| Summary: | Late-onset sporadic Alzheimer’s disease (LOAD) seems to contain a “hidden” component that cannot be explained by classical Mendelian genetics, with advanced aging being the strongest risk factor. More surprisingly, whole genome sequencing analyses of early-onset sporadic Alzheimer’s disease cohorts also revealed that most patients do not present classical disease-associated variants or mutations. In this short review, we propose that <i>BMI1</i> is possibly epigenetically silenced in LOAD. Reduced <i>BMI1</i> expression is unique to LOAD compared to familial early-onset AD (EOAD) and other related neurodegenerative disorders; moreover, reduced expression of this single gene is sufficient to reproduce most LOAD pathologies in cellular and animal models. We also show the apparent amyloid and Tau-independent nature of this epigenetic alteration of <i>BMI1</i> expression. Lastly, examples of the mechanisms underlying epigenetic dysregulation of other LOAD-related genes are also illustrated.
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