Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis
Cardiovascular Research
Abstract
Type of funding sources: Private company. Main funding source(s): New Amterdam Pharma
Elevated levels 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.
Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (µg/mL) on plasma lipids, cardiovascular disease, Lewy body dementia (LBD), as well as Parkinson’s dementia. Replication was sought by performed Apo-A1 and Apo-B weighted MR analyses of CETP variants. Genetic associations with protein expression in cerebrospinal fluid (CSF) and brain were consulted to identify potential associations of plasma CETP with dementia implicated proteins.
MR analysis of lower CETP concentration (per µg/mL) recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on CHD (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); Figure. 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. The aforementioned associations were replicated using Apo-B and Apo-A1 weighted analyses; Figure. Additionally, MR was employed to link plasma CETP concentration to the levels of CSF and brain proteins such as EPHA2 and CSF-1, which are in development as dementia drug targets.
These results suggest that inhibition of CETP may be a viable strategy to treat dementia.
Effects of lower CETP activity on cardiovascular and neurological traits estimated through cis Mendelian randomization using three distinct weighting strategies. N.b. The MR effects are estimated by alternatingly selecting instruments based on the genetic association with lower CETP concentration (µg/mL), higher Apolipoprotein-A1 (Apo-A1 in g/L), and lower Apolipoprotein-B (Apo- B in g/L). The estimated odds ratio (OR) is indicated by a circle if the p-value was smaller than 0.05/26, or by a star otherwise, with the horizontal bars representing 95% confidence intervals (95%CI), a neutral effect of 1 is indicated by the dashed vertical line.
