title: Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study.
abstract: 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.
authors.affiliation: *Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco ∥Department of Medicine, Division of General Medical Disciplines, Stanford University, Stanford, CA Departments of †Social and Behavioral Sciences §Nutrition, Harvard School of Public Health, Boston, MA ‡Department of Medicine, Division of General Internal Medicine, University of Washington, Seattle, WA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Walter
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Marden
authors.forename: Laura D
authors.initials: LD
authors.lastname: Kubzansky
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Mayeda
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.forename: Shun-Chiao
authors.initials: SC
authors.lastname: Chang
authors.forename: Marilyn
authors.initials: M
authors.lastname: Cornelis
authors.forename: David H
authors.initials: DH
authors.lastname: Rehkopf
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.forename: M Maria
authors.initials: MM
authors.lastname: Glymour
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin; D057182:Mendelian Randomization Analysis / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D007328:Insulin