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Two strong but related candidates are the repressor element-1 silencing transcription factor (REST), which in adult neurons impairs plasticity; and a miRNA, for example, miRNA124, that represses REST. Another possible explanation is that only those patients with MCI who will not progress to AD are the ones that have gene expressions in the opposite direction as in AD. The solution to the paradox may have pragmatic value. © 2020 The Authors. Alzheimer's Dementia Translational Research Clinical Interventions published by Wiley P