We previously developed single App knock-in mouse models of Alzheimer's disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation ( and mice). We have now generated knock-in mice devoid of the Swedish mutations ( mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in mice, but not in mice, indicating that the mice are more suitable for preclinical studies of β-secretase inhibition given that most patients with AD do not carry the Swedish mutations. Comparison of isogenic knock-in lines revealed that multiple factors, including elevated C-terminal fragment β (CTF-β) and humanization of Aβ might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic , knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.