Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-beta (Abeta) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Abeta levels in both brain interstitial fluid and plasma without affecting Abeta elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Abeta, but also decreases in both soluble and deposited Abeta in hippocampus and cortex. Irrespective of caffeine treatment, plasma Abeta levels did not correlate with brain Abeta levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Abeta1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Abeta levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Abeta levels are not an accurate index of brain Abeta levels/deposition or cognitive performance in aged AD mice.