beta-Amyloid　(A　beta)　plaque,　representing　the　progressive　accumulation　of　the　protein　that　mainly　consists　of　A　beta,　is　one　of　the　prominent　pathological　hallmarks　of　Alzheimer＇s　disease　(AD).　Label-free　imaging　of　A　beta　plaques　holds　the　potential　to　be　a　histological　examination　tool　for　diagnosing　AD.　We　applied　label-free　multiphoton　microscopy　to　identify　extracellular　A　beta　plaque　as　well　as　intracellular　A　beta　accumulation　for　the　first　time　from　AD　mouse　models.　We　showed　that　a　two-photon-excited　fluorescence　signal　is　a　sensitive　optical　marker　for　revealing　the　spatial-temporal　progression　and　the　surrounding　morphological　changes　of　A　beta　deposition,　which　demonstrated　that　both　extracellular　and　intracellular　A　beta　accumulations　play　an　important　role　in　the　progression　of　AD.　Moreover,　combined　with　a　custom-developed　image-processing　program,　we　established　a　rapid　method　to　visualize　different　degrees　of　A　beta　deposition　by　color　coding.　These　results　provide　an　approach　for　investigating　pathophysiology　of　AD　that　can　complement　traditional　biomedical　procedures.　(C)　The　Authors.　Published　by　SPIE　under　a　Creative　Commons　Attribution　4.0　Unported　License.