Neuropathological changes of a patient with AD treated with verubecestat

Abstract Background Clinical trials with BACE‐1 inhibitors in patients with Alzheimer’s disease (AD) have been discontinued due to safety concerns. The adverse effects included reversible early cognitive worsening and brain atrophy. Some data suggest that these effects could be due to an off‐target effect of the inhibitor on other BACE‐1 substrates that could impact synaptic function and structure. However, the precise underlying mechanisms of these effects in humans remain controversial. Method We describe the neuropathological examination of a patient with AD treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat. Result Brain examination showed small plaque size, reduced dystrophic neurites around plaques, and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated sporadic AD (SAD) cases. We also describe a detailed analysis of synaptic morphology in this case. Conclusion Our findings suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD. Neuropathological data could help to understand the effect of BACE inhibition in humans.