Optical visualization of pathological changes in Alzheimer's disease (AD) can facilitate exploration of disease mechanisms and treatments. However, existing optical imaging methods have limitations on mapping pathological evolution in the whole mouse brain. Previous research indicated endogenous fluorescence contrast of senile plaques. Therefore, we develop cryo-micro-optical sectioning tomography (cryo-MOST) to capture intrinsic fluorescence distribution of senile plaques at a micrometer-level resolution in the whole brain. Validation using immunofluorescence demonstrates the capacity of cryo-MOST to visualize and distinguish senile plaques with competent sensitivity and spatial resolution. Compared with imaging in room temperature, cryo-MOST provides better signal intensity and signal-to-noise ratio. Using cryo-MOST, we obtained whole-brain coronal distribution of senile plaques in a transgenic mouse without exogenous dye. Capable of label-free brainwide visualization of Alzheimer's pathology, cryo-MOST may be potentially useful for understanding neurodegenerative disease mechanisms and evaluating drug efficacy.