Detrimental Effects of ApoE ε4 on Blood-Brain Barrier Integrity and Their Potential Implications on the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) epsilon 4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood-brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE epsilon 4 in AD, information about the effect of peripheral ApoE epsilon 4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE epsilon 4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE epsilon 4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE epsilon 4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives.