Abstract
Previous observational studies have reported an association between impaired glucose metabolism and Alzheimer’s disease. This study aimed to examine the causal association of glycemic traits with Alzheimer’s disease. We used a two-sample Mendelian randomization approach to evaluate the causal effect of six glycemic traits (type 2 diabetes, fasting glucose, fasting insulin, hemoglobin A1c, homeostasis model assessment- insulin resistance and HOMA-β-cell function) on Alzheimer’s disease. Summary data on the association of single nucleotide polymorphisms with these glycemic traits were obtained from genome-wide association studies of the DIAbetes Genetics Replication And Meta-analysis and Meta-Analyses of Glucose and Insulin-related traits Consortium. Summary data on the association of single nucleotide polymorphisms with Alzheimer’s disease were obtained from the International Genomics of Alzheimer's Project. The Mendelian randomization analysis showed that 1-standard deviation higher fasting glucose and lower HOMA-β-cell function (indicating pancreatic β-cell dysfunction) were causally associated with a substantial increase in risk of Alzheimer’s disease (odds ratio=1.33, 95% confidence interval: 1.04-1.68, p=0.02; odds ratio=1.92, 95% confidence interval: 1.15-3.21, p=0.01). However, no significant association was observed for other glycemic traits. This Mendelian randomization analysis provides evidence of causal associations between glycemic traits, especially high fasting glucose and pancreatic β-cell dysfunction, and high risk of Alzheimer's disease.
Highlights
Alzheimer’s disease is a major and increasing global health challenge in elderly people without available curative treatment [1]
The inverse-variance weighted (IVW) method showed that 1-standard deviation (SD) higher fasting glucose and lower HOMA-β-cell function (HOMA-β) were causally associated with a substantial increase in risk of Alzheimer’s disease (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.04-1.68, p=0.02; OR=1.92, 95% CI: 1.15-3.21, p=0.01) (Figure 1)
Similar association was observed in fasting glucose using the penalized robust IVW, weighted mode-based estimate (MBE) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods, but not using the Mendelian randomization (MR)-Egger, simple median and weighted median methods of MR analyses (Table 1)
Summary
Alzheimer’s disease is a major and increasing global health challenge in elderly people without available curative treatment [1]. Several epidemiological studies have suggested that some modifiable risk factors, such as type 2 diabetes and insulin resistance, were associated with cognitive decline or Alzheimer’s disease [3,4,5,6,7]. Positive association was not observed in another study [8]. Observational studies might be confounded by potential confounders and reverse causation [9]. Whether the association between glucose metabolism and Alzheimer’s disease observed in observational studies reflect causal association needs further investigation. The causal association between impaired glucose metabolism and Alzheimer’s disease is still controversial
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