Abstract
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 BMI1 is possibly epigenetically silenced in LOAD. Reduced BMI1 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 BMI1 expression. Lastly, examples of the mechanisms underlying epigenetic dysregulation of other LOAD-related genes are also illustrated.
Highlights
Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, Whitehead Institute of Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Neuroscience, University of Montreal, Montreal, QC H1T 2M4, Canada
Activated DDR proteins such as p-ATM, p-ATR and p-Chk1 are at higher levels in Late-onset sporadic Alzheimer’s disease (LOAD) brains compared to control and early-onset Alzheimer’s disease (AD) (EOAD) samples [15]. These observations are interesting considering that LOAD brains possibly exhibit a diminished repair capacity that is not limited to the regions most affected by AD pathologies [34]
This could suggest the existence of LOAD-associated genetic variant(s) affecting BMI1 expression, incomplete epigenetic reprogramming at specific loci or the restoration of pathological epigenetic changes upon neuronal differentiation
Summary
The etiology of Alzheimer’s disease (AD) has proven difficult to sort out. Dominant mutations in three genes, Amyloid-beta precursor protein (APP), Presenilin-1 (PSEN1) and Presenilin-2 (PSEN2), are responsible for familial early-onset AD (EOAD) while sporadic late-onset AD (LOAD) can be associated with genetic risk factors like APOE and CLU in some, but not all, cases [1]. Penetrant mutations in APP, PSEN1 and PSEN2 are only present in a relatively small portion of sporadic early-onset AD cases [2]. These known pathogenic gene variants are found in some LOAD cases [3]. Recent genetic screenings have yielded dozens of novel possible mutations in over 20 candidate genes associated with sporadic early-onset AD cases [4]. As aging is largely driven by the accumulation of DNA damage and epigenomic perturbations, see review in Maynard et al, 2015, a better understanding of the link between aging and LOAD is fundamental to our understanding of this disease [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
