LECANEMAB ANTIBODY ASSOCIATES WITH PRE- AND POSTSYNAPTIC AMYLOID-BETA IN HUMAN POSTMORTEM ALZHEIMER'S DISEASE CORTEX

Recently, Aß-targeting passive immunotherapies including the antibody lecanemab have 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. Thus, how this antibody slows cognitive decline remains incompletely understood.
The strongest pathological correlate of cognitive decline in human AD is a loss of synapses, which is exacerbated in the halo surrounding neuritic amyloid plaques—posited to occur due to toxic Aß oligomers enriched within this halo and often seen within surviving synapses. Here, we hypothesised that, through clearing synaptic Aß, lecanemab could temper plaque-associated synapse loss, thereby contributing to slowed cognitive decline.
Employing array tomography (AT), we aimed to investigate whether, after immunolabelling of human postmortem tissue with lecanemab antibody, any evidence of colocalisation with excitatory synaptic puncta could be observed. Comparing between Braak VI AD Cases (N = 20) and age-matched controls (N = 19), we performed 3-dimensional colocalisation of pre- and postsynapses with lecanemab to profile up to 1.62 million synapses. We demonstrate here that, in postmortem human temporal cortex (BA20/21), lecanemab binds extracellular plaques; exhibiting increased colocalisation with synapses in AD—especially those at risk of loss within the neuritic plaque halo. These data show that lecanemab antibody recognises Aß within synapses, supporting the idea that that lecanemab treatment could slow cognitive decline, at least in part, via clearance of toxic Aß from synapses or, alternatively, via clearing dysfunctional Aß-containing synapses, likely via microglia-mediated mechanisms.