|Title||Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Walter, S, Marden, JR, Kubzansky, LD, Mayeda, ER, Crane, PK, Chang, S-C, Cornelis, MC, Rehkopf, D, Mukherjee, S, M. Glymour, M|
|Journal||Alzheimer Dis Assoc Disord|
|Date Published||2016 Jan-Mar|
|Keywords||Alzheimer disease, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Humans, Insulin, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Risk Factors|
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.
|User Guide Notes|
|Alternate Journal||Alzheimer Dis Assoc Disord|
|PubMed Central ID||PMC4879683|
|Grant List||082604/2/07/Z / / Wellcome Trust / United Kingdom |
U24 AG021886 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
T32 NS048005 / NS / NINDS NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
503176 / / Medical Research Council / United Kingdom
AG081220 / AG / NIA NIH HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
K01 AG047280 / AG / NIA NIH HHS / United States