A cryo-electron microscopy (cryo-EM) study reveals the atomic structures of paired helical filaments (PHFs) and straight filaments (SFs) from Alzheimer's disease (AD) brain. The structures, determined at 3.4–3.5 Å resolution, show that PHFs and SFs consist of two identical protofilaments made of residues 306–378 of Tau, arranged in a combined cross-β/β-helix structure. These structures define the seed for Tau aggregation and are ultrastructural polymorphs, differing in inter-protofilament packing. The findings demonstrate that cryo-EM can provide atomic-level details of amyloid filaments from patient-derived material, offering insights into neurodegenerative diseases. PHFs and SFs are composed of two protofilaments with C-shaped subunits, with PHFs showing an approximate 2₁ screw symmetry between protofilaments. The core of both PHFs and SFs is made of residues V306-F378, including all of R3 and R4, and 10 amino acids carboxy-terminal to the repeats. The structures show that the core is composed of eight β-sheets arranged in a C-shaped architecture, with a β-helix region and cross-β architecture. The amino-terminal end of the core is formed by the hexapeptide 306VQIVYK311, which forms a complementary packing interface with residues 374–378 from the opposing β8. PHFs and SFs differ in their lateral contacts between the two protofilaments, with PHFs forming identical structures related by helical symmetry, while SFs pack asymmetrically. The structures show that the core is composed of a combination of two structural motifs closely associated with amyloid and prion structures – cross-β packing and β-helices. The study also highlights the importance of the core structure in the seeded assembly of Tau in AD brain. The cryo-EM structures of PHFs and SFs provide a basis for understanding the differences between molecular conformers of Tau aggregates and explain how different isoforms are incorporated into the filaments. The findings demonstrate that amyloid structures from human brain may be obtained by cryo-EM, opening new possibilities for studying the molecular mechanisms underlying a wide range of neurodegenerative diseases. The study also highlights the importance of the core structure in the seeded assembly of Tau in AD brain.A cryo-electron microscopy (cryo-EM) study reveals the atomic structures of paired helical filaments (PHFs) and straight filaments (SFs) from Alzheimer's disease (AD) brain. The structures, determined at 3.4–3.5 Å resolution, show that PHFs and SFs consist of two identical protofilaments made of residues 306–378 of Tau, arranged in a combined cross-β/β-helix structure. These structures define the seed for Tau aggregation and are ultrastructural polymorphs, differing in inter-protofilament packing. The findings demonstrate that cryo-EM can provide atomic-level details of amyloid filaments from patient-derived material, offering insights into neurodegenerative diseases. PHFs and SFs are composed of two protofilaments with C-shaped subunits, with PHFs showing an approximate 2₁ screw symmetry between protofilaments. The core of both PHFs and SFs is made of residues V306-F378, including all of R3 and R4, and 10 amino acids carboxy-terminal to the repeats. The structures show that the core is composed of eight β-sheets arranged in a C-shaped architecture, with a β-helix region and cross-β architecture. The amino-terminal end of the core is formed by the hexapeptide 306VQIVYK311, which forms a complementary packing interface with residues 374–378 from the opposing β8. PHFs and SFs differ in their lateral contacts between the two protofilaments, with PHFs forming identical structures related by helical symmetry, while SFs pack asymmetrically. The structures show that the core is composed of a combination of two structural motifs closely associated with amyloid and prion structures – cross-β packing and β-helices. The study also highlights the importance of the core structure in the seeded assembly of Tau in AD brain. The cryo-EM structures of PHFs and SFs provide a basis for understanding the differences between molecular conformers of Tau aggregates and explain how different isoforms are incorporated into the filaments. The findings demonstrate that amyloid structures from human brain may be obtained by cryo-EM, opening new possibilities for studying the molecular mechanisms underlying a wide range of neurodegenerative diseases. The study also highlights the importance of the core structure in the seeded assembly of Tau in AD brain.