The study investigates the differential regulation of brain amyloid-β (Aβ) peptide clearance by human apolipoprotein E (apoE) isoforms, which are known to influence Alzheimer's disease (AD) risk and onset. Using a mouse model of AD (PDAPP/TRE), the authors found that the concentration of soluble Aβ and its clearance from the brain interstitial fluid (ISF) depend on the human apoE isoform expressed. Specifically, the ISF concentration of soluble Aβ and its clearance were higher in mice expressing apoE4 compared to those expressing apoE3 or apoE2. This was observed in both young and aged mice, suggesting that the effect of apoE isoform on Aβ clearance is not age-dependent. The study also used in vivo stable isotopic labeling kinetics to measure fractional synthesis rates (FSRs) of Aβ, which showed no differences among the three isoforms. These findings provide direct in vivo evidence that apoE isoform-dependent differences in Aβ clearance modulate the onset of Aβ accumulation in transgenic mice and humans, potentially contributing to the differential risk and onset of AD associated with different apoE genotypes.The study investigates the differential regulation of brain amyloid-β (Aβ) peptide clearance by human apolipoprotein E (apoE) isoforms, which are known to influence Alzheimer's disease (AD) risk and onset. Using a mouse model of AD (PDAPP/TRE), the authors found that the concentration of soluble Aβ and its clearance from the brain interstitial fluid (ISF) depend on the human apoE isoform expressed. Specifically, the ISF concentration of soluble Aβ and its clearance were higher in mice expressing apoE4 compared to those expressing apoE3 or apoE2. This was observed in both young and aged mice, suggesting that the effect of apoE isoform on Aβ clearance is not age-dependent. The study also used in vivo stable isotopic labeling kinetics to measure fractional synthesis rates (FSRs) of Aβ, which showed no differences among the three isoforms. These findings provide direct in vivo evidence that apoE isoform-dependent differences in Aβ clearance modulate the onset of Aβ accumulation in transgenic mice and humans, potentially contributing to the differential risk and onset of AD associated with different apoE genotypes.