The blood-brain barrier (BBB), a highly dynamic interface between the central nervous system and the peripheral circulation, plays a critical role in maintaining brain homeostasis (Abbott et al., 2010). The integrity of the BBB is fundamental to proper brain function, and its breakdown facilitates entry into the brain of neurotoxic blood-derived products, cells and pathogens and is associated with inflammatory and immune responses, which can initiate multiple neurodegenerative pathways (Sweeney et al., 2018).

Apolipoprotein E (APOE) is a key protein in lipid metabolism, with three major isoforms (ε2, ε3, and ε4) encoded by different alleles of the APOE gene. Notably, the ε4 variant is strongly associated with an elevated risk of developing late-onset Alzheimer's disease (AD) (Roses, 1996).

Multiple experimental studies have confirmed that BBB breakdown causes capillary leakage in Alzheimer’s disease (AD) models of β-amyloidosis (Park et al., 2017, Sagare et al., 2013) and in APOE ε4 transgenic mice (Alata et al., 2015, Bell et al., 2012, Nishitsuji et al., 2011a). However, while in vitro and animal in vivo studies have shed valuable light on the potential role of APOE ε4 in BBB permeability, there is a paucity of human in vivo evidence supporting this association (Bell et al., 2012, Blanchard et al., 2020, Cicognola et al., 2023, Deane et al., 2008, Freeze et al., 2020, Freeze et al., 2017, Kurz et al., 2022, Methia et al., 2001, Montagne et al., 2020, Moon et al., 2021; Nishitsuji et al., 2011b; Riphagen et al., 2020; Teng et al., 2017).

Evaluating BBB permeability in vivo poses a significant challenge due to the protected location and complex structure of the brain. Nonetheless, indirect markers such as the cerebrospinal fluid (CSF)/serum albumin ratio has been employed as proxy for BBB integrity (Reiber, 2001). Albumin, synthesized exclusively by the liver, can cross the BBB mainly when its integrity is compromised. Thus, an elevated CSF/serum albumin ratio is indicative of increased BBB permeability (Tibbling et al., 1977). Likewise, both kappa and lambda free light chains (FLCs), components of immunoglobulins, are synthesized by plasma cells and a change in their CSF/serum ratio may also reflect changes in BBB permeability, when an intrathecal synthesis has been excluded (Berven et al., 2007). Although in vitro models indicate an impact of APOE on BBB integrity in AD, studies using the CSF/serum albumin ratio in vivo have yielded inconsistent results (Janelidze et al., 2017, Lin et al., 2021, Montagne et al., 2020, Riphagen et al., 2020).

In this study we explore the potential role of the APOE genotype in modulating BBB permeability in patients with dementia, utilizing the CSF/serum albumin ratio and the assessment of CSF/serum kappa and lambda FLCs ratio as indirect markers of BBB integrity. By shedding light on the influence of APOE on BBB permeability, we aim to enhance our understanding of the gene's role in neurodegenerative disorders.