The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD). Evidence suggests that the effect of apoE isoforms on amyloid-β (Aβ) accumulation in the brain plays a critical role in AD pathogenesis. Like in humans, apoE4 expression in animal models that develop Aβamyloidosis results in greater Aβand amyloid deposition than with apoE3 expression. However, whether decreasinglevels of apoE3 or apoE4 would promote or attenuate A β-relatedpathology has not been directly addressed. To determine the effect of decreasing human apoE levels on Aβaccumulation in vivo, we generated human APOE isoform haplo insufficient mouse models by crossing APPPS1 -21 mice with APOE isoform knock-in mice. By genetically manipulating APOE gene dosage, we demonstrate that decreasing human apoE levels, regardless of isoform status, results in significantly decreased amyloid plaque deposition and microglial activation. These differences in amyloid load between apoE3- and apoE4-expressing mice were not due to apoE4 protein being present at lower levels than apoE3. These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen A βamyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach.