WHOLE-BRAIN MAPPING OF AGE-DEPENDENT AMYLOID-Β AND TAU PATHOLOGY IN THE 3XTG-AD MOUSE MODEL

Alzheimer’s disease (AD) progression is characterized by heterogeneous and region-specific accumulation of amyloid-β (Aβ) and tau pathology, yet how these traits jointly evolve across the whole brain remains incompletely understood. Here, we aimed to characterize the spatial and temporal progression of AD pathological hallmarks in the 3xTg-AD mouse model using an integrated whole-brain quantitative framework. Female 3xTg-AD mice were analyzed at 3, 6, 9, and 12 months of age using immunofluorescence for Aβ and hyperphosphorylated tau, followed by atlas-based quantification with the QUINT workflow. Region-specific pathology measures were normalized and analyzed using dimensionality reduction approaches (PCA, UMAP, and supervised CEBRA), decoding analyses, and ablation strategies to identify brain regions most informative of age progression. Intracellular Aβ was detected as early as 3 months, predominantly in anterior cortical regions, hippocampal CA1, and amygdala, whereas extracellular plaques emerged later, becoming prominent at 9–12 months. Tau pathology initially localized to CA1 before spreading to additional hippocampal, cortical, and amygdalar regions with age. Unsupervised embeddings revealed limited age structure, while supervised CEBRA embeddings organized animals along trajectories driven by pathological burden rather than chronological age alone. Decoding and ablation analyses identified hippocampal, cortical association, and amygdalar regions as key contributors to age-related differences. Together, these findings provide a comprehensive whole-brain view of AD pathology progression, highlighting early intracellular pathology, regional heterogeneity, and non-linear disease trajectories that parallel key features of human AD progression. Funding: PID2022-141733NB-I00 from the MCIU/AEI/10.13039/501100011033/FEDER, UE; and CIAICO/2023/041 from the Conselleria d’Educació, Cultura i Universitats (Generalitat Valenciana).