The class
Drug-target Mendelian randomization finds lower CETP concentration cuts Lewy body and Parkinson's dementia risk, especially in APOE-e4 carriers (Alzheimers Res Ther 2024)
Original title: Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis
Since CETP inhibition raises HDL cholesterol and apolipoprotein A1 while lowering LDL cholesterol, both linked to dementia risk, researchers used drug-target Mendelian randomization to anticipate the effects of lower CETP concentration on cardiovascular outcomes and dementia-related traits, including autopsy-confirmed Lewy body dementia and Parkinson's dementia. Lower CETP concentration reproduced the lipid effects of CETP-inhibitor trials and was protective for coronary heart disease (odds ratio 0.92, 95% CI 0.89 to 0.96) and small vessel stroke (0.90, 95% CI 0.85 to 0.96), while also being associated with higher total brain volume, lower Lewy body dementia risk (OR 0.81, 95% CI 0.74 to 0.89) and lower Parkinson's dementia risk (OR 0.26, 95% CI 0.14 to 0.48). The Lewy body dementia effect was substantially stronger in APOE-e4 carriers (OR 0.61, 95% CI 0.51 to 0.73) than non-carriers (OR 0.89, 95% CI 0.79 to 1.01), suggesting CETP inhibition could be a viable dementia treatment strategy, particularly for APOE-e4 carriers.
Original abstract
Background: Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia.
Methods: Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson's dementia.
Results: MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson's dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10- 4.
Conclusions: These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.