Association of cardiovascular disease management drugs with Lewy body dementia: a case-control study

Abstract

Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70-0.74, P-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83-0.87, P-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62-0.72, P-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62-0.72, P-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80-0.92, P-value = 5.16 × 10^-5; White: odds ratio = 0.85, 95% confidence interval = 0.82-0.88, P-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.

Keywords: Lewy body dementia; Medicare; cardiovascular disease; genomic analysis; prescription drugs.

Graphical Abstract

Figure 1

Study design. This graphical representation showcases the two-stage study design. Stage 1 consisted of a prescription drug evaluation using LBD cases and controls sampled from the US Medicare database. In Stage 2, we studied the polygenic overlap between cardiovascular disease traits and LBD using genomic data.

Figure 2

Conditional quantile–quantile (Q–Q) plots and shared variant estimates. The conditional Q–Q plots show the relationship between the expected (x-axis) versus the observed (y-axis) −log₁₀  P-values of the single nucleotide polymorphism (SNP) associations in the primary phenotype (e.g. LDL cholesterol) stratified by the P-values in the conditional trait (e.g. LBD). We show four strata: all SNPs, SNPs with two-sided P-values ≤0.1 (orange lines), P-values ≤0.01 (green lines) and P-values ≤0.001 (red lines). The dashed, diagonal line indicates the expected Q–Q plot under the null hypothesis for genome-wide associations. The increasing degree of leftward deflection from the null in the conditional phenotypes indicates polygenic overlap. Using MiXeR modelling of polygenic overlap, all three tested traits [LDL cholesterol, Type 2 diabetes (T2D) and primary hypertension] show genetic overlap when conditioned on LBD. The log-likelihood plots illustrate the goodness-of-model-fit, plotting the negative log-likelihood function against the π₁₂ parameter (number of influencing variants shared between two tested traits).

Figure 3

Associations of cardiovascular drugs with LBD. (A) This plot shows the adjusted logistic regression results of cardiovascular disease treatment drugs associated with LBD risk (n = 64). The ORs are plotted on the x-axis and the −log₁₀  P-values are on the y-axis. The threshold for significance is indicated by a dashed line. The green background colour highlights drugs associated with decreased LBD risk, and the red background colour highlights drugs with increased LBD risk. Among the drugs with increased LBD risk, we point out propranolol, an anti-hypertensive drug that is commonly prescribed for LBD patients due to anti-tremor properties. We also noted insulins as associated with increased risk for disease, which may indicate that metabolic impairment is optimized when prodromal LBD patients seek medical care for cognitive changes. We attributed the increased risk of propranolol and insulins reflecting reverse causality to LBD patients seeking medical care for symptomatic management of neurological changes. (B) Plot showing the effect of the cholesterol-lowering drugs (number of group members g = 22), anti-diabetics (g = 35) and anti-hypertensives (g = 92) on LBD risk based on the 3-year lag model of the US Medicare prescription database.

Figure 4

Polygenic overlap between cardiovascular traits and LBD. Venn diagrams based on MiXeR modelling from GWASs of cardiovascular traits and LBD (n = 2591 cases and 4027 controls) illustrate the polygenic overlaps between (A) LBD and LDL cholesterol, (B) LBD and T2D and (C) LBD and hypertension. The estimated number of causal variants shared between LBD and each respective cardiovascular trait are shown in the grey intersection. The estimated number of influencing variants that are unique to LBD are shown in blue, while variants uniquely influencing each cardiovascular trait are shown in orange. Standard errors are shown in parentheses. The size of each circle reflects the extent of polygenicity of each trait, with larger circles indicating a bigger number of causal variants. The estimates of genetic correlation, as measured by r_g values, are shown at the bottom of each panel. The red bars highlight the significant positive correlations between LBD and each of the three tested cardiovascular traits. T2D, Type 2 diabetes mellitus.