Pre- and Post-synapses Contain Lecanemab-reactive Amyloid-β in Post-mortem Human Alzheimer’s Disease Brain

Overview

1. Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, UK
2. UK Dementia Research Institute, University of Edinburgh, UK
3. Leuven Brain Institute VIB-KU Leuven, Belgium
4. UK Dementia Research Institute, University College London, UK

Abstract

Recently, the amyloid-beta (Aβ) targeting antibody lecanemab has demonstrated modest therapeutic efficacy in slowing cognitive decline in people with Alzheimer’s disease (AD). Lecanemab clears amyloid plaques from the brain; however, plaque load does not correlate strongly with cognitive function. The strongest neuropathological correlate of cognitive decline in AD is synapse loss, which is exacerbated in the halo surrounding neuritic amyloid plaques where Ab accumulates in remaining synapses. Here, we hypothesised that, through clearing plaques and the associated halo of soluble Aβ that can directly damage synapses, lecanemab could temper plaque-associated synapse loss. High-resolution imaging of temporal cortex tissue from people who died with AD (N=20) and age-matched controls (N=19) reveals lecanemab staining within individual pre and post-synaptic excitatory terminals in addition to plaque staining. The percentage of pre-synapses containing lecanemab-positive Aβ was over 200% higher in AD and the percentage of post-synapses was over 150% higher in AD than control tissue, with highest levels of synaptic lecanemab staining observed near plaques. These data demonstrate that lecanemab antibody recognises Aβ within synapses, warranting future work to determine whether lecanemab treatment slows cognitive decline, at least in part, through both clearing plaques and facilitating clearance or neutralisation of synaptic Aβ.

Reproduced under the paper's license (CC BY), from the paper cited above.

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All spreadsheets and analysis scripts from the final accepted manuscript will be available on Edinburgh DataShare (https://datashare.ed.ac.uk/handle/10283/3076 DOI for these data to be added after peer review). Raw images are available from the corresponding author.

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Version 2, 28 September 2026

• Authors: added Colin Smith (0000-0002-4507-5132); Bart De Strooper (0000-0001-5455-5819); removed Colin Smith; Bart De Strooper

Version 1, 28 September 2026: the first record

Recorded: type, journal, dates, 9 authors, 5 keywords, 1 funder, 26 references.

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This paper

Holt, K., Chang, Y. Y., Li, M., Albertini, G., Smith, C., Tulloch, J., De Strooper, B., Hardingham, G. E., & Spires-Jones, T. L. (2026). Pre- and Post-synapses Contain Lecanemab-reactive Amyloid-β in Post-mortem Human Alzheimer’s Disease Brain. medRxiv (preprint). https://doi.org/10.64898/2026.05.08.26352549

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