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Published on: November 14, 2017

Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation

Kudakwashe Mukumbi1, Yanrong Liu2, Zixin Shi1

  • 1Department of Applied Computing, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, USA.

Medrxiv : the Preprint Server for Health Sciences
|June 29, 2026
PubMed

Insights

Low-density lipoprotein cholesterol (LDL-C) may not directly cause dementia, but is linked to Dementia with Lewy bodies. Late-life associations are complex, influenced by timing and treatment, not just cholesterol levels.

Area of Science:

  • Cardiovascular science
  • Neuroscience
  • Genetics

Background:

  • The heart-brain axis connects cardiovascular and neurodegenerative diseases via shared vascular and inflammatory pathways.
  • Low-density lipoprotein cholesterol (LDL-C) is a known cause of atherosclerotic cardiovascular disease (ASCVD), but its role in dementia risk is debated, with conflicting associations in midlife versus late-life.
  • The 'cholesterol paradox' highlights uncertainty regarding LDL-C's late-life impact on dementia.

Purpose of the Study:

  • To investigate the causal relationship between LDL-C and various dementia subtypes, including Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), and Frontotemporal dementia (FTD).
  • To address the cholesterol paradox by integrating genetic (Mendelian randomization) and observational (target trial emulation) approaches.
  • To evaluate the impact of lipid-lowering treatments on dementia risk in older adults.

Main Methods:

  • Employed a triangulated causal inference framework combining two-sample Mendelian randomization (MR) and observational target trial emulation.
  • Utilized genetic variants associated with LDL-C as instrumental variables for MR analyses of AD, DLB, FTD, and any dementia (AnyDem).
  • Conducted an active-comparator new-user design comparing statin versus ezetimibe initiation in adults aged ≥60 years, using propensity score overlap weighting and Cox proportional hazards models.

Main Results:

  • Genetically predicted LDL-C was associated with an increased risk of DLB (OR 1.65), but not AD or AnyDem; FTD results were inconsistent.
  • Sensitivity analyses for DLB indicated potential heterogeneity and pleiotropy.
  • Observational analysis showed statin initiation associated with higher risks of ASCVD and AnyDem, but these associations attenuated after lipid adjustment and lagged analyses, suggesting residual confounding and reverse causation.

Conclusions:

  • LDL-C may reflect cumulative vascular and metabolic risk rather than being a direct causal factor for AD or overall dementia, though a subtype-specific link to DLB exists.
  • Late-life associations between LDL-C and dementia are influenced by factors such as timing of exposure, reverse causation, and treatment selection.
  • Findings emphasize the need for cautious interpretation of late-life observational data concerning LDL-C and dementia risk.
Abstract

Keywords:
Heart–brain axiscardiovascular diseasecausal inferencedementialow-density lipoprotein cholesterol

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