期刊
ALZHEIMER DISEASE & ASSOCIATED DISORDERS
卷 30, 期 1, 页码 15-20出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/WAD.0000000000000128
关键词
dementia; Alzheimer disease; type 2 diabetes mellitus; Mendelian Randomization study; insulin sensitivity
资金
- National Institute of Neurological Disorders and Stroke [NINDS T32 NS048005]
- French National Foundation on Alzheimer's disease and related disorders
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant
- Inserm
- Institut Pasteur de Lille, Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]
- NIA [AG081220]
- AGES [N01-AG-12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center
- Erasmus University
- Alzheimer's Association [ADGC-10 196728]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL105756] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [T32NS048005] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG008122, U24AG021886, N01AG012100, R01AG033193, K01AG047280, U01AG016976, U01AG032984] Funding Source: NIH RePORTER
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 -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.
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