The apolipoprotein E gene (APOE) has three genetic variants (i.e., ?2, ?3, and ?4), and the ?4 variant of the APOE is the strongest genetic risk factor for Alzheimer's disease (AD). This means that APOE plays a major role in the development of AD. The expression levels of APOE gene products (mRNA and protein) are potential candidates that may partially explain APOE's effects in AD. But studies on APOE expression in AD have always yielded conflicting data, and there is no consensus on whether ?4 carriers produce higher or a lower APOE mRNA/protein. Such conflicting results have significantly obscured interpretation of APOE's expression role in AD. Clearly, gaps exist between APOE's expression, the ?2/?3/?4 alleles, and AD status. There is a need for better understanding their relationship. In our preliminary study, we have found that only a fraction of APOE mRNA extends the full length of the gene; that is, the majority of mRNAs are prematurely terminated and cannot produce functional apoE proteins. We have also detected the presence of novel circular RNAs in APOE RNA pools. These data suggest that APOE's RNA transcription is complex and may pose more biological consequences than previously thought; and that past APOE mRNA expression studies may have been flawed for not measuring the true functional full-length mRNA. Deciphering the interplay between various APOE RNA transcripts, the production of full-length mRNA, and the ?2/?3/?4 alleles will lead us to better understand the effects of APOE expression in AD. In this study, we hypothesize that only a fraction of APOE mRNA extend the full length of the gene to produce apoE protein; the ?2/?3/?4 alleles differentially modulate the production of these functional full-length mRNAs, thereby adding diverse effects to AD risk. Our long-term goal is to fully understand gene regulation of APOE and to use this knowledge to develop strategies for AD prevention and/or intervention. Our short-term goal is to clarify the relationship between APOE RNAs transcription, the ?2/?3/?4 variants, and AD risk and to understand the molecular mechanisms that regulate APOE RNAs production. We have designed three specific aims for the study.
Aim 1 will investigate APOE RNAs and correlate their expression levels with the ?2/?3/?4 allele variants, and AD status in human postmortem brain.
Aim 2 will characterize the epigenetic mechanisms that modulate the APOE RNAs transcription in human cell lines.
Aim 3 will investigate the function, biogenesis, and distribution of the newly discovered APOE circular RNA in human cell lines and body fluid. Our work will not diminish the role of apoE protein; instead, it will dissect the contributions of APOE RNA from apoE protein to complement APOE gene's comprehensive effects in AD.

Public Health Relevance

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). This study aims to elucidate the effects of APOE RNA expression in AD. We have observed that not all APOE mRNA extend to their full length to produce the apoE protein. This anomaly may be caused by the presence of APOE's ?2/?3/?4 allele variants that alter RNA transcription through epigenetic mechanisms. We hypothesize that APOE full- length mRNA is the only functional RNA for producing apoE protein and that ?2/?3/?4 can differentially modulate production of functional APOE mRNA to modify AD risk. Our short-term goals are to establish an association between the expressions of APOE RNAs, ?2/?3/?4 alleles, and AD risk; decipher the molecular mechanisms that regulate APOE RNAs production. Our long-term goal is to understand the role of APOE expression in AD and to apply this knowledge to develop strategies for AD prevention and/or intervention.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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VA Puget Sound Healthcare System
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Foraker, Jessica; Millard, Steven P; Leong, Lesley et al. (2015) The APOE Gene is Differentially Methylated in Alzheimer's Disease. J Alzheimers Dis 48:745-55