Abstract
BACKGROUND: The impact of diabetes on the risk of Alzheimer's disease remains uncertain. This study aimed to explore this issue from multiple perspectives by using the Mendelian randomization (MR) approach. METHODS: Instrumental variables for predicting six diabetic traits (including insulin and blood glucose), eight metabolic risk factors for diabetes (including total cholesterol and blood pressure), and seven diabetic genes were extracted from their summary data. These data were derived from multiple European cohorts and included 31,684 to 810,865 subjects respectively. The two-sample MR, multivariate MR, and summary-data-based Mendelian randomization (SMR) methods were employed to determine the associations of these traits or genes with the risk of Alzheimer's disease. RESULTS: The two-sample MR showed that elevated fasting insulin and total cholesterol levels were associated with an increased risk of dementia in Alzheimer's disease (P = 0.022, P = 0.041). Elevated systolic and diastolic blood pressure levels were associated with a decreased risk of dementia in Alzheimer's disease (P = 0.036, P = 0.025). The multivariate MR reported that adjusting for telomere length (a well-established biomarker of aging) did not change these findings (P < 0.05). Additionally, the two-sample MR showed that type 1 and type 2 diabetes did not affect the risk of Alzheimer's disease. The SMR also indicated that the diabetic genes did not affect the risk of this disease. CONCLUSION: Multiple MR approaches concluded that fasting insulin, total cholesterol, and blood pressure, rather than diabetes, were potential metabolic variables that had an impact on the risk of Alzheimer's disease. However, aging might not be involved in these correlations.