Background: Alzheimer's disease (AD) is ranked as the most prevalent neurodegenerative disease. However, the exact molecular mechanisms underlying pathophysiological alterations in AD remain unclear, especially at the prodromal stage. The decreased proteolytic degradation of Aβ, blood-brain barrier (BBB) disruption, and neuroinflammation are considered to play key roles in the course of AD. Methods: Male APPswe/PS1dE9 C57BL/6 J double-transgenic (APP/PS1) mice in the age range from 1 month to 6 months and age-matched wild type mice were used in this study, intending to investigate the expression profiles of Aβ-degrading enzymes for Aβ degradation activities and zonula occludens-1 (zo-1) for BBB integrity at the prodromal stage. Results: Our results showed that there were no significant genotype-related alterations in mRNA expression levels of 4 well-characterized Aβ-degrading enzymes in APP/PS1 mice within the ages of 6 months. Interestingly, a significant decrease in zo-1 expression was observed in APP/PS1 mice starting from the age of 5 months, suggesting that BBB disrupt occurs at an early stage. Moreover, treatment of fish oil (FO) for 4 weeks remarkably increased zo-1 expression and significantly inhibited the glial activation and NF-κB activation in APP/PS1 mice. Conclusion: The results of our study suggest that FO supplement could be a potential therapeutic early intervention for AD through protecting the BBB integrity and suppressing glial and NF-κB activation.