The self-aggregation of amyloid-β (Aβ) and tau proteins are closely implicated in Alzheimer's disease (AD). Recent evidence indicates that Aβ and tau proteins can cross-interact to form co-aggregates, which aggravates the development of AD. However, their transient heterooligomer conformations and co-aggregation molecular mechanisms are largely unknown. Herein, we utilize replica exchange molecular dynamics simulations to investigate the conformational ensembles formed by the central hydrophobic core of Aβ (Aβ_16–22) and each of two fibril-nucleating core segments of tau (PHF6* and PHF6). Both PHF6 and PHF6* are found to co-aggregate with Aβ_16–22 into β-sheet-rich heterooligomers. Intriguingly, PHF6 and Aβ_16–22 peptides formed closed β-barrels, while PHF6* and Aβ_16–22 formed open β-barrels, implying their distinct co-aggregation property. Compared to Aβ_16–22-PHF6*, Aβ_16–22-PHF6 heterooligomers have higher β-sheet content, and contain longer β-strands and larger β-sheets, indicative of stronger co-aggregation ability of PHF6 with Aβ_16–22. Further analyses reveal that hydrophobic and π-π stacking interactions between Y310 of PHF6 and Aβ_16–22 are crucial for the closed β-barrel/larger β-sheet formation in Aβ_16–22-PHF6 heterooligomers. These results highlight the paramount importance of PHF6 fragment, particularly Y310 residue, as a potential target for inhibiting Aβ-tau co-aggregation, which could help for effective therapeutic design in mitigating Aβ-tau co-aggregation related amyloidogenesis.