The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer’s Disease

Simple Summary Modifications of gene expression (epigenetic alterations) have been implicated in the pathogenesis of complex diseases, such as Alzheimer's disease (AD). Apolipoprotein E (ApoE), a major lipid carrier in the central nervous system, possesses three variants, E2, E3, and E4, with APOE4 increasing the risk of developing AD. The APOE gene undergoes epigenetic modifications. Diet, lifestyle, and pollutants might interact with the human genome. It is possible that environment and lifestyle can modify AD risk through epigenetic mechanisms involving the APOE gene and its promoter (a sequence of DNA to which proteins bind to initiate transcription) conditioning the imbalance between ApoE isoforms. One of the epigenetic mechanisms is DNA methylation at three sites of APOE CpG islands. A comprehensive interpretation of APOE-mediated effects within AD pathophysiology includes epigenetic mechanisms by which the equilibrium of its isoforms is regulated.Abstract Sporadic Alzheimer's disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Carriers of one copy of the apolipoprotein E gene (APOE) epsilon 4 allele have a 4-fold increased AD risk, while APOE epsilon 4/epsilon 4-carriers have a 12-fold increased risk of developing AD in comparison with the APOE epsilon 3-carriers. The main longevity factor is the homozygous APOE epsilon 3/epsilon 3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene may affect tau- and amyloid-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significantly associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotide sites of APOE.