Defining high- and low-risk APOE õ4 haplotypes for AlzheimerâÂÂs disease

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The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), with an impact orders of magnitude larger than all other AD-linked genes combined. In the past, mainstream research of APOE in AD has focused on structural and functional differences among apoE protein isoforms. Yet, despite the broad and valuable hypotheses that work has generated, the exact mechanism by which APOE contributes to AD remains elusive, thus hindering development of precise APOE-based therapeutic strategies. In order to develop more effective approaches to treat and ultimately prevent AD, it will require outside the box thinking and research efforts aimed at identifying the underlying mechanisms of APOE’s role in AD. Several lines of emerging evidence suggest the presence of other AD-risk loci in close proximity to APOE. For example, recent genome-wide association studies (GWAS) have consistently identified APOE and its adjacent regions to be strongly associated with AD. In our preliminary study, we analyzed the genetic association of an extended APOE region using Alzheimer’s Disease Genetics Consortium (ADGC) GWAS data. We observed that multiple single nucleotide polymorphisms (SNPs) all carry strong AD association signals independent of the APOE ε4 allele. This region consists of 11 critical SNPs that span four genes (i.e., PVRL2, TOMM40, APOE, and APOC1), most of which have AD-specific mRNA expression in postmortem brain. From this evidence and observations, we hypothesize that multiple genes and loci in the extended APOE region contribute to AD risk, and genetic variants of these loci compose distinct haplotypes that differentially regulate local gene expression to modify the AD risk. This concept forms the foundation of the current proposed study. We have designed a research plan, and our short-term goals are to identify APOE-ε4 independent genetic loci associated with AD, and to precisely define how genetic variability in this extended APOE region contributes to AD risk. We will first construct molecular haplotypes across this region and determine their genetic association with AD risk. We will then investigate how these haplotype variants correlate to gene expression and explore any underlying regulatory mechanisms. Our long-term goal is to use this knowledge to develop more precise APOE locus-based prediction, prevention, and/or therapeutic strategies for AD.