Neuropsychiatric disorders are prevalent diseases whose causes and mechanisms remain unknown due to its complexity. In this context, translating experimental findings from humans to the clinic represents a major challenge that new technologies are assessing. Here we propose the use of a neurohistopathology pipeline to perform systematic multiscale analysis of pathological human brains and identify the cellular, molecular and circuit underpinnings of neurodegenerative and psychiatric disorders. We have developed and adapted new tissue clearing and labeling techniques in large scale samples, which in combination with light-sheet microscopy and advanced image-processing tools can 3D map different structures present in diseased and non-diseased archival human brains. We combined this approach with whole brain histological mapping of cellular and molecular markers from tissue sections and high-resolution imaging of subcellular structures in pathological hot spots. Therefore, here we demonstrated the validity of this approach to study diseases such as Alzheimer’s in different parts of its anatomy. Overall, the multimodal mapping of the human brain offers promising avenues for investigating the mechanisms of brain disorders, identifying new biomarkers and devising novel preventive and therapeutic interventions.