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This investigation reveals distinct metabolic differences in Alzheimer’s disease dementia progression among Type 2 diabetes patients, suggesting neuro-metabolic vulnerability.
Background and Purpose Type 2 diabetes (T2D) is a major metabolic risk factor for Alzheimer's disease dementia (ADD), yet it remains unclear whether cognitive decline in T2D follows a distinct cerebral metabolic trajectory. We investigated whether [ 1 8 F]FDG‐PET hypometabolism differs between T2D patients with mild cognitive impairment (MCI) versus ADD, and whether peripheral metabolomic profiles mirror AD‐sensitive brain vulnerability. Methods Nineteen patients with T2D (11 MCI, 8 ADD) underwent [ 1 8 F]FDG‐PET and plasma metabolomics. Cerebral glucose metabolism was assessed voxel‐wise and region‐wise using global‐mean normalization, with group comparisons adjusted for age, sex, HbA1c, and systolic blood pressure. Metabolite group differences and ROI–metabolite associations were evaluated using multiple‐comparison–corrected statistical models. Results ROI analyses showed lower global‐mean–normalized FDG uptake in T2D + ADD versus T2D + MCI, with the right hippocampus and right parahippocampal gyrus (PHG) remaining significant after BH–FDR correction. Voxel‐wise analysis identified one FWE‐corrected cluster of relative hypometabolism in T2D + ADD centered in the left inferior temporal gyrus. Several metabolites differed between groups at the uncorrected level, but none remained significant after BH–FDR correction. ROI–metabolite coupling patterns were stage dependent: in T2D + MCI, right parahippocampal uptake was negatively correlated with glutamine and amino acids and positively correlated with lipoproteins (BH–FDR significant), whereas in T2D + ADD the same ROI showed positive correlations with dimethylglycine (DMG), dimethylamine (DMA), albumin‐lysyl, and 2‐oxoglutarate, and the left inferior temporal gyrus correlated negatively with amino acids. Conclusions In T2D, ADD is characterized by medial temporal and lateral temporal–parietal hypometabolism accompanied by stage‐specific peripheral metabolite coupling, supporting a progression‐sensitive neuro‐metabolic vulnerability signature.
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Hammawa et al. (2026) studied this question.