The study aimed to investigate the aberration of brain spontaneous activity and synchronization in type 2 diabetes mellitus (T2DM) patients homozygous for the apolipoprotein E (APOE)-ε3 allele. In the APOE-ε3 homozygotes, 37 T2DM patients and 37 well-matched healthy controls (HC) were included to acquire blood sample measurements, neuropsychological tests, and brain functional MRI data. The amplitude of low-frequency fluctuations (ALFF) analysis was conducted to identify the brain areas with abnormal spontaneous activity. Then, the identified brain areas were taken as seeds to compute their functional connectivity (FC) with other brain regions. The two-sample t-test or the Mann–Whitney U test were applied to reveal significant differences in acquired measurements between the two groups. The potential correlations among the three types of measurements were explored using partial correlation analysis in the T2DM group. The T2DM group had elevated glycemic levels and scored lower on the cognitive assessment but higher on the anxiety and depression tests (p < 0.05). The T2DM group exhibited higher ALFF in the left middle occipital gyrus, and the left middle occipital gyrus had lower FC with the left caudate nucleus and the left inferior parietal gyrus (p < 0.05). No significant correlations were observed. T2DM patients homozygous for the APOE-ε3 allele exhibited aberrant brain spontaneous activity and synchronization in brain regions associated with vision-related information processing, executive function, and negative emotions. The findings may update our understanding of the mechanisms of brain dysfunction in T2DM patients in a neuroimaging perspective.

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