Added PubMed Id Alzheimer’s disease (AD) is a looming public health disaster with limited interventions. Desperately needed progress in therapeutic development rests on more detailed understanding of molecular pathogenesis. The vast majority of existing data for AD pathogenesis in humans is from standard neuropathologic assessments, e.g., neuritic plaques and neurofibrillary tangles or biochemical measurement of a limited number of analytes directly related to neuropathologic features, e.g., amyloid-β peptides and hyperphosphorylated tau. Standard neuropathologic evaluation is highly valuable as the only tool that provides comprehensive assessment of diseases that afflict an individual brain, but it also is severely limited in its ability to investigate molecular pathogenesis. Advances in mass spectrometry-based proteomics techniques provide robust quantitative measures, allowing for insight into the protein phenotype in brains with AD neuropathology. Careful selection of individuals in multiple research cohorts enabled us, for the first time, to investigate the full spectrum of molecular signatures specific to autosomal dominant AD dementia (ADD), sporadic ADD with minimal comorbidities, individuals without dementia who had high histopathologic burden of AD, and cognitively normal individuals with no or minimal AD histopathologic burden.