Predominant CNS synthesis of CSF Apolipoprotein E: Evidence from CSF/serum quotient analysis

Background Apolipoprotein E (ApoE) is the most abundant apolipoprotein in the central nervous system, exists in three isoforms (ApoE2, ApoE3, ApoE4) and plays a role in neuronal repair, synaptogenesis and neurodegeneration. ApoE4 increases Alzheimer’s disease (AD) risk, while ApoE2 is relatively protective. Peripheral and central ApoE pools are largely distinct, with the majority of ApoE produced in the liver and only a fraction synthesized intrathecally. Clarifying the origin and compartmentalization of ApoE isoforms in cerebrospinal fluid (CSF) is essential for developing ApoE-targeted therapies. Methods Paired CSF and serum from AD and non-AD patients with or without blood-CSF barrier dysfunction were analyzed by a newly established capillary-based Western blot for Pan-ApoE and ApoE4. To assess the intrathecally synthesized Pan-ApoE and ApoE4 fraction, their CSF/serum quotients were analyzed using the Felgenhauer plot and a theoretical ApoE Reiber curve. Moreover, the relationship between CSF and serum ApoE concentrations as well as their dependency of blood-CSF barrier function are evaluated. Results ApoE4 concentrations in blood were more than tenfold higher than in CSF. CSF/serum quotients were 0.122 for Pan-ApoE and 0.178 for ApoE4, indicating that more than 98% of CSF ApoE is synthesized intrathecally, with only a minimal contribution from peripheral blood via passive transfer, as indicated by the Felgenhauer plot. Mild to moderate correlations were observed between CSF and serum levels of Pan-ApoE and ApoE4. CSF/serum quotients of both Pan-ApoE and ApoE4 are independent of blood-CSF barrier function and substantially exceed values predicted by the theoretical Reiber curve, supporting predominant intrathecal ApoE synthesis. Conclusions Most CSF ApoE, including the ApoE4 isoform, is synthesized intrathecally with minimal peripheral contribution and is largely independent of blood-CSF barrier function. Therefore, ApoE-targeting therapies for neurodegenerative diseases, such as Alzheimer’s disease, should primarily focus on brain-derived rather than peripheral ApoE.