Two-sample Mendelian randomization study on the causal association between air pollution and Alzheimer′s disease

doi:10.3969/j.issn.1674-8115.2025.01.010

Abstract

Abstract:

Objective ·To explore the causal relationship between air pollution and the risk of Alzheimer′s disease (AD) by using two-sample Mendelian randomization (MR). Methods ·Based on the data from the genome-wide association study (GWAS), a two-sample MR analysis was conducted to evaluate the causal relationship between air pollution and the risk of AD. Air pollution indicators, including particulate matter 2.5 (PM_2.5), particulate matter 2.5-10 (PM_2.5-10), particulate matter 10 (PM₁₀), nitrogen dioxide and nitrogen oxides, were used as exposure factors, and summarized data were aggregated from the UK Biobank database. The PM_2.5 dataset included 423 796 cases, with correlation analysis conducted on 9 851 867 single nucleotide polymorphisms (SNPs); the PM_2.5-10 dataset included 423 796 cases, with correlation analysis conducted on 9 851 867 SNPs; the PM₁₀ dataset included 455 314 cases, with correlation analysis conducted on 9 851 867 SNPs; the nitrogen dioxide dataset included 456 380 cases, with correlation analysis conducted on 9 851 867 SNPs; the nitrogen oxides dataset included 456 380 cases, with correlation analysis conducted on 9 851 867 SNPs. AD was used as the outcome factor, and data were obtained from the International Genomics of Alzheimer′s Project (IGAP). The AD dataset included 25 580 cases and 48 466 controls, with correlation analysis of 7 067 513 SNPs. SNPs significantly associated with AD were used as instrumental variables. The main analysis was conducted by using the inverse variance weighted (IVW) method, and four methods including weighted median, MR-Egger regression, mode-based simple estimation and mode-based weighted estimation were used for quality control. Heterogeneity testing, gene pleiotropy testing and sensitivity analysis were conducted to assess the reliability of the study results. Results ·Heterogeneity testing indicated no evidence of heterogeneity among SNPs associated with air pollution indicators and AD (both IVW and MR-Egger results, P>0.05). Gene pleiotropy testing did not detect any pleiotropic effects (MR-Egger results, P>0.05). Sensitivity analysis confirmed the stability of the PM_2.5 results. IVW analysis revealed a statistically significant association between PM_2.5 and AD in European populations (P<0.001), while no statistically significant associations were observed between PM_2.5-10 (P=0.664), PM₁₀ (P=0.664), nitrogen dioxide (P=0.284), nitrogen oxides (P=0.567) and AD. Conclusion ·There is a significant causal relationship between PM_2.5 exposure and the risk of AD, with PM_2.5 exposure increasing the incidence of AD. However, no evidence has been found to suggest that PM_2.5-10, PM₁₀, nitrogen dioxide or nitrogen oxides cause an increased risk of AD.

Key words: Alzheimer′s disease (AD), air pollution, Mendelian randomization (MR), causal inference

CLC Number:

R749.1

ZHANG Yingying, ZHANG Junyao, SONG Jiwei, WANG Shengjie, YAO Junyan. Two-sample Mendelian randomization study on the causal association between air pollution and Alzheimer′s disease[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(1): 87-94.

Figures/Tables 7

TrendMD

References 39

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Exposure	Outcome	SNP/n	MR method	P value	OR value	95%CI	Pleiotropy P value	Heterogeneity P value
PM_2.5	AD	48	MR-Egger	0.874	0.863	0.141‒5.295	0.278	0.453
			WM	0.031	2.186	1.073‒4.453
			IVW	<0.001	2.302	1.421‒3.729		0.444
			Simple mode	0.192	2.777	0.615‒12.550
			Weighted mode	0.291	2.175	0.524‒9.024
PM_2.5-10	AD	4	MR-Egger	0.432	0.905	0.741‒1.106	0.300	0.967
			WM	0.890	0.992	0.878‒1.119
			IVW	0.664	1.023	0.924‒1.131		0.576
			Simple mode	0.945	1.007	0.828‒1.225
			Weighted mode	0.782	0.980	0.860‒1.116
PM₁₀	AD	4	MR-Egger	0.432	0.905	0.741‒1.106	0.300	0.967
			WM	0.890	0.992	0.878‒1.119
			IVW	0.664	1.023	0.924‒1.131		0.576
			Simple mode	0.945	1.007	0.828‒1.225
			Weighted mode	0.782	0.980	0.860‒1.116
Nitrogen dioxide	AD	84	MR-Egger	0.973	0.978	0.271‒3.531	0.705	0.428
			WM	0.303	1.354	0.756‒2.423
			IVW	0.284	1.239	0.837‒1.834		0.457
			Simple mode	0.216	2.512	0.591‒10.670
			Weighted mode	0.294	2.063	0.538‒7.910
Nitrogen oxides	AD	67	MR-Egger	0.682	0.703	0.131‒3.764	0.563	0.206
			WM	0.892	0.960	0.536‒1.721
			IVW	0.567	1.137	0.733‒1.762		0.223
			Simple mode	0.444	0.578	0.144‒2.330
			Weighted mode	0.538	0.649	0.165‒2.549

Exposure	Outcome	SNP/n	MR method	P value	OR value	95%CI	Pleiotropy P value	Heterogeneity P value
PM_2.5	AD	48	MR-Egger	0.874	0.863	0.141‒5.295	0.278	0.453
			WM	0.031	2.186	1.073‒4.453
			IVW	<0.001	2.302	1.421‒3.729		0.444
			Simple mode	0.192	2.777	0.615‒12.550
			Weighted mode	0.291	2.175	0.524‒9.024
PM_2.5-10	AD	4	MR-Egger	0.432	0.905	0.741‒1.106	0.300	0.967
			WM	0.890	0.992	0.878‒1.119
			IVW	0.664	1.023	0.924‒1.131		0.576
			Simple mode	0.945	1.007	0.828‒1.225
			Weighted mode	0.782	0.980	0.860‒1.116
PM₁₀	AD	4	MR-Egger	0.432	0.905	0.741‒1.106	0.300	0.967
			WM	0.890	0.992	0.878‒1.119
			IVW	0.664	1.023	0.924‒1.131		0.576
			Simple mode	0.945	1.007	0.828‒1.225
			Weighted mode	0.782	0.980	0.860‒1.116
Nitrogen dioxide	AD	84	MR-Egger	0.973	0.978	0.271‒3.531	0.705	0.428
			WM	0.303	1.354	0.756‒2.423
			IVW	0.284	1.239	0.837‒1.834		0.457
			Simple mode	0.216	2.512	0.591‒10.670
			Weighted mode	0.294	2.063	0.538‒7.910
Nitrogen oxides	AD	67	MR-Egger	0.682	0.703	0.131‒3.764	0.563	0.206
			WM	0.892	0.960	0.536‒1.721
			IVW	0.567	1.137	0.733‒1.762		0.223
			Simple mode	0.444	0.578	0.144‒2.330
			Weighted mode	0.538	0.649	0.165‒2.549

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