This study investigates the structural differences between amyloid-β (Aβ) and tau filaments in individuals with Down syndrome (DS) and Alzheimer's disease (AD). The researchers used cryo-electron microscopy (cryo-EM) to analyze Aβ and tau filaments from two DS brains. They found two types of Aβ40 filaments (IIIa and IIIb) that differ from those in sporadic AD, while two types of Aβ42 filaments (I and II) are identical to those in sporadic and familial AD. Tau filaments, including paired helical filaments (PHFs) and straight filaments (SFs), were found to be identical to those in AD, suggesting a common mechanism for amyloid aggregation. The study highlights the importance of understanding these differences to assess the inclusion of DS individuals in AD clinical trials. The findings provide insights into the pathogenic mechanisms leading to AD in DS, emphasizing the similarities between AD in DS and sporadic AD.This study investigates the structural differences between amyloid-β (Aβ) and tau filaments in individuals with Down syndrome (DS) and Alzheimer's disease (AD). The researchers used cryo-electron microscopy (cryo-EM) to analyze Aβ and tau filaments from two DS brains. They found two types of Aβ40 filaments (IIIa and IIIb) that differ from those in sporadic AD, while two types of Aβ42 filaments (I and II) are identical to those in sporadic and familial AD. Tau filaments, including paired helical filaments (PHFs) and straight filaments (SFs), were found to be identical to those in AD, suggesting a common mechanism for amyloid aggregation. The study highlights the importance of understanding these differences to assess the inclusion of DS individuals in AD clinical trials. The findings provide insights into the pathogenic mechanisms leading to AD in DS, emphasizing the similarities between AD in DS and sporadic AD.