Long‐term potentiation–like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset

<jats:sec><jats:title>Objective</jats:title><jats:p>Alzheimer's disease (AD) is considered an age‐related disorder. However, it is unclear whether AD induces the same pathological and neurophysiological modifications in synaptic functions independently from age of disease onset. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and sensory‐motor integration in AD patients with a wide range of disease onset.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We evaluated newly diagnosed sporadic AD (n = 54) in comparison with healthy age‐matched controls (HS; n = 24). Cortical plasticity mechanisms of long‐term potentiation (LTP) or of long‐term depression (LTD) were assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory‐motor integration was evaluated by means of short afferent inhibition (SAI) protocol.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>AD patients show after iTBS an impairment of LTP‐like cortical plasticity forming a paradoxical LTD in comparison to HS. LTD‐like cortical plasticity is similar between AD and HS. LTP‐like cortical plasticity is not associated with age, but AD patients presenting with more altered LTP‐like cortical plasticity have more‐severe cognitive decline at 18 months. SAI is impaired in AD and shows a strong association with the individual age of subjects rather than with disease age of onset.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be described primarily as a disorder of LTP‐like cortical plasticity not influenced by physiological aging and associated with a more‐severe cognitive decline. Ann Neurol 2016;80:202–210</jats:p></jats:sec>