Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study

Alzheimer Dis Assoc Disord. Jan-Mar 2016;30(1):15-20. doi: 10.1097/WAD.0000000000000128.


Background: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result.

Methods: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including β-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation.

Results: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95% CI, 1.02, 1.34). In the Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant.

Conclusions: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall.

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / genetics*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Genetic Predisposition to Disease*
  • Humans
  • Insulin
  • Mendelian Randomization Analysis / methods
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Risk Factors


  • Insulin