Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis

Abstract

Objective: To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease.

Design: Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables.

Setting: International Genomics of Alzheimer's Project.

Participants: 17 008 cases of Alzheimer's disease and 37 154 controls.

Main outcome measures: Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis.

Results: This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer's. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10^-6) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10^-5) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer's (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer's and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer's. Genetically predicted alcohol consumption, serum folate, serum vitamin B₁₂, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer's disease.

Conclusion: These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer's disease.

Fig 1

Principles of Mendelian randomisation analysis for modifiable risk factor and risk of Alzheimer’s disease and assumptions that need to be met to obtain unbiased estimates of causal effects. Broken lines represent potential pleiotropic or direct causal effects between variables that would violate Mendelian randomisation assumptions. SNP₁, SNP₂, SNP_j=single nucleotide polymorphisms

Fig 2

Odds ratios for associations between genetically predicted higher educational attainment, intelligence, and lifestyle and dietary factors and Alzheimer’s disease. Estimates are per year of education completed, 1 unit higher log odds of college/university completion, 1 SD higher intelligence, 10 cigarettes/day, drink of alcohol/week, cup of coffee/day, 20% increase of 25-hydroxyvitamin D concentration, and 1 SD serum folate, serum vitamin B₁₂, and total homocysteine. *Excludes one outlying genetic variant (rs1051730) in or near neuronal nicotinic acetylcholine receptor genes (CHRNA3, CHRNA5, and CHRNB4). SNPs=single nucleotide polymorphisms

Fig 3

Odds ratios for associations between genetically predicted cardiometabolic and inflammatory factors and Alzheimer’s disease. Estimates are per approximate 1 SD increase of continuous risk factors and per 1 unit higher log odds of type 2 diabetes. *Excludes one pleiotropic genetic variant near the APOE gene (also near APOC1 and TOMM40 genes). SNPs=single nucleotide polymorphisms; HDL=high density lipoprotein; LDL=low density lipoprotein