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Impact of glucose on risk of dementia: Mendelian randomisation studies in 115,875 individuals

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AIMS/HYPOTHESIS: Mendelian randomisation studies have not shown a clear causal effect of high plasma glucose on the risk of Alzheimer's disease. We tested the hypothesis that high plasma glucose caused by genetic variation has a causal effect on the risk of unspecified dementia, Alzheimer's disease and vascular dementia in the general population.

METHODS: A Mendelian randomisation design was used with data from 115,875 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study. Findings for Alzheimer's disease were validated in a two-sample Mendelian design with 455,258 individuals, including 71,880 individuals with Alzheimer's disease or a parent with Alzheimer's disease.

RESULTS: In observational multifactorial-adjusted analyses, HRs were 1.15 (95% CI 1.01, 1.32; p = 0.039) for unspecified dementia, 0.91 (95% CI 0.79, 1.06; p = 0.22) for Alzheimer's disease and 1.16 (95% CI 0.86, 1.55; p = 0.34) for vascular dementia in individuals with a glucose level higher than 7 vs 5-6 mmol/l. Corresponding HRs in individuals with vs without type 2 diabetes were 1.42 (95% CI 1.24, 1.63; p < 0.001), 1.11 (95% CI 0.95, 1.29; p = 0.18) and 1.73 (95% CI 1.31, 2.27; p < 0.001). In genetic causal analyses, a 1 mmol/l higher plasma glucose level had RRs of 2.40 (95% CI 1.18, 4.89; p = 0.016) for unspecified dementia, 1.41 (95% CI 0.82, 2.43; p = 0.22) for Alzheimer's disease and 1.20 (95% CI 0.82, 1.75; p = 0.36) for vascular dementia. Summary-level data from the Meta-Analyses of Glucose and Insulin-related Traits Consortium (MAGIC) combined with a consortium of the Alzheimer's Disease Sequencing Project (ADSP), the International Genomics of Alzheimer's Project (IGAP), the Alzheimer's Disease Working Group of the Psychiatric Genomics Consortium (PGC-ALZ) and the UK Biobank (UKB) gave an RR for Alzheimer's disease of 1.02 (95% CI 0.92, 1.13; p = 0.42), and this consortium combined with Copenhagen studies gave an RR for Alzheimer's disease of 1.03 (95% CI 0.93, 1.13; p = 0.36).

CONCLUSIONS/INTERPRETATION: Observational and genetically high plasma glucose are causally related to the risk of unspecified dementia, but not to Alzheimer's disease or vascular dementia.

Original languageEnglish
JournalDiabetologia
Volume63
Issue number6
Pages (from-to)1151-1161
Number of pages11
ISSN0012-186X
DOIs
Publication statusPublished - Jun 2020

ID: 60073946