INTEGRATING GENETICS, PROTEOMICS, AND IN VITRO MODELING TO ELUCIDATE SLCO1A2-MEDIATED CEREBROSPINAL FLUID CLEARANCE IN IDIOPATHIC NORMAL PRESSURE HYDROCEPHALUS

In idiopathic normal pressure hydrocephalus (iNPH) cerebrospinal fluid (CSF) clearance is impaired, which leads to metabolic waste accumulating in the brain. Co-occurring iNPH and Alzheimer’s disease (AD) pathologies are common, showing altered CSF levels of amyloid-beta-42 (A-beta-42), total Tau, and phosphorylated Tau (pTau), which suggests shared mechanisms. We identified four iNPH-associated loci with a FinnGen genome‑wide association study, including SLCO1A2, which showed two independent signals suggesting previously unknown haplotype structure. SLCO1A2 encodes organic anion transporting polypeptide 1A2 (OATP1A2) regulating key processes in barrier-mediated clearance. We aim to identify novel molecular mechanisms influencing OATP1A2-mediated CSF clearance with combined proteomics, genetics and biomarker studies, and validate the mechanisms with an in vitro blood-CSF barrier model.Whole-genome sequencing data from 317 Kuopio iNPH cohort patients and 718 imputed genotypes were used to define SLCO1A2 haplotypes. We will test the effects of SLCO1A2 haplotypes by associating them with phenotypes within the Kuopio iNPH cohort, including cortical A-beta-42 and Tau immunohistochemistry, CSF proteomics, and functional and cognitive data. We will validate the results on A-beta-42 and Tau clearance testing cellular uptake by in vitro model of blood–CSF barrier.Our preliminary findings suggest that SLCO1A2 haplotypes influence the onset age of iNPH and AD, and are associated with altered CSF Tau, Tau/A-beta-42, and pTau/A-beta-42 ratios.We conclude that these results support a functional role for OATP1A2 in blood-CSF barrier-mediated clearance of neurodegeneration-related proteins. Our integrative genotype-phenotype approach enables identification of CSF clearance-related genetic mechanisms and highlights SLCO1A2 as a potential contributor to regulate CSF clearance.