biostudies-literatureFleeman RMNIA NIH HHSNIAAA NIH HHSNINDS NIH HHSNIH HHS154-169https://www.ebi.ac.uk/biostudies/studies/S-EPMC9892258biostudies-literatureUnknown123The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as thNeurobiology of agingPredictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.PMC9892258R01 AA029403S10 OD026980F31 AG071131R01 AG072513T32 NS115667Smith GCProctor EASnyder AMArnold ACCrowley NAKuhn MKFleeman RMChan DCfalsePredictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as th2023-01-01T00:00:00Z2023 Mar2026-06-02T19:25:37.991Z2025-04-03T23:50:12.758ZS-EPMC98922583657259410.1016/j.neurobiolaging.2022.11.015