Significance The clinical and pathological variability among patients with Alzheimer’s disease (AD) remains largely unexplained. Evidence is growing that this heterogeneity may be influenced by the heterogeneous molecular architecture of misfolded amyloid-β peptide (Aβ) in the brain. To test this hypothesis, we used unique fluorescent ligands to interrogate the molecular structure of Aβ in amyloid plaques from patients who had died with etiologically distinct subtypes of AD. We found that Aβ-amyloid plaques in the brain cluster as clouds of conformational variants that differ among certain subtypes of AD. The conformational features of AD plaques were partially transmissible to transgenic mice in a seeding paradigm, suggesting a mechanism whereby different molecular strains of Aβ propagate their features within the brain.