The role of apolipoprotein E in Alzheimer's adaptive immunity

Apolipoprotein E (APOE) polymorphic alleles are the main genetic determinants of AD risk. An unexplored function of ApoE in AD pathobiology is that of its role in immune modulation and susceptibility to viral infection. T cells that initially encounter antigen in the periphery can enter the cerebrospinal fluid (CSF) via the systemic circulation. However, the antigens underlying this process are not clear. Preliminary data shown here demonstrates a peripheral adaptive immune signature of AD characterized by an increased number of CD8 effector T cells. Our data further indicates APOE allele-dependent differences in CD8 T effector cell numbers in AD blood. Strikingly, CD8 effector T cells were also present in patient CSF and T cell receptor (TCR) sequencing indicates their clonal expansion against the Epstein-Barr virus (EBV) BZLF1 antigen. Further, analysis of CSF TCR sequences indicates increased CD8 T effector cell clonal expansion against EBV in APOE4 carriers. These results indicate that antigen-experienced T cells patrol the intrathecal space of brains affected by AD in an APOE allele-specific manner. We hypothesize that CD8 T cells patrol the blood and CSF of APOE4 AD patients and contribute to neuroinflammation via aberrant anti-viral antigen control. Specific Aim 1 will utilize single cell RNA sequencing (scRNAseq) and immunohistochemistry to determine the influence of APOE alleles on adaptive immunity in the AD brain. Specific Aim 2 will use high throughput scRNAseq to assess B and T cell clonal expansion in peripheral blood of various APOE carriers combined with sophisticated bioinformatic approaches to compare the transcriptomes of anti-viral adaptive immune cells in an APOE allele-dependent manner. Specific Aim 3 will employ ApoE structure correctors and CRISPR gene editing to determine the mechanistic impact of ApoE on the anti-viral immune response and T cell killing of neurons. These studies will be conducted in the lab of Dr. David Gate, an early-stage investigator who has extensive experience studying T cells, anti-viral immunity and neurodegeneration. Collaborators include Dr. Robert Mahley (Gladstone Institute), who has expertise in ApoE biology, Dr. Robert Vassar (Northwestern University), who has expertise in AD pathobiology, and Dr. Marsel Mesulam, who will provide access to patient specimens through the Northwestern Mesulam Center for Cognitive Neurology and Alzheimer’s Disease.