Evidence of a Causal Association Between Cancer and Alzheimer’s Disease: a Mendelian Randomization Analysis

Abstract

ObjectivesTo determine whether cancer confers protection against Alzheimers disease and to evaluate the relationship in the context of smoking-related cancers versus non-smoking related cancers\n\nDesignMendelian randomization analysis using cancer-associated genetic variants as instrumental variables\n\nSettingInternational Genomics of Alzheimers Project\n\nParticipants17,008 Alzheimers disease cases and 37,154 controls\n\nMain outcome measuresOdds ratio of Alzheimers disease per 1-unit higher log odds of genetically predicted cancer\n\nResultsWe found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84-0.99, p=0.019), leukemia (OR 0.98, 95% CI 0.96-0.995, p=0.012), and breast cancer (OR 0.94, 95% CI 0.89-0.99, p=0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of Alzheimers disease, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of Alzheimers disease (OR 0.98, 95% CI 0.96-0.988, p=0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with Alzheimers disease than non-smoking related cancers (5.2% lower odds, OR 0.95, 95% CI 0.92-0.98, p=0.0026, vs. 1.9% lower odds, OR 0.98, 95% CI 0.97-0.995, p=0.0091).\n\nConclusionsGenetically predicted lung cancer, leukemia, breast cancer, and all cancers in aggregate are associated with lower odds of incident Alzheimers disease. Furthermore, the risk of Alzheimers disease was lower in smoking-related versus non-smoking related cancers. These results add to the substantial epidemiological evidence of an inverse association between history of cancer and lower odds of Alzheimers disease, by suggesting a causal basis for this relationship.