Treatments for Alzheimer's disease (AD) and cognitive decline is a health priority in our aging population and especially in elderly with type 2 diabetes (T2D) who are at high risk of developing these conditions. Compelling small scale studies suggest that high dietary and serum levels of Advanced Glycation End products (AGEs), a group of glucose-derived compounds, chronically elevated in T2D, contribute to cognitive impairment and increased AD and vascular brain pathology in old age. However, there is scarcity of large scale longitudinal studies of well-characterized older adults with T2D making it difficult to obtain evidence linking dietary and serum AGEs with impaired cognition in T2D elderly and whether serum AGEs mediate the associations of dietary AGEs with cognition. These gaps in knowledge impede the development of treatments based on AGEs to decrease the growing burden of AD and cognitive decline. To fill these gaps, the overall goal of this proposal is to test the hypothesis that dietary and circulating AGEs are related to impaired cognition in T2D elderly through an association with AD-related and cerebrovascular neuropathologies. To achieve these aims, we will enroll 921 non-demented community-dwelling T2D older adults from the Israel Diabetes and Cognitive Decline Study (IDCD; R01 AG034087) who undergo annual cognitive testing. This study proposes a comprehensive assessment of dietary and serum AGEs levels. In 255 IDCD participants we will quantify blood brain barrier (BBB) dysfunction (using novel contrast-enhanced MRI), cerebral blood flow (CBF; via ASL-MRI), cerebrovascular reactivity (with Transcranial Doppler), carotid plaque volume burden (via 3D ultrasound), and amyloid (via PET). This comprehensive large-scale study will 1) provide evidence that dietary and serum AGEs levels are related to incident dementia and cognitive decline in older adults with T2D, 2) identify the key neuropathological indices linking dietary and serum AGEs with cognition and 3) test if serum AGEs mediate the association of dietary AGEs with cognition and neuropathology. These data are crucial for developing treatments targeting AGEs for late-life T2D-related cognitive impairment. Thus, these data have the potential to decrease the growing burden of cognitive impairment and affect the brain health of millions in our aging population.
A comprehensive assessment of dietary and serum levels of Advanced Glycation End products (AGEs) in older adults with type 2 diabetes will determine if AGEs are associated with incident dementia, cognitive decline, and neuropathological indices of cerebrovascular and Alzheimer's disease (AD). Identifying modifiable metabolites associated with impaired cognition, has potential to lead to new treatments that may decrease the growing burden of impaired cognition in T2D elderly and in the aging community as a whole.
