Cholinergic basal forebrain (CBF) projection systems are defective in late Alzheimer's disease (AD). We examined the brains of 12-month-old singly and doubly transgenic mice overexpressing mutant amyloid precursor protein (APP swe ) and/or presenilin-1 (PS1 M146L ) to investigate the effects of these AD-related genes on plaque and tangle pathology, astrocytic expression, and the CBF projection system. Two types of β-amyloid (Aβ)-immunoreactive (ir) plaques were observed: type 1 were darkly stained oval and elongated deposits of Aβ, and type 2 were diffuse plaques containing amyloid fibrils. APP swe and PS1 M146L mouse brains contained some type 1 plaques, while the doubly transgenic (APP swe /PS1 M146L ) mice displayed a greater abundance of types 1 and 2 plaques. Sections immunostained for the p75 NGF receptor (p75 NTR ) revealed circular patches scattered throughout the cortex and hippocampus of the APP swe /PS1 M146L mice that contained Aβ, were innervated by p75 NTR -ir neurites, but displayed virtually no immunopositive neurons. Tau pathology was not seen in any transgenic genotype, although a massive glial response occurred in the APP swe /PS1 M146L mice associated with amyloid plaques. Stereology revealed a significant increase in p75 NTR -ir medial septal neurons in the APP swe and PS1 M146L singly transgenic mice compared to the APP swe /PS1 M146L mice. No differences in size or optical density of p75 NTR -ir neurons were observed in these three mutants. p75 NTR -ir fibers in hippocampus and cortex were more pronounced in the APP swe and PS1 M146L mice, while the APP swe /PS1 M146L mice showed the least p75 NTR -ir fiber staining. These findings suggest a neurotrophic role for mutant APP and PS1 upon cholinergic hippocampal projection neurons at 12 months of age.