AbstractAimsAmyloid precursor protein (APP) 𝛽‐C‐terminal fragment (𝛽CTF) may have a neurotoxic role in Alzheimer's disease (AD). 𝛽CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of AD. Synapses degenerate early during the pathogenesis of AD. We studied whether the 𝛽CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS).MethodsWe used array tomography to determine APP at synapses in human AD tissue. We measured 𝛽CTF, A𝛽40, A𝛽42 and phosphorylated tau181 (p‐tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls.ResultsAPP colocalised with pre‐ and post‐synaptic markers in human AD brains. APP 𝛽CTF was enriched in AD synaptosomes.ConclusionsWe demonstrate that 𝛽CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for 𝛽CTF in synapse degeneration. Therapies aimed at mitigating 𝛽CTF accumulation could be potentially beneficial in AD.