biostudies-literatureGilbert MAGMedical Research CouncilWellcome Trust913-919https://www.ebi.ac.uk/biostudies/studies/S-EPMC11269202biostudies-literatureUnknown631(8022)A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures¹. In Alzheimer's disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer's disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles aNatureCryoET of β-amyloid and tau within postmortem Alzheimer's disease brain.PMC11269202MR/T011149/1204963/Z/16/Z208395108466MR/V022644/1209407/Z/17/Z221524Geibel MRadford SEO'Sullivan TJHalfon YHoozemans JJMSchertel AFatima NWilkinson MGilbert MAGMorrema THJRanson NAFrank RAWJenkins JRead RJfalseCryoET of β-amyloid and tau within postmortem Alzheimer's disease brain.A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures¹. In Alzheimer's disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer's disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles a2024-01-01T00:00:00Z2024 Jul2026-05-04T06:38:28.993Z2025-04-19T13:14:35.291ZS-EPMC112692023898760310.1038/s41586-024-07680-x