Background: Recently, lecanemab has demonstrated modest therapeutic efficacy in slowing cognitive decline for individuals diagnosed with Alzheimer’s Disease (AD)—attributed to a sustained clearance of Aβ plaques from the brain via an, as yet, poorly understood mechanism.  However, it is well-understood that plaque load alone is a comparatively poor correlate of cognitive decline; thus, provoking questions as to how lecanemab acts within the brain to preserve cognition.

The strongest neuropathological correlate of cognitive decline in human AD is a region-specific loss of synapses, which is exacerbated in the halo surrounding neuritic plaques—posited to result from toxic Aβ oligomers enriched within this halo that are often seen within surviving synapses.  Here, we hypothesised that, through clearing this synaptic Aβ, lecanemab could temper plaque-associated synapse loss; thereby contributing in part to slowed cognitive decline. 

We aimed to investigate whether, following immunolabelling of human postmortem AD tissue with lecanemab antibody, any evidence of colocalisation with excitatory synaptic puncta could be observed.  Second to this, we investigated whether excitatory synapses colocalised with lecanemab were predominantly those “at risk” within the toxic neuritic plaque halo, a region correlating spatially with profound synapse loss.

 

Methods: Employing array tomography (AT) for single-synapse quantification, we co-stained lecanemab with presynapses (synaptophysin) and excitatory postsynapses (PSD-95).  Comparing between Braak VI AD cases (N = 20) and age-matched controls (N = 19), we performed 3-dimensional colocalisation of excitatory synapses with lecanemab in relation to disease status and/or plaque presence, profiling up to 1.62 million synapses in total.

 

Results: We demonstrate that lecanemab antibody positively labels extracellular plaques and exhibits increased colocalisation with excitatory synapses in AD over controls.  Surviving “at risk” synapses within the synaptotoxic halo of dense core neuritic plaques more frequently colocalise with lecanemab in the AD brain.

 

Conclusions: Lecanemab antibody recognises Aβ within synapses and, in AD, vulnerable synapses within the neuritic plaque halo are more likely to associate with lecanemab.  These data support the notion that lecanemab treatment could slow cognitive decline, at least in part, via clearance of toxic Aβ from these “at risk” synapses—or clearing dysfunctional Aβ-containing synapses themselves—likely via microglial recruitment.