The effects of APOE4 and familial Alzheimer's disease mutations on free fatty acid profiles in mouse brain are age‐ and sex‐dependent

APOE4 encoding apolipoprotein (Apo)E4 is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is key in intercellular lipid trafficking. Fatty acids are essential for brain integrity and cognitive performance and are implicated in neurodegeneration. We determined the sex‐ and age‐dependent effect of AD and APOE4 on brain free fatty acid (FFA) profiles. FFA profiles were determined by LC–MS/MS in hippocampus, cortex, and cerebellum of female and male, young (≤3 months) and older (>5 months), transgenic APOE3 and APOE4 mice with and without five familial AD (FAD) mutations (16 groups; n = 7–10 each). In the different brain regions, females had higher levels than males of either saturated or polyunsaturated FFAs or both. In the hippocampus of young males, but not of older males, APOE4 and FAD each induced 1.3‐fold higher levels of almost all FFAs. In young and older females, FAD and to a less extent APOE4‐induced shifts among saturated, monounsaturated, and polyunsaturated FFAs without affecting total FFA levels. In cortex and cerebellum, APOE4 and FAD had only minor effects on individual FFAs. The effects of APOE4 and FAD on FFA levels and FFA profiles in the three brain regions were strongly dependent of sex and age, particularly in the hippocampus. Here, most FFAs that are affected by FAD are similarly affected by APOE4. Since APOE4 and FAD affected hippocampal FFA profiles already at young age, these APOE4‐induced alterations may modulate the pathogenesis of AD. Free fatty acid (FFA) profiles were determined in brain regions of young and older mice, carrying human APOE4 or APOE3, without or with five familial Alzheimer's disease mutations (FAD). FFA profiles were affected by APOE4 and FAD mostly in the hippocampus. In young males, all FFA species were more abundant in APOE4 and FAD mice, but no longer in older mice. In females, the relative amount of a number of FFAs was already affected at young age, becoming more prominent in older females. Changes in FFA profiles early in life may play a role in the pathogenesis of Alzheimer's disease.