Translating Genetics into Biomarkers and Therapies: apoE/Ab and apoJ/Ab Complex Levels and Lipidation State as AD Biomarkers Modulated by VPA

This application has two major novel goals. First, we have developed novel ELISAs to quantify complexes of ApoE-Aß and ApoJ (clusterin)-Aß. We will test the hypothesis that these complexes serve as biomarkers for AD by applying these ELISAs to well-characterized CSF samples from AD and non-AD, apoE4+ and apoE4- individuals. The second major goal is based on our novel data that the AD-protective alleles of SNPs in CLU (APOJ) and ABCA7, are associated with modest increases in expression of these two cholesterol-related genes. Hence, drugs that increase CLU and ABCA7 are predicted to reduce AD risk. Recently, our in vitro studies found that valproic acid (VPA) increased CLU expression about 10-fold more than its AD-protective allele and ABCA7 about 6-fold more than its protective allele. Hence, we hypothesize that VPA may reduce AD risk significantly more than the ~15% reduction associated with the individual SNPs. The key to this hypothesis is the extent that VPA actions on CLU and ABCA7 in vitro are replicated in humans in vivo. For work with CLU per se, we have a funded CTSA proposal to quantify ApoJ per se in CSF before and during VPA treatment. Overall, we propose the following Specific Aims: 1. Test the utility of ApoE-Aß and ApoJ-Aß complexes as AD biomarkers by quantifying these complexes as well as free ApoE, ApoJ and Aß in a series of human CSF samples, controlling for AD status and APOE genotype, and 2. Extend our current VPA work quantifying ApoJ per se to include testing the ability of VPA to modulate ApoE-Aß and ApoJ-Aß complexes as well as free ApoE and Aß. Additionally, we will quantify VPA actions at the mRNA level by quantifying CLU and ABCA7 in lymphocytes from these individuals. In summary, this two-pronged study will evaluate (i) ApoE-Aß and ApoJ -Aß complexes as an AD biomarker, (ii) the repurposing potential of VPA as an AD preventative by evaluating VPA effects on relevant targets in vivo, and (iii) leverage CSF and blood samples from our funded study by expanding our hypothesis to additional relevant functional readouts. Overall, this novel proposed work will provide critical “proof of concept” tests for (i) ApoE-Aß and ApoJ-Aß as AD biomarkers and (ii) our hypothesis that VPA will pharmacologically modulate an AD protective pathway identified through genetic studies.