FASTING GLUCOSE AND WHITE MATTER INTEGRITY: BENEFICIAL FOLLOWED BY DETRIMENTAL ASSOCIATIONS OVER TIME IN PRECLINICAL AD AND ALONG THE AD SPECTRUM

Pre- and type 2 diabetes (“diabetes”) increase the risk for Alzheimer's disease (AD). In normal aging, higher fasting glucose has been consistently associated with less white matter integrity in temporal and frontal areas. However, it is largely unknown how AD genetic risk factors or clinical diagnosis influence associations between fasting glucose and both baseline and longitudinal changes in white matter microstructure. Diffusion tensor imaging (DTI) was conducted in 12,740 UK Biobank and 233 ADNI participants respectively at baseline and over 5 visits spanning 3 years. Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were assessed in 7 JHU-defined AD-sensitive white matter tracts: fornix, parahippocampal and cingulate cingulum, corpus callosum, superior longitudinal and uncinate fasciculi, and tapetum. Main effects and interactions were tested with type 2 diabetes or fasting glucose, AD parental family history status or Apolipoprotein E ε4 (APOE4) status, and baseline clinical diagnosis. Further interactions with chronological Age or Time were explored. In UK Biobank, among participants with diabetes (n=764), AD parental history tripled the statistical effect beyond of having diabetes only for all tracts and diffusion measures except the fornix and cingulate cingulum. For example, in parahippocampal cingulum, AD parental history + diabetes had 3.5% lower FA and 11% greater RD vs. 1% lower FA and 3% greater RD for diabetes. Among non-APOE4 carriers, diabetes was related to more axonal integrity regardless of age. For APOE4 carriers, having diabetes was linked to more axonal integrity in middle-age (40-65 years) but precipitous loss in old age (>65 years) (Figure 1). In ADNI, similar AD parental family history and APOE4 status associations were seen. Among clinical groups, for all tracts and diffusion measures, higher fasting glucose predicted more tract integrity in normals, but less integrity in MCI and especially AD (Figure 2). These relationships became stronger over 3 years.