In summary, this study demonstrated that ApoE deficiency aggravated cognitive function and hippocampal synaptic ultrastructural damage in aging mice, aggravated the dysregulation of hippocampal SYP and PSD-95 protein expression, affected the gut microbial composition and hippocampal metabolic profile in aging mice, and aggravated dyslipidemia and oxidative stress in aging mice. Here, DLG4 is linked to metabolic syndrome.