Characterization of the knock-in AppSAA mouse model as a powerful tool for Alzheimer's disease preclinical research.

Alzheimer's disease (AD) research demands models that exhibit age-related, biologically relevant amyloid pathology. To address this, the humanized AppSAA knock-in mouse model was characterized to identify clinically relevant therapeutic windows. From 4 to 19 months of age, homozygous AppSAA mice and controls were assessed using various techniques.

Whole-brain 3D plaque imaging, cerebral amyloid angiopathy (CAA) quantification, multiplex neuropathology, brain transcriptomics, plasma biomarkers, hippocampal synaptic analysis, and context-dependent memory testing were performed at 12 months. Plaques, CAA, plaque-associated neuroinflammation, and dystrophic neurites progressively accumulated with advancing age in both groups.

At 12 months, brain transcriptomes of AppSAA mice aligned with human amyotrophic lateral sclerosis (ALS)-AD co-expression modules, while plasma levels of pTau-217, GFAP, and SNAP25 increased with age.

AppSAA mice retained associative memory, but exhibited memory interference and dendritic spine loss in the CA1 region that worsened near plaques. The AppSAA model faithfully reproduces age-dependent, human-relevant AD phenotypes, establishing defined therapeutic windows for preclinical research. The model is freely accessible from The Jackson Laboratory.