Emerging insights into the role of albumin with plasma exchange in Alzheimer's disease management.

Alzheimer's disease (AD) is a neurodegenerative process that inexorably leads to progressive deterioration of cognition function and, ultimately, death. Central pathophysiologic features of AD include the accumulation of extracellular plaques comprised of amyloid-ß peptide (Aß) and the presence of intraneuronal neurofibrillary tangles. However, a large body of evidence suggests that oxidative stress and inflammation are major contributors to the pathogenesis and progression of AD. To date, available pharmacologic treatments are only symptomatic. Clinical trials focused on amyloid and non-amyloid-targeted treatments with small molecule pharmacotherapy and immunotherapies have accumulated a long list of failures. Considering that around 90 % of the circulating Aß is bound to albumin, and that a dynamic equilibrium exists between peripheral and central Aß, plasma exchange with albumin replacement has emerged as a new approach in a multitargeted AD therapeutic strategy (AMBAR Program). In plasma exchange, a patient's plasma is removed by plasmapheresis to eliminate toxic endogenous substances, including Aß and functionally impaired albumin. The fluid replacement used is therapeutic albumin, which acts not only as a plasma volume expander but also has numerous pleiotropic functions (e.g., circulating Aß- binding capacity, transporter, detoxifier, antioxidant) that are clinically relevant for the treatment of AD. Positive results from the AMBAR Program (phase 1, 2, an 2b/3 trials), i.e., slower decline or stabilization of disease symptoms in the most relevant clinical efficacy and safety endpoints, offer a glimmer of hope to both AD patients and caregivers.