Lead compounds directed to the 5 leader of the Amyloid Precursor Protein transcript (i.e., paroxetine (SSRI), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic)) were employed in a pilot study to evaluate their anti-amyloid efficacy in the TgCRND8 transgenic mouse model for Alzheimers Disease (AD). The relative levels of Ab peptide were reduced after exposure of mice to paroxetine (N= 5), NAC (N= 7), and erythromycin (N= 7) relative to matched placebo counterparts. Paroxetine limited the levels of APP holoprotein and total Aβ peptide levels (measurements of Aβ were performed at two separate sites by quantitative western blotting and ELISA assay). The paroxetine data provided proof-of-concept for our strategy for further screening the APP 5UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. Erythromycin and azithromycin were macrolide antibiotics that markedly changed the cleavage of the APP C-Terminal Fragment (CTF) in SH-SY5Y cells. Erythromycin provided orally to TgCRND8 mice consistently (100%) reduced brain Aβ(1-42) levels. These data demonstrated a highly statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed, particularly since erythromycin has recently been exposed to mice for a further 6 months (N= 6). It will be possible to employ the chemical structures of paroxetine and erythromycin as starting points for drug design and development for AD therapeutics.