Glycemic traits and Alzheimer’s disease: a Mendelian randomization study

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.

An expanded GWAS of T2D in Europeans were performed with a GWAS stage 1 and Metabochip stage 2. The DIAGRAM stage 1 analyses comprised a total of 26,676 T2D cases and 132,532 control participants from 18 GWAS (ARIC, BioMe, deCODE, DGDG, DGI, EGCUT-370, EGCUT-OMNI, EPIC-InterAct, FHS, FUSION, GoDARTS, HPFS, KORAgen, NHS, PIVUS, RS-I, ULSAM, WTCCC). The Metabochip stage 2 follow up comprised 14,545 T2D case and 38,994 control subjects from 16 studies (D2D2007, DANISH, DIAGEN, DILGOM, DRsEXTRA, EMIL-Ulm, FUSION2, NHR, IMPROVE, InterACT-CMC, Leipzig, METSIM, HUNT/TROMSO, SCARFSHEEP, STR, Warren2/58BC) with Metabochip data, in which the participants did not overlap those included in stage 1. Stage 1 study sizes ranged between 80 and 7,249 T2D cases and from 455 to 83,049 controls. The Metabochip follow-up study sizes ranged from 101 and 3,553 T2D cases and from 586 to 6,603 controls. For SNVs not captured on Metabochip directly or by proxy, follow-up in 2,796 individuals with T2D and 4,601 controls from the EPIC-InterAct study was performed. In addition, 9,747 T2D cases and 61,857 controls from the GERA study were used to follow-up six low frequency variants not captured on Metabochip. All study participants were of European ancestry and were from the United States and Europe (PMID: 28566273).

Meta-analyses of glucose and insulin-related traits consortium (MAGIC)
MAGIC represents a collaborative effort to combine data from multiple GWAS to identify additional loci that impact on glycemic and metabolic traits. MAGIC investigators have initially studied fasting glucose, fasting insulin, 2h glucose and HbA1c, as well as performed meta-analysis of more sophisticated measures of insulin secretion and sensitivity.
GWAS meta-analysis data results for fasting glucose are from models adjusted for age and sex, and from up to 133,010 non-diabetic participants of European ancestry from 66 studies. Fasting insulin results are for lntransformed fasting insulin as the outcome and are adjusted for age, sex and are reported both with and without BMI adjustment, and from up to 108,557 individuals of European ancestry from 56 studies (PUBMED: 22885924).
Ancestry-specific and transethnic genome-wide metaanalysis summary statistics for association with HbA1c in up to 159,940 individuals from 82 cohorts of European (N=123,665), African (N=7,564), East Asian (N=20,838) and South Asian (N=8,874) ancestry. All participants were free of diabetes. HbA1c trait values are untransformed and adjusted for age, sex and studyspecific covariates (PMID: 28898252). Only data of European ancestry were used in the present analysis.
The fasting insulin and fasting glucose datasets were generated by performing a meta-analysis of up to 21 genome-wide association studies (GWAS) informative for fasting glucose, fasting insulin and indices of β-cell function (HOMA-β) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 lead SNPs were performed in up to 76,558 additional individuals of European ancestry. Fasting glucose trait values are not transformed. Trait values for fasting insulin, HOMA-IR, HOMA-β and fasting proinsulin have been naturally log transformed. All datasets are adjusted for age, sex and study-specific covariates (PMID: 20081858).

International Genomics of Alzheimer's Project (IGAP)
IGAP is a large two-stage study based upon GWAS on individuals of European ancestry. In stage 1, IGAP used genotyped and imputed data on 7,055,881 SNPs to meta-analyse four GWAS datasets with a total of 17,008 Alzheimer's disease cases and 37,154 controls (The Alzheimer Disease Genetics Consortium [ADGC], The Cohorts for Heart and Aging Research in Genomic Epidemiology consortium [CHARGE], The European Alzheimer's disease Initiative [EADI], and The Genetic and Environmental Risk in AD consortium [GERAD]). In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. The present study used the dataset of stage 1 of the IGAP (PMID: 24162737).
The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips was funded by the French National