Abstract
Background: Several studies have linked type 2 diabetes (T2D) to an increased risk of developing Alzheimer’s disease (AD). This has led to an interest in using antidiabetic treatments for the prevention of AD. However, the underlying mechanisms explaining the relationship between T2D and AD have not been completely elucidated.Objective: Our objective was to examine cerebral 18F-fluorodeoxyglucose (FDG) uptake during normal aging and in AD patients in regions associated with diabetes genetic risk factor expression to highlight which genes may serve as potential targets for pharmaceutical intervention.Methods: We calculated regional glucose metabolism differences in units of standardized uptake values (SUVR) for 386 cognitively healthy adults and 335 clinically probable AD patients. We then proceeded to extract gene-expression data from the publicly available Allen Human Brain Atlas (HBA) database. We used the nearest genes to 46 AD- and T2D-associated SNPs previously identified in the literature, and mapped their expression to the same 34 cortical regions in which we calculated SUVRs. SNPs with a donor consistency of 0.40 or greater were selected for further analysis. We evaluated the associations between SUVR and gene-expression across the brain.Results: Of the 46 risk-factor genes, 15 were found to be significantly correlated with FDG-PET brain metabolism in healthy adults and probable AD patients after correction for multiple comparisons. Using multiple regression, we found that five genes explained a total of 72.5% of the SUVR variance across the healthy adult group regions, while four genes explained a total of 79.3% of the SUVR variance across the probable AD group regions. There were significant differences in whole-brain SUVR as a function of allele frequencies for two genes.Conclusions: These results highlight the association between risk factor genes for T2D and regional glucose metabolism during both normal aging and in probable AD. Highlighted genes were associated with mitochondrial stability, vascular maintenance, and glucose intolerance. Pharmacological intervention of these pathways has the potential to improve glucose metabolism during normal again as well as in AD patients.
Highlights
There is a considerable body of literature on associations between type 2 diabetes (T2D) and dementia, especially Alzheimer’s disease (AD)
We found that Single Nucleotide Polymorphism (SNP) located in two genes (SRR and TCF7L2) were most strongly associated with the conversion of mild cognitive impairment (MCI) to probable AD
Using 31 T2D associated SNPs previously identified in our Girard et al.’s (2018) study, as well as 15 T2D associated SNPs validated by Mahajan et al (2018), we evaluated associations between SUVR and gene-expression across the brain
Summary
There is a considerable body of literature on associations between type 2 diabetes (T2D) and dementia, especially Alzheimer’s disease (AD). Cheng et al (2012) found that participants with T2D had a 21% higher risk for mild cognitive impairment (MCI), 46% higher risk for AD, and 51% higher risk for any dementia than participants without diabetes. This association has led to an increased interest in using anti-diabetic treatment for the prevention of AD. Several studies have linked type 2 diabetes (T2D) to an increased risk of developing Alzheimer’s disease (AD). This has led to an interest in using antidiabetic treatments for the prevention of AD. The underlying mechanisms explaining the relationship between T2D and AD have not been completely elucidated
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