Abstract
One of the puzzling observations concerning mild cognitive impairment (MCI) and Alzheimer's disease (AD), is that many gene expressions in MCI may be in the opposite direction of those seen in AD. Several examples of this paradox are provided. The likely explanation lies in in the control mechanisms of gene transcription. These mechanisms include (1) modification of DNA and histones by methylation or acetylation, affecting the balance between the Compass group of proteins that enhances mRNA formation, and the Polycomb group that suppresses it; (2) compensation for the loss of one gene's function by another gene with overlapping functions; (3) reduced control of the entire neural RNA production; and (4) response to microRNAs (miRNA). Although data are inadequate to exclude with certainty any one of the indicated mechanisms, the available evidence favors overall reduced control of neural mRNA production, including the effect of miRNA. The switch occurs at a specific stage, somewhere between Braak 0-1 and Braak 2-3, in the progression from MCI to AD, which reduces the number of its likely causes. 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.