Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis

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 B(12), 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.