AI Insight
This study examined post-mortem brain tissue from 20 Alzheimer's disease (AD) patients and 19 age-matched controls to investigate whether lecanemab, an FDA-approved anti-amyloid antibody, recognizes amyloid-beta (AΞ²) specifically within synaptic terminals. Using high-resolution imaging of the temporal cortex, researchers found that lecanemab-reactive AΞ² was present in both pre- and post-synaptic excitatory terminals, with over 200% more pre-synaptic and over 150% more post-synaptic involvement in AD compared to controls. Synaptic AΞ² accumulation was most pronounced in the vicinity of amyloid plaques, suggesting a spatial relationship between plaque halos and synaptic AΞ² burden.
Why it matters
These findings provide a potential mechanistic explanation for lecanemab's modest cognitive benefits beyond simple plaque clearance, suggesting the drug may also act by targeting synapse-associated AΞ², which is the neuropathological feature most closely linked to cognitive decline in AD. This could guide the development of more targeted therapies and inform patient selection for anti-amyloid treatments.
β οΈ Preprint β Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhΓ€ngigen Experten begutachtet. Die Ergebnisse sind vorlΓ€ufig und sollten mit Vorsicht interpretiert werden.
Recently, the amyloid-beta (A{beta}) 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 A{beta} accumulates in remaining synapses. Here, we hypothesised that, through clearing plaques and the associated halo of soluble A{beta} 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 A{beta} 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 A{beta} 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 A{beta}.