Bridging the barrier: insights into blood biomarkers and therapeutic strategies targeting choroid plexus and BBB dysfunction in alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and accounts for approximately 60-80% of total dementia patients. Currently, accurate diagnosis for AD relies on cerebrospinal fluid (CSF) sampling or a positron emission tomography (PET) scan, methods that cannot be done in primary care centers where most people go with cognitive complaints. This Limitation calls for the urgent need to develop blood-related diagnostic tests that could facilitate early detection and enable timely treatment. Recent CSF proteomic research categorized AD into five molecular subtypes with discrete Genetic risk profiles. Subtypes 1-3, namely neuronal hyperplasticity, innate immune activation, and RNA dysregulation, were characterized by more classical AD-related changes, like accumulation of amyloid/tau and synaptic and immune dysfunction, respectively. On the contrary, non-traditional AD mechanisms in subtypes 4-5 were choroid plexus (CP) dysfunction and blood-brain barrier (BBB) dysfunction, emphasizing clearance deficits in association with brain barrier dysfunction. The unchanged tau levels later may be explained by an alternate disease mechanism (clearance dysfunction). These subtypes included BBB and CP dysfunction. Biomarker identification based on the mechanism of disease progression would increase the precision of diagnoses, allowing for tailored interventions and aiding in the creation of novel therapies for subtypes that might not react favorably to conventional amyloid/tau-targeting strategies. Finding biomarkers specific to each subtype would aid in patient classification, resulting in more individualized therapy as opposed to a "one-size-fits-all" strategy. The present review emphasized the importance of identifying blood-based biomarkers (BBMs) related to brain barrier dysfunction from CSF studies and personalized treatment strategies to streamline the diagnostic workup, and may be utilized in standard clinical practice for the early detection of AD.