Elevated blood glucose levels are associated with the progression of brain hypometabolism, and HDL-C and APOE4 add to this association

BackgroundBrain glucose hypometabolism has consistently been found in neurodegenerative disorders, including Alzheimers disease (AD). High blood glucose and HDL cholesterol (HDL-C) levels have also been linked to neurodegeneration and AD. However, there is limited understanding of the relationships between dementia-related risk factors in the brain and blood. MethodsA linear mixed model was used to examine the relationship between blood glucose and HDL-C levels and the progression of brain hypometabolism, adjusting for APOE4 and other clinical covariates. The hypometabolic convergence index (HCI) was measured by fluorodeoxyglucose-18 (FDG) positron emission tomography (PET) in participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). Data visualizations were generated to understand the joint effects of plasma glucose, HDL-C, and APOE4 on HCI. ResultsThere were 336 individuals (781 observations), of whom 22.62% had AD. The majority were male (63.98%) and of white race, and 48.51% were carriers of APOE4. Over time, high blood glucose level was associated with the progression of brain glucose hypometabolism ({beta}=0.33, 95% CI: 0.02, 0.64, p<0.05). A high plasma HDL-C level ({beta}=1.22, 95% CI: 0.09, 2.35, p<0.05), more study visits ({beta}=1.67, 95% CI: 1.37, 1.98, p<0.001), and being an APOE4 allele carrier ({beta}=1.29, 95% CI: 0.15, 2.42, p<0.05) were also significant predictors of brain hypometabolism progression. APOE4 carrier status and number of visits account for the largest proportion of the variance from the fixed effects model. Random effects due to participant characteristics and fixed effects together accounted for 95.2% of the model variance. Subgroup analysis revealed that these effects were observed only in those without AD. ConclusionHigh plasma glucose levels facilitated the progression of brain hypometabolism. The effect was more prominent in the APOE4 double-carriers with elevated HDL-C. Elevated blood glucose may reflect systemic insulin resistance, which could impair brain glucose uptake, resulting in brain hypometabolism. Controlling blood glucose and HDL-C levels in APOE4 carriers may improve brain metabolism, potentially delaying the onset of dementia.