Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice.

Physical exercise promotes systemic and neural adaptations that support healthy brain aging and may mitigate Alzheimer's disease (AD) progression. However, the capacity of the AD-afflicted brain to mount and translate exercise-responsive molecular adaptations into neuroprotection remains unclear. Here, we examined the effects of long-term voluntary wheel running (VWR) on molecular, neuropathological, and behavioral outcomes in independently studied male and female 5xFAD mice. VWR elicited expected metabolic and transcriptional remodeling of inguinal white adipose tissue, confirming engagement of exercise-responsive peripheral biology. In contrast, hippocampal transcriptional responses were modest, with few differentially expressed genes and coordinated changes emerging primarily at the pathway level. These responses involved synaptic, neuroimmune, mitochondrial, neurotrophic, and monoaminergic processes and differed qualitatively between the two groups. Several components of the canonical hippocampal exercise response also failed to converge into coordinated cellular adaptations: synaptic protein abundance changed without altering synapse density, while neurotrophic, neurogenic, and vascular responses showed little correspondence across molecular and cellular measures. VWR also produced little change in hippocampal amyloid pathology or behavioral function despite sustained exercise engagement. Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects. These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.