Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer’s disease
Abstract Neurotoxic intermediates formed during amyloid-β(Aβ) aggregation are thought to drive Alzheimer’s disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify Aβ intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this framework to recombinant Aβ42, an Alzheimer’s knock-in mouse model and human Alzheimer’s brain tissue, we find two functionally distinct intermediate populations present across all systems. They form through separate aggregation routes and differ in their neurotoxicity, abundance and susceptibility to inhibition. Both damage neurons and glia, but only one converts into plaques. Suppressing these intermediates pharmacologically in mice reduces plaque burden, attenuates astrogliosis and improves cognition. Our findings connect model systems with human pathology and identify intermediate formation pathways as actionable therapeutic targets across protein-misfolding disorders.
Authors
- Juan A. Varela (ORCID: https://orcid.org/0000-0003-1901-1378)
- Alexander J. Dear (ORCID: https://orcid.org/0000-0003-3055-607X)
- Thomas C. T. Michaels (ORCID: https://orcid.org/0000-0001-6931-5041)
- Emma F Garland (ORCID: https://orcid.org/0000-0002-8501-4326)
- Georg Meisl (ORCID: https://orcid.org/0000-0002-6562-7715)
- Jan Johansson (ORCID: https://orcid.org/0000-0002-8719-4703)
- J. Robin Highley (ORCID: https://orcid.org/0000-0002-4969-6526)
- Willem Hendrik Molenkamp (ORCID: https://orcid.org/0009-0005-2500-3958)
- Suman De (ORCID: https://orcid.org/0000-0003-1675-0773)
- Hollie E. Wareing (ORCID: https://orcid.org/0000-0003-0785-4116)
- Axel Abelein (ORCID: https://orcid.org/0000-0002-8079-3017)
- Simon Bell (ORCID: https://orcid.org/0000-0002-2781-6478)
- Agnieszka N. Urbanek (ORCID: https://orcid.org/0009-0005-0014-3700)
- David Rhodes
- Gefei Chen
- Ruixin Zhang
- Harry J Baker
Institutions
- University of St Andrews (GB)
- University of Cambridge (GB)
- Karolinska Institutet (SE)
- ETH Zurich (CH)
- UK Dementia Research Institute (GB)
- Institute of Biochemistry (CH)
- University of Sheffield (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-11-09
- DOI
- https://doi.org/10.1038/s41467-026-79028-0
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- UK Research and Innovation
- National Institute for Health and Care Research
- Department of Health and Social Care
- Engineering and Physical Sciences Research Council