P4-321: synergistic interaction between homocysteine and blood glucose for age-specific brain atrophy in non-demented individuals

Previous studies indicated that both type 2 diabetes mellitus (DM) and high plasma homocysteine are associated with cognitive impairment or dementia. Moreover, the association of homocysteine with cognitive decline is known to be greater in the presence of DM, suggesting interaction between homocysteine and DM or blood glucose control. However, little information is available for the neuropathological links underlying the interaction. We aimed to investigate the interaction effect of homocysteine and blood glucose or presence of DM on aging-related brain change and Alzheimer's disease (AD)-related in vivo brain pathologies measured by multi-modal neuroimaging modalities in non-demented middle- or old-aged individuals. This study included 460 non-demented [(291 cognitively normal (CN) and 139 mild cognitive impairment (MCI)] subjects who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease (KBASE), an ongoing cohort study initiated in 2014. All participants underwent comprehensive clinical and neuropsychological assessment, blood tests including fasting glucose (FBS) and HbA1C, [11C] Pittsburgh Compound B (PiB) positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET and brain magnetic resonance imaging. Plasma homocysteine was significantly associated with spatial pattern of atrophy for recognition of brain aging (SPARE-BA) index after controlling potentials confounders, which captures aging-specific brain atrophy patterns (Habes et al., 2016), while blood HbA1C showed trend level association with SPARE-BA. The interaction effect between homocysteine and HbA1C on SPARE-BA was also significant: i.e., homocysteine-related SPARE-BA decline was greater in participants with higher HbA1C than those with lower HbA1C (Figure). Similarly, the presence of DM moderated the effect of homocysteine on SPARE-BA (Figure). In contrast, we did not find any interaction between homocysteine and HbA1C (or DM) regarding global amyloid deposition, adjusted hippocampal volume, AD-signature region cerebral glucose metabolism, and white matter hyperintensity volume.