Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation Within the Heart–Brain Axis
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Background
The heart–brain axis links cardiovascular and neurodegenerative disease through shared vascular and inflammatory mechanisms. Although low-density lipoprotein cholesterol ( LDL-C) is an established causal factor in atherosclerotic cardiovascular disease (ASCVD), its relationship with dementia remains uncertain, with midlife elevations associated with increased risk but late-life associations often appearing null or inverse. To address this cholesterol paradox, we integrated mendelian randomization (MR) with an active-comparator new-user target trial emulation.
Methods
We applied a triangulated causal inference framework integrating two-sample MR with observational target trial emulation. Genetic variants associated with LDL-C were used as instrumental variables to evaluate Alzheimer’s disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), and any dementia (AnyDem), with causal estimates derived using inverse-variance weighted models and sensitivity analyses for heterogeneity and pleiotropy. In parallel, an active-comparator new-user design compared statin versus ezetimibe initiation among adults aged ≥60 years using propensity score (PS) overlap weighting and Cox proportional hazards models to evaluate cardiovascular and dementia outcomes.
Results
Genetically predicted LDL-C was associated with increased risk of DLB (OR 1.65, 95% CI 1.30–2.10; p<0.001), but not AD or AnyDem; FTD estimates were inconsistent. Sensitivity analyses suggested heterogeneity and possible pleiotropy for DLB. In the observational analysis (n=6,977), statin initiation was associated with higher risks of ASCVD (HR 1.26, 95% CI 1.11–1.45) and AnyDem (HR 1.66, 95% CI 1.16–2.38), although estimates attenuated after lipid adjustment and lagged analyses, suggesting residual confounding, treatment selection, and reverse causation in late-life observational associations.
Conclusions
These findings suggest that LDL-C reflects accumulated vascular and metabolic risk rather than a direct causal driver of AD or overall dementia, although a subtype-specific association was observed for DLB. Late-life associations appeared influenced by timing, reverse causation, and treatment selection, warranting cautious interpretation.
