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The loss of cognitive function in Alzheimer's disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing “ H- line” yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4- month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12– 14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention. J. Comp. Neurol. 521:2181– 2194, 2013. © 2012 Wiley Periodicals, Inc.We have used longitudinal in vivo two- photon microscopy to study a new bigenic mouse model of Alzheimer's disease (5xFAD- YFP) that exhibits massive loss of fluorescently labeled layer 5 pyramidal neurons. Imaging of this transgenic mouse enabled the study of spine stability 500- 600 μ m below the pia mater, progressive atrophy of axons, appearance and growth of amyloid plaques, and eventual loss of neocortical pyramidal neurons.