Transgenic mice with Alzheimer's disease (AD) mutations have been widely used to model changes in neuronal structure and function. While there are clear gross structural changes in post-mortem brains of AD patients, most mouse models of AD do not recapitulate the considerable loss of neurons. Furthermore, possible connections between early subtle structural changes and the loss of neurons are difficult to study. In an attempt to start unraveling how neurons are affected during the early stages of what becomes full neurodegeneration, we crossed a mouse model of familial AD, which displays massive neocortical neurodegeneration (the 5xFAD mouse), with the fluorescent H-line YFP mouse. This novel bigenic mouse model of AD, which we have named the 5XY mouse, expresses YFP in principal neurons in the cortex such that even fine details of cells are clearly visible. Such bright fluorescence allowed us to use high-resolution confocal microscopy to quantify changes in spine density in the somatosensory cortex, prefrontal cortex, and hippocampus at 2, 4, and 6 months of age. A significant loss of spines on basal dendrites in the somatosensory and prefrontal cortices of 6-month-old 5XY female mice was found. There was no observed spine loss at 6 months of age on the oblique dendrites of the hippocampus in the same mice. These data suggest that spine loss is an early event in the degeneration of the neocortical neurons in 5xFAD mice and a likely contributor to the cognitive impairments reported previously in this AD mouse model.