Miao Tian, MD PhD, Grace Fortes Monis, MD PhD

The guidelines on the use of therapeutic Apheresis in clinical practice published in JCP 2019 has showed strong consideration for the addition of a new fact sheet on Alzheimer’s disease (AD) based on the preliminary data on the use of therapeutic plasma exchange (PE) in treating AD. However, due to limited published evidence for this therapeutic effect at that time, the disease was not selected for inclusion in the guideline (1).

A recent study published by Boada et al in October 2020 (2) provides strong evidence of the therapeutic effects of PE in AD. This 14-month, randomized, controlled, phase 2b/3 clinical trial examined the effects of plasma exchange with albumin replacement in patients with mild to moderate AD. A total of 347 patients were randomized into three PE treatment groups with different doses of albumin and intravenous immunoglobulin replacement, and into one placebo (sham PE) group. The patients received 6-week period of weekly conventional PE followed by 12-month period of monthly low volume PE. A total of 4709 apheresis procedures were performed over 41 sites in Spain and the United States. The authors discovered that PE treated patients with moderate AD performed significantly better than placebo for co-primary endpoints (the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) and Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog)) and for global assessment endpoints (the clinical dementia rating sum of boxes (CDR-sb) and Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC)). The study indicates that PE with albumin replacement could slow cognitive and functional decline in AD patients.

Alzheimer’s disease is the most common neurodegenerative disease that affects memory, thinking and behavior (3). The extracellular aggregates of amyloid β peptide (Aβ) and intracellular neurofibrillary tangles of phosphorylated tau protein deposits are hallmarks of AD pathology. However, the initial biological trigger of the disease process is unknown (4). No pharmacological treatments available so far for AD have yet been shown to stop or slow the disease progress, although some neurotransmission modulators such as AChEI and NMDAR antagonist may temporarily improve symptoms (5,6). The preclinical research studies have shown that human albumin is able to bind Aβ (7) and the Aβ levels of cerebrospinal fluid may be modified by sequestration of albumin bound-Aβ in the peripheral blood which alters the balance to induce CSF Aβ to pass to plasma in animal models (8-11). These basic research studies proposed that Aβ could be a valid therapeutic target. Indeed, the initial pilot study of PE in AD patients showed that 7 patients undergoing 6 PE in 3 weeks and 1 year of follow-up had more stable cognitive status scores than expected (12). In a phase 2 clinical trial, the safety, tolerability and preliminary efficacy of PE with 5% albumin in 42 mild to moderate AD patients were evaluated (13). This 21-week, double blind and controlled study showed that patients treated with PE had improvement in memory and language functions, which persisted after PE was discontinued. The above mentioned larger and more rigorous phase 2b/3 clinical trial (2) further confirmed the therapeutic effects of PE in AD patients.

Plasma exchange is often used to treat hematologic, immunological and metabolic disorders (1). These recent studies support that PE could also be applied as a new therapeutic approach for AD.

References

  1. Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34(3):171-354.
  2. Boada M, López OL, Olazarán J, et al. A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study. Alzheimers Dement. 2020 Oct;16(10):1412-1425.
  3. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005 Dec 17;366(9503):2112-7
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  9. DeMattos RB, Bales KR, Cummins DJ, et al. Peripheral anti-A antibody alters CNS and plasma A clearance and decreases brain A burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2001;98:8850-5
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  13. Boada M, Anaya F, Ortiz P, et al. Efficacy and safety of plasma exchange with 5% albumin to modify cerebrospinal fluid and plasma amyloid-𝛽 concentrations and cognition outcomes in Alzheimer’s disease patients: a multicenter, randomized, controlled clinical trial. J Alzheimers Dis. 2017;56:129-143