Synaptic impairment: The new battlefield of Alzheimer's disease

We read with interest the paper from Mecca et al.1, showing a widespread synaptic loss across the brains of Alzheimer’s disease (AD) patients using positron emission tomography imaging of synaptic vesicle glycoprotein 2A. The authors highlight that synaptic degeneration, triggered by amyloid and tau deposition, is an early event in AD pathophysiology, preceding the occurrence of neurodegeneration and atrophy. In vivodemonstrationof synaptic impairment inADpatients is crucial for (1) better comprehension of the physio-pathological cascade of events occurring in the disease, (2) the opportunity for using plasticity impairment as a biomarker in clinical trials, and (3) new therapeutic scenarios targeting synaptic efficiency. We believe that the current set of data is strongly reinforced by recent neurophysiological works investigating in vivo synaptic plasticity mechanisms such as long-term potentiation (LTP) assessed at the cortical level bymeans of transcranial magnetic stimulation (TMS) protocols. Disruption of LTP-like cortical plasticity was originally reported in small samples of AD patients in analogy with mouse models.2,3 In previous studies from our group we confirmed that AD patients are characterized by a consistent impairment of LTP-like cortical plasticity,4 as assessed with intermittent theta burst stimulation, a repetitive TMS protocol that uses short trains of high-frequency stimuli mirroring the electrophysiological studies performed on the hippocampal slices of animal models. We showed in large samples of AD patients that alteration of the LTP mechanism occurs independently of age at disease onset,5 and is associated with memory impairment6 and higher CSF tau levels7,8—especially when linked to apolipoprotein E gene (APOE) ε4 polymorphism9 and to disease progression.10 The widespread reduction of the binding to the synaptic marker observed byMecca et al, also at neocortical areas such as frontal regions, is in line with our claim that the evaluation of cortical plasticity with TMS techniques might provide reliable information about physio-pathological events occurring in AD. From a clinical perspective, we agree with the authors that the baseline evaluation of synaptic plasticity in AD patients could have important diagnostic and prognostic properties, and we look forward to seeing follow-up data from their cohort. Indeed, given the precocious failure of plasticity mechanisms in AD, investigating the synaptic machinery in subjects with initial memory complaints could characterize early functional abnormalities and identify changes predictive of progression and response to treatments.9 In fact, being able to select patients with an expected slower or faster cognitive decline is of major interest for assessing the efficacy of new AD therapies and for stratifying clinical trial cohorts.10 Moreover, as the authors emphasized, it can be envisioned a possible role in clinical settings for techniques that assess synaptic efficiency as tools for evaluating the response to treatments in clinical trials. Finally, and maybe even more interestingly, the paper from Mecca et al. reinforces the notion that a new therapeutic approach could be focused on synaptic dysfunction. In light of the failure of the ongoing trials aimed at reducing the protein toxicity in AD, new efforts focused on identifying the early mechanisms of disease pathogenesis, driven or exacerbated by the aging process, may prove more relevant to slow the progression rather than the current disease-based models. From this perspective, the current results, together with the above-mentionedneurophysiological data, support thehypothesis that preventing synapse loss and improving synaptic function may be considered a promising therapeutic approach to counteract the cognitive impairment in AD pathology. We think that the time (and tools) has come for opening new scenarios in the battle against AD.