Background: Epidemiological studies suggested that caffeine/coffee could be an effective therapeutic agent against Alzheimer disease (AD). The mechanism has not been well established; however, molecular genetic analyses suggest that many genes influence it. Methods: Using developing zebrafish ( Danio rerio ), we studied the regulatory effect of caffeine on AD molecular factors, APP, Psen1, Psen2, ApoE, and Sorl1, and on receptor expression of two cell communication systems involved in the disease, adenosine (AR) and dopamine receptors (DR). Results: All genes are already expressed at early developmental stages. No morphological changes were found at tested concentrations and control. Caffeine significantly down-regulated the expression of all AD tested genes at 24 h post-fertilization (hpf) and APP, Sorl1, and Psen1 at 96 and 168 hpf. A 2aa and A 2ab receptors have higher affinity for caffeine than A 2b . Significant down-regulation occurred in A 2b at 168 hpf in both concentrations. Caffeine blocked the expression of drd 2a and drd 2c at 24 hpf but significantly stimulated the expression at 96 and 168 hpf. Conclusions: Zebrafish is a promising organism in studying AD at the molecular level because all tested factors are already expressed at early developmental stages. Caffeine has a regulatory effect on all tested genes and may protect against the disease via amyloid pathway as well as AR and DR.