Mutations in the amyloid precursor protein (APP) gene result in elevated production and deposition of the 42 amino acid β-amyloid (Aβ1–42) peptide and early-onset Alzheimer's disease (AD). To accurately examine the effect of the APP FAD mutations in vivo, we introduced yeast artificial chromosomes (YACs) containing the entire genomic copy of human APP harboring FAD mutations into transgenic mice. Our current results demonstrate that mutant APP YAC transgenic mice exhibit many features characteristic of human AD, including regional deposition of Aβ with preferential deposition of Aβ1–42, extensive neuritic abnormalities as evidenced by staining with APP, ubiquitin, neurofilament, and hyperphosphorylated tau antibodies, increased markers of inflammation, and the overlapping deposition of Aβ with apolipoproteins E and J. Our results also suggest that APP YAC transgenic mice possess unique pathological attributes when compared to other transgenic mouse models of AD that may reflect the experimental design of each model.