Age-related emergence of behavioral deficits and amyloid pathology in the J20 mouse model of Alzheimer's disease.

Transgenic mouse models carrying familial Alzheimer's disease mutations are widely used in preclinical research, yet phenotypic variability across age and sex can complicate experimental design and interpretation. Here, we performed an age-stratified behavioral and pathological phenotyping of the hAPP-J20 mouse model using independent cohorts of female and male mice at 3, 6, and 9 months of age (n=5-21 per group depending on the assay). Animals underwent a battery of cognitive and non-cognitive assays assessing well-being-related behaviors (nesting, splash test), locomotion and exploration (open field), anxiety-like behavior (elevated O-maze), working memory (Y-maze spontaneous alternation), and spatial learning and memory (Barnes maze). In parallel, amyloid pathology was quantified using ELISA measurements of Aβ1-40 and Aβ1-42 levels and histological assessment of hippocampal plaque burden. J20 mice exhibited early behavioral alterations detectable at 3 months, including impaired working memory, increased locomotor activity, and alterations in self-care behaviors. Spatial learning alterations were detectable from 3 months, whereas robust spatial-memory deficits became more consistently evident at later ages. Soluble and insoluble Aβ species increased progressively with age, whereas hippocampal plaque pathology was minimal at 3 months and rose markedly at 6 and 9 months. Analyses including sex as an independent factor identified endpoint-specific sex-related effects but did not support a consistent sex-specific trajectory. Overall, non-cognitive and working memory deficits emerge early, while spatial memory impairment and amyloid pathology dominate at later stages. This study provides a reference framework to guide age- and sex-appropriate experimental design in preclinical studies using the J20 model.