The neurotrophin brain-derived neurotrophic factor (BDNF) is important in development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are consistently downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus (DG) granule cells (GCs), has been understudied, and never in controlled in vivo conditions. We examined MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either genotype or sex. Notably, we found a correlation between MF BDNF protein and GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. Remarkably, there was relatively little evidence of Aβ in GCs or the GC layer even at old ages. Results indicate MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity-dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect other vulnerable neurons from increased Aβ levels and therefore has translational implications.