Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease.

Two distinct amyloid-β42 intermediate populations are found across recombinant Aβ42, an Alzheimer's knock-in mouse model, and human Alzheimer's brain tissue, differing in neurotoxicity and abundance.

• Why it matters: Neurotoxic Aβ intermediates are rare and transient in the human brain, leaving their identities and formation routes unclear despite their proposed role in Alzheimer’s pathology.
• What they did: The study combines super-resolution microscopy, single-molecule functional imaging, and kinetic modelling to classify intermediates by membrane-disrupting activity and link them to aggregation pathways in multiple systems.
• The result: One intermediate population converts into plaques, and pharmacologically suppressing these intermediates in mice reduces plaque burden, attenuates astrogliosis, and improves cognition.

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