Diabetic phenotypes and late-life dementia risk: A mechanism-specific mendelian randomization study

Stefan Walter, Jessica R. Marden, Laura D. Kubzansky, Elizabeth R. Mayeda, Paul K. Crane, Shun Chiao Chang, Marilyn Cornelis, David H. Rehkopf, Shubhabrata Mukherjee, M. Maria Glymour*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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 b-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.

Original languageEnglish (US)
Pages (from-to)15-20
Number of pages6
JournalAlzheimer Disease and Associated Disorders
Issue number1
StatePublished - 2016


  • Alzheimer disease
  • Dementia
  • Insulin sensitivity
  • Mendelian Randomization study
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • Gerontology


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