Up to 25% of individuals in the United States have low serum vitamin B12 levels, leading to hematologic impairment (megaloblastic anemia) and/or neurologic deficits (loss of coordination, memory loss, psychosis). Comorbid B12 deficiency is associated with worse neurologic outcomes in patients with Alzheimer’s disease (AD) and Parkinson’s disease. Therefore, improvements in the diagnosis and treatment of B12 deficiency, either as a primary disease or a comorbid condition, have the potential to substantially improve brain health at a population level. We recently discovered an autoimmune cause of B12 deficiency restricted to the central nervous system (CNS), termed autoimmune B12 central deficiency (ABCD). Using unbiased antigen discovery technology, we identified autoantibodies targeting the transcobalamin receptor (CD320) which inhibit cellular uptake of B12, an essential cofactor for hematopoiesis and myelination. Anti-CD320 is highly predictive (96% specificity) of low B12 in the CSF despite normal B12 in the blood and remarkably prevalent (~10%) in patients with dementia. Complementing this autoimmune association, genetic polymorphisms in CD320 are associated with cognitive impairment in elderly individuals. However, the functional consequences and mechanism of this genetic association is unknown. In this proposal, we aim to investigate the proteomic, radiographic, and clinical consequences of genetic polymorphisms in metabolite transporters at the blood brain barrier. A unified autoimmune and genetic understanding of metabolite transport may lead to substantial improvements in brain health, ameliorate the burden of unexplained neurologic disease, and identify a modifiable contributor to cognitive dysfunction in patients with comorbid neurodegenerative disorders like AD.
