Increasing fasting glucose is associated with Alzheimer’s disease–related neuropathological and structural decline in older adults

Background Research on risk factors for dementia and in preclinical populations has shown that glucose regulation may be involved in amyloid synthesis, cognitive processing, and neurodegeneration; however, the extent to its involvement is unclear. Fasting glucose is a straightforward measure that could be a window into metabolic changes either associated with or preceding dementia. Method We sought to test whether a change in fasting glucose over one year was related to multi‐modal brain imaging measures of neuropathological changes in the brain associated with dementia. We leveraged longitudinal biospecimens and neuroimaging measures collected during the Alzheimer’s Prevention through Exercise (APEX) trial (n=109) to examine the longitudinal relationship between change in fasting glucose and change in neurodegeneration and cerebral amyloid over 1 year of follow‐up. Result The group of individuals with stable or improving fasting glucose (n=65) exhibited less atrophy and regional amyloid accumulation compared to the group whose fasting glucose worsened over 1 year (n=44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus, reduced diffusion in limbic white matter, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by APOE4 carrier status. Increasing fasting glucose may reflect changes in cellular bioenergetics associated with Alzheimer’s disease neuropathophysiology. Conclusion Dysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine if treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.