Optical visualization of Alzheimer’s disease (AD) pathological changes is crucial to facilitate exploration of disease mechanism and treatment. We developed cryo-micro-optical sectioning tomography (cryo-MOST) to acquire brainwide map of senile plaques. Using intrinsic fluorescence emission intensified under ultra-low temperature, we accomplished senile plaque visualization at a micron-level resolution. A whole-brain coronal distribution of senile plaque in a transgenic mouse was successfully acquired without any exogenous dye. We believe cryo-MOST would be a potential tool for understanding neurodegenerative disease mechanism and evaluating drug efficacy.