This study reports the cryo-EM structures of amyloid-β (Aβ) and tau filaments in the brains of two individuals with Down syndrome (DS), revealing differences and similarities with Alzheimer's disease (AD). The research identifies two types of Aβ40 filaments (IIIa and IIIb) and two types of Aβ42 filaments (I and II) in DS, with the latter being similar to those found in sporadic and familial AD. Tau filaments in DS are identical to those in AD, suggesting a common mechanism for amyloid-induced tau aggregation. The study highlights that while Aβ pathology in DS resembles AD, there are distinct structural features in Aβ filaments, particularly in Aβ40 filaments, which may be unique to DS. These findings are crucial for understanding AD in DS and assessing the inclusion of DS individuals in AD clinical trials. The research also underscores the importance of Aβ and tau pathology in DS, emphasizing the need for further investigation into the pathogenic mechanisms underlying AD in DS. The results provide insights into the structural differences between Aβ filaments in DS and AD, which could inform the development of targeted therapies for AD in DS.This study reports the cryo-EM structures of amyloid-β (Aβ) and tau filaments in the brains of two individuals with Down syndrome (DS), revealing differences and similarities with Alzheimer's disease (AD). The research identifies two types of Aβ40 filaments (IIIa and IIIb) and two types of Aβ42 filaments (I and II) in DS, with the latter being similar to those found in sporadic and familial AD. Tau filaments in DS are identical to those in AD, suggesting a common mechanism for amyloid-induced tau aggregation. The study highlights that while Aβ pathology in DS resembles AD, there are distinct structural features in Aβ filaments, particularly in Aβ40 filaments, which may be unique to DS. These findings are crucial for understanding AD in DS and assessing the inclusion of DS individuals in AD clinical trials. The research also underscores the importance of Aβ and tau pathology in DS, emphasizing the need for further investigation into the pathogenic mechanisms underlying AD in DS. The results provide insights into the structural differences between Aβ filaments in DS and AD, which could inform the development of targeted therapies for AD in DS.