Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD).Recently, we observed substantial age-related hippocampal neuron loss in APP751 SL /PS1 M146L transgenic mice but not in PS1 M146L mice. Here, we investigated APP751 SL mice, PS1 M146L mice, and APP751 SL / PS1 M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysinimmunoreactive presynaptic boutons (SIPBs). Wildtype mice, APP751 SL mice and PS1 M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751 SL mice and PS1 M146L mice showed age-related SIPB loss within SR. Importantly, APP751 SL /PS1 M146L mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular A␤ deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. Alzheimer's disease (AD) is a progressive neurodegenerative disorder comprising cognitive and memory deterioration, progressive impairment of activities of daily living, and several neuropsychiatric symptoms. 1 The neuropathology of AD is characterized by disturbances in neural circuits, such as loss of neurons and synapses, and by protein aggregations of ␤-amyloid and hyperphosphorylated tau. 2-4 Accumulating evidence has indicated a crucial role for failure and loss of synapses in AD pathophysiology. 2,4,[5][6][7] Postmortem morphological studies on AD neuropathology have demonstrated significantly reduced synaptic connectivity in brain regions such as the neocortex and hippocampus. 3,6,7 Reductions in synaptic densities showed a strong correlation with cognitive decline in AD. 5 However, the reasons for the reduced connectivity in AD remain poorly understood. 8 According to the "␤-amyloid (A␤) hypothesis of AD," A␤ accumulation is the primary driving force in AD pathogenesis. This hypothesis is supported by the fact that mutations in the amyloid precursor protein (APP) and in presenilin (PS) 1 and PS2, causing early-onset cases of AD, modify APP processing and result in enhanced generation of A␤. 4 We have developed a transgenic mouse model of AD expressing human mutant APP751 (carrying the Swedish and London mutations KM670/671NL and