EARLY COGNITIVE STIMULATION ENHANCES STRIATAL NETWORK RESILIENCE DESPITE INCREASED Β-AMYLOID BURDEN IN AN ALZHEIMER’S DISEASE RAT MODEL

Alzheimer’s disease (AD) involves progressive β-amyloid (Aβ) pathology and large-scale network dysfunction that extend to subcortical regions at later disease stages. The striatum, functionally heterogeneous and increasingly implicated in AD progression, remains poorly characterized with respect to cognitive intervention effects. This study investigated how the timing of cognitive stimulation modulates striatal Aβ pathology and functional connectivity in TgF344-AD rats. Male and female transgenic and wild-type animals were assigned to untrained, early-trained (from 3 months of age), or late-trained (from 11 months) groups and followed longitudinally until 19 months of age. Aβ-plaque burden was quantified in ventral, dorsomedial, and dorsolateral striatal subregions, and resting-state fMRI was used to assess functional connectivity. Across groups, plaque density followed a consistent subregional gradient, with the highest burden in the ventral striatum, followed by the dorsomedial and dorsolateral striatum. Early cognitive training significantly increased both plaque number and plaque size in the dorsomedial and dorsolateral striatum compared to untrained animals, whereas late training exerted minimal effects on Aβ accumulation. Functional connectivity analyses revealed that early-trained rats, particularly transgenic animals, exhibited more symmetrical interhemispheric connectivity of the dorsomedial striatum and broader functional coupling with cortical regions. In contrast, late training induced only modest connectivity changes. These findings demonstrate that early cognitive stimulation differentially affects striatal subregions, exacerbating β-amyloid pathology in the dorsal striatum while promoting more balanced and widespread functional network organization. Overall, cognitive stimulation enhances striatal functional integration despite increased or unchanged β-amyloid burden, with effects strongly dependent on intervention timing and striatal subregion