C on the relationships between Aβ and tau deposition Note: For the purpose of demonstration, participants were divided into (A) two and (B) three LDL-C subgroups. Multiple linear regression model included Aβ, LDL-cholesterol subgroup, and their interaction term as independent variables; tau retention as dependent variable; and age, gender, education, APOE ε4 positivity, and VRSnoDLP as covariates. Statistical significance was observed with the interaction term between Aβ deposition and LDL-C (p < 0.05), as detailed in the manuscript. Abbreviations: Aβ, beta-amyloid; APOE, apolipoprotein; LDL-C, low density lipoprotein cholesterol; VRSnoDLP, vascular risk score reflecting vascular risk burden other than dyslipidemia.