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AMBAR Study Demonstrates the Feasibility of Two Plasma Exchange Modalities for Alzheimer's Treatment

April 19, 2023


Background: In the Alzheimer Management by Albumin Replacement (AMBAR) study, mild-to-moderate Alzheimer's disease (AD) patients were treated with a plasma exchange (PE) program. Feasibility and safety of PE in this specific population are poorly understood and were analyzed in detail in this study.

Methods: Qualified patients were treated with 6 weeks of weekly conven- tional therapeutic plasma exchange (TPE) with albumin replacement followed by monthly low-volume plasma exchange (LVPE) for 12 months. The patients were divided into four groups: placebo (sham PE treatment), low-albumin (20 g), low-albumin + intravenous immunoglobulin (IVIG) (10 g), and high- albumin (40 g) + IVIG (20 g). Adverse events (AEs) were recorded and ana- lyzed for all PE treatment groups and PE modalities.

Results: PE procedure-related AEs were more common  in the active treat- ment groups (16.9% out of 1283 TPE and 12.5% out of 2203 LVPE were

associated with at least one AE, a similar rate than in other PE indications)than in the placebo group (0.7% out of 1223 sham PE). Percentage of procedures with at least one AEs was higher with central venous access compared toperipheral venous access in all three active treatment groups (20.1% vs 13.1%,respectively).Conclusion: The TPE and LVPE procedures used in the AMBAR study onmild-to-moderate AD population were as safe and feasible as in other therapeutic applications of PE or routine plasmapheresis.KEYWORDSadverse event, Alzheimer's disease, apheresis, cognition, dementia, intravenousimmunoglobulin, plasma exchange, plasmapheresis, venous access


With the growth of older populations around the world, increasing incidence of dementia is a prominent public health problem. In 2020, an estimated 55 million people were living with dementia worldwide.1 The number of people suffering from dementia is projected to increase to

131.5 million by 2050.2 Sixty to eight percent of these cases of dementia are classified as Alzheimer's disease (AD).3 AD is characterized by memory impairment, cog- nitive decline, psycho-affective and behavioral disorders, and loss of communication and spatial skills.4 In addi- tion, microscopic changes have been observed (postmor- tem) in the brains of AD patients. Amyloid plaques and neurofibrillary tangles are found in the brains of AD patients and both are associated with the functional decline  and  death  of  neuronal  cells.  The  plaques  are

made up of amyloid β peptides (Aβ), while the neurofi-

brillary tangles are composed of phosphorylated tau proteins.5,6

At present, standard treatment for AD is symptom- atic, consisting of acetylcholinesterase inhibitors and N- methyl-D-aspartate receptor antagonists.7 However, although new treatments of AD directed toward affecting

the underlying mechanisms of the disease—specifically Aβ accumulation and deposition—have met to date with little success,8-10 recent studies with anti-Aβ antibodies are contributing to the understanding of the Aβ patho- physiology associated with reduction of Aβ plaques.11-14 The Alzheimer Management by Albumin Replacement

(AMBAR) study has taken a new, unique approach to AD by attempting to alter the disease process through plasma exchange (PE) with albumin replacement.15

Aβ is found in the plasma and cerebrospinal fluid

(CSF) as a product of normal cellular metabolism. In both compartments, Aβ is highly protein-bound and albumin is the predominant protein. The majority of Aβ in plasma

(89%) is bound to albumin at one to one ratio.16 Based on the finding that Aβ in the CSF is in equilibrium with Aβ in plasma,17 removal of Aβ (bound to albumin) by PE would draw Aβ out of the CSF to re-establish Aβ levels in plasma.18-21 In the AMBAR study, PE was performed by replacement with therapeutic Aβ-free albumin22 to not only maintain osmotic pressure and prevent hypovolemia23 but to provide new potential binding sites for plasma Aβ and further sequestration of Aβ. In addition, PE with albu- min replacement could restore the antioxidant capacity of

plasma albumin which is reduced in AD22,24-26 and facili- tate the removal of other potentially harmful metabolites (eg, autoantibodies, alloantibodies, and toxins).23,27

The AMBAR study, which was preceded by a pilot28 and a phase 2 studies,29,30 was the first study to utilize PE in a phase 2b/3 trial in the patients with AD. Primary and secondary clinical results of the AMBAR study, which have been previously reported,31,32 demonstrated that PE slowed the decline, stabilized or even improved the disease symptoms as assessed by cognitive, neuropsychological, global assessment, and neuropsychiatric test scales.

Given the lack of experience with the application of PE in elderly patients with cognitive decline such as AD, the focus of this study is on the unique application of PE modalities in the patients with AD, including the use of a new low-volume plasma exchange (LVPE) technique as well as of sham PE procedures.


  1. | Regulatory compliance

The prospective, randomized, controlled AMBAR trial was conducted at 41 sites in Spain and the United States. This study was conducted in accordance with applicable regula- tory guidelines and the International Council for

FIGURE 1 Outline of treatment periods and distribution of treatment groups in the AMBAR study.

IVIG, intravenous immunoglobulin; LVPE, low-volume plasma exchange; TPE, therapeutic plasma exchange

Harmonization of Technical Requirements for Pharma- ceuticals for Human Use, and Good Clinical Practice. The protocol, the informed consent form, and the patient infor- mation sheets were approved by Institutional Review Boards or Ethics Committees from the sites and the Health Authorities in Spain and the United States. The informed consent was obtained from each patient or their qualified representative prior to enrollment in the study.

  1. | Patient selection

The “safety population” (ie, all patients included in the study and subjected to at least one PE session)31 consisted of 322 patients (54% women and 46% men), average age

of 69.0 ± 7.7 years, with a diagnosis of mild-to-moderate AD (by National Institute of Neurological and Communi- cation Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria) and had an aver- age Mini-Mental State Examination score of 21.6 ± 2.6. Details on demographic and clinical characteristics of patients as well as full inclusion and exclusion criteria are available in the primary paper31 and summarized in Table SI.

  1. | Treatment groups

Enrolled patients were randomly assigned to one of four groups (1:1:1:1). PE with albumin (Albutein 5%, Grifols) replacement for the intensive phase and PE with albumin (Albutein 20%, Grifols) replacement for the maintenance

phase was administered in two different doses (“low” and “high” albumin), to three of the groups. Two of the PE groups also received IVIG (Flebogamma 5% DIF, Grifols,

Barcelona, Spain). A simulated noninvasive PE procedure (“sham”) that did not involve any fluid transfer was per- formed on the placebo group (details below).

The treatment period in the AMBAR study was 14 months. Weekly PE was performed for 6 weeks in the treatment groups during a therapeutic plasma exchange (TPE) treatment period, followed by a 12-month period of monthly LVPE treatments.15,31 Figure 1 summarizes the treatment periods and the distribution of patients in the treatment groups.

  1. | Conventional (therapeutic) PE treatment

A commercial continuous flow cell separator was used for TPE. During the TPE treatments, approximately one plasma volume (2500-3000 mL of plasma or 35-45 mL/kg based on height, weight, and hematocrit) was removed and replaced by an equal volume of 5% albumin (125-150 g) under continuous flow. Each session was carried out at an infusion rate of 60-100 mL/min. An infusion  typically started at a low rate, and was increased as tolerated.

  1. | LVPE treatment

For LVPE, a prototype modified from commercial plasma donation devices (Autopheresis-C; Fenwal, Lake Zurich, IL or Aurora; Fresenius Kabi, Bad Homburg, Germany) devel-

oped by Fresenius Kabi and Grifols was used. Further information on LVPE devices is provided in the “LVPE devices” section of the Supporting Information Material.

Central or peripheral venous access for TPE was cho- sen by the personnel at the study sites based on their practice. When chosen, placement and verification of central venous access was performed according to exist- ing standard procedures at the study site. All LVPE pro- cedures were performed via peripheral venous access.15,31 LVPE differs from routine plasmapheresis (plasma donation) only in that there is the replacement of

FIGURE 2 Preparation of sham central venous catheter assembly used in sham therapeutic plasma exchange (TPE). A, Shown is the hydrocolloid patch on pediatric urostomy bag prior to removal of the bag. B, Shown are the bevel cut on the catheter tip and the point of insertion through the ostomy patch. C, Central venous catheter assembly has been inserted through the ostomy patch and sutured in place. D, Sham central venous catheter completed with dressings in place

removed plasma with albumin or IVIG, hence PE. In contrast to TPE, in the LVPE treatments the flow was dis- continuous: first, 690-880 mL of plasma (using a plasma donation nomogram based on weight, see Table SII) were removed,  and  afterwards  it  was  replaced  with  100  to

200 mL 20% albumin (20 g albumin = “low-albumin”

and 40 g albumin = “high-albumin”). This plasma vol- ume is similar to that removed during a routine plasma-

pheresis. Participating centers could decide to administer saline solution after LVPE to prevent hypovolemia and blood pressure-related adverse events (AEs) caused by the discontinuity between cell separation and albumin infusion.

In two of the groups (“low-albumin + IVIG” and “high-albumin + IVIG”), the albumin infusions were alternated with IVIG (10 g IVIG = “low IVIG” or 20 g IVIG = “high IVIG”) every 4 months during the LVPE

period15,31 (see Figure 1). Albumin dosage was adjusted based on the volume of plasma removed while IVIG doses were fixed (Table SII).

  1. | Sham PE treatment

Patients in the placebo group were given sham treat- ments at  the same time  points as PE was performed in the active treatment groups (Figure 1). Sham treatments were designed to simulate PE as realistically as possible to maintain patient blinding (Figure 2). No plasma was removed and no albumin or IVIG was administered dur- ing sham treatments. Further information on sham treat-

ment is provided in the “Sham PE treatment” section of

the Supporting Information Material.

  1. | Safety assessments and analysis

The primary safety assessment was the percent of TPE (including consideration to venous access: central vs peripheral) and LVPE procedures  associated  with  at least one AE related to the study procedure. AEs with

an onset ≤72 h after the end of a PE procedure were

considered related to procedure. In addition, the per- centage of TPE and LVPE procedures associated with an AE that was or was not related to the PE procedure was assessed.

Statistics were descriptive, and included frequencies and percentages for categorical variables, and means, medians, and/or ranges for continuous variables.

  1. | RESULTS 

  1. | Study and procedure completion rates

The distribution of enrolled patients into the four groups is shown in Table 1. One patient randomized to placebo group received inadvertently a real central venous cathe- ter. The patient  was  then  included  in  the  high- albumin + IVIG group but analyzed in the placebo group for efficacy analysis and considered as a treated patient for safety analysis. A total of 4709 PE procedures were performed (3486 real; 1223 sham). TPE made up 1283 of the active treatments and 2203 were LVPE.

  1. | PE procedure characteristics

Elapsed time for the TPE procedures were similar across all treatment groups for the first treatment (approximately 110 min) and was shortened slightly over the course of the TPE procedures (96.1-107.8 min for last TPE). The duration of the sham procedure was shorter than the TPE (approxi- mately 60 min vs approximately 100-110 min).

When the number of planned PE procedures com- pleted was examined over the course of the study, the percentage of procedures completed was highest in the placebo and low-albumin groups (79.7% and 79.5%, respectively) compared with the groups that included

IVIG treatment: 64.0% for low-albumin + IVIG and 67.1% for the high-albumin + IVIG group.

The volume of PE during the six TPE procedures was very similar across procedures and across active treat- ment groups: from 2385.6 ± 68.7 to 2674.4 ± 63.7 mL (mean ± SE). The plasma volume exchanged was also similar  across  the  active  treatment  groups  during  the

12   LVPE   procedures:   from   719.9 ± 22.1   to   885.0

± 163.7 mL.

  1. | All AEs (regardless of relationship to procedure)

When all AEs within 72 h of PE were assessed for all PE procedures, the percentage of PE affected with any AE ranged from 4.1% in the placebo group to 18.8% in the high-albumin + IVIG group. The low-albumin group had AEs in 16.4% of the procedures, similar to the low- albumin + IVIG group (15.7%).

When all AEs were summarized (regardless of tim- ing), AEs were found to be more common in the active treatment groups than in the placebo group (90.1% vs 70.9%, respectively, of patients reported at least 1 AE dur- ing the study).

  1. | Procedure-related AEs

Out of the 4709 total PE procedures, 501 (10.6%) were associated with 637 procedure-related  AEs  within  the 72 h after procedure completion. The percentage of pro- cedures associated with at least one AE was higher for the TPE procedures (16.9%) than for the LVPE proce- dures (12.5%).

The rate of procedures with at least one AE was similar in all the active treatment groups: 13.5% for the low- albumin group, 12.5% for the low-albumin + IVIG group

FIGURE 3 Adverse events (AEs) over the course of the study by treatment group. IVIG, intravenous immunoglobulin; LVPE, low-volume plasma exchange; TPE, therapeutic plasma exchange period

and 16.5% for the high-albumin + IVIG group. Conversely, for the placebo (sham treatment) group the rate was 0.7%.

  1. | TPE vs LVPE-related AEs

When procedure-related AEs were broken down  into TPE and LVPE treatments, the pattern was the same as that seen for all PE procedures. For TPE procedures the incidence of procedures with at least one associated AEs was as follows: placebo 1.1%; low-albumin 17.4%, low- albumin + IVIG 15.2%, and high-albumin + IVIG 18.3%. For the LVPE procedures, procedures with  at least one associated AEs were similarly low in the pla- cebo group (0.5%) and higher in the active treatment groups: low-albumin 11.3%; low-albumin + IVIG 10.9%, and high-albumin + IVIG 15.4%. These results are sum- marized in Figure 3. AEs frequency  was  distinctly higher during the TPE phase of the study compared to the LVPE phase.

The most frequently reported types (MedDRA Pre- ferred Term) of procedure-related AEs based on numbers

(% of PE with at least 1 related AE) of TPE or LVPE were: General Disorders and Administration Site Conditions (4.2% and 2.8%, respectively; mainly catheter- and injec- tion site-related AEs), nervous system disorders (3.5% and 2.6%, respectively; mainly dizziness, paresthesia, and presyncope), and Vascular Disorders (2.5% and 4.4%, respectively; mainly hypotension). Further details are provided in Table SIII.

  1. | Central vs peripheral access- related AEs

The percentage of TPE procedures with at least one procedure-related AE was calculated for central and peripheral venous access (Table 2). Percentage of proce- dures with at least one AE was higher with central access compared to peripheral access in all three active treat- ment groups (20.1% vs 13.1%, respectively). The incidence of procedures with at least one associated AE in the pla- cebo group was very low (1.4% central and 0.9% peripheral).

The most frequently reported types (MedDRA Pre- ferred Term) of procedure-related AEs based on numbers (% of PE with at least 1 related AE) of TPE with central access were general disorders and administration site conditions (6.0%, mainly catheter site erythema), and nervous system disorders (4.7%, mainly dizziness, pares- thesia, and syncope). In TPE with peripheral access, no AE category stand out over others. Further details are provided in Table SIV.


PE has been used safely in multiple neurological disor- ders, such as severe acute inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multiple scle- rosis, and others.23,33-38 PE is a well-studied  procedure and AEs could theoretically be anticipated based on clini- cal experience and the existing information on the safety profile of the administered products, albumin and IVIG, used in the AMBAR trial.39,40 However, PE had never been tested in AD, typically an aged patient population with associated health issues.

The basic safety analysis of the AMBAR trial previ- ously reported that 90% of the PE procedures were uneventful,31 as expected based on the safety profile for PE  previously   reported.37,41-43   The   high   percentage of finalized procedures and the relatively low incidence of AEs highlighted the feasibility and safety, respectively, of this procedure in mild-to-moderate AD patients. Here we extended the safety analysis emphasizing the proce- dure type (TPE vs LVPE), the different PE treatment modalities (albumin doses; with/without IVIG) and TPE venous access (central vs peripheral).

The large number of proven and potential therapeutic indications for PE can be interpreted that the procedure is generally considered safe. This has been substantiated in multiple studies.44-47 Similar to the results of the pre- sent study, Guptill et al. found a low rate of serious com- plications with PE and a greater frequency of AEs with central access when compared to peripheral access.46 When the safety of PE was studied in a geriatric popula- tion and compared to a nongeriatric population, it was determined that frequency and nature of AEs were simi- lar.45 These results agree with the current study, in that TPE was found to be a safe and tolerable procedure even in elderly populations with serious medical conditions.

In the current study, the safety and utility of LVPE, a new PE modality based on conventional plasma dona- tion, was also demonstrated. The low incidence of AEs with the LVPE procedures in this study agrees with pub- lished literature on the safety of plasma donation. Plasma

donation is a very common and well-tolerated procedure with an estimated 48.7 million donations occurring in the United States in 2018.48 The relative safety of these dona- tions is indicated by the previously described studies and by data from the U.S. Food and Drug Administration. Studies of AEs associated with plasma donation have shown that these events are very rare.49,50

Some of the most common AEs previously reported in the primary results of the AMBAR study were clearly related to the procedure itself: extravasation and injection site reactions.31 However, some of the other AEs have been reported  as  associated  with  the  administration  of  the

replacement fluids—albumin and IVIG. Hypotension is

one of the most common side effects reported after admin- istration of albumin.51 Hypotension has been reported with IVIG as well.52 The higher incidence of hypotension in the LVPE can be ascribed to the discontinuity between cell sep- aration and albumin infusion in the procedure. Injection site reactions and dizziness have been also previously reported in the primary results of the AMBAR study31 and after IVIG administration.52 The higher incidence of AEs in the treatment groups that received albumin and IVIG may account for the higher withdrawal rate in these groups.

When overall AEs (related and unrelated to proce- dures) were considered, the number of patients with AEs reported in the placebo group was 69.6%. This suggests that the overall population in this study had underlying health issues. In fact, medical records taken at baseline before treatment inception showed that 98.8% of the overall patient population reported relevant medical conditions,31 which could account for the number of nonprocedure-related AEs in the study.

Limitations of the AMBAR trial include that AD patients were diagnosed based on the clinical phenotype rather than on biomarkers, as well as a possible imperfec- tion of the blinding procedure, in addition to the shorter time allotted for the placebo procedure compared to the elapsed time for the actual procedure in treated groups. However, the low consent withdrawal rate observed in the placebo group suggest that blinding was effective.


Overall, PE using albumin with or without IVIG was fea- sible and well-tolerated by AD patients, which are typi- cally an elderly population with associated health issues. Frequency and nature of procedure-related AEs were similar to those observed in other PE-treated diseases. The large number of successful TPE + LVPE procedures conducted in this specific population suggests that PE could be a viable therapeutic approach to treat AD.


The authors thank patients for their indispensable contribu- tion. Jordi Bozzo PhD, CMPP and Michael K James, PhD (Grifols) are acknowledged for medical writing and edito- rial support in the preparation of this manuscript. The AMBAR study is funded by Grifols, a manufacturer of ther- apeutic human serum albumin and intravenous immune globulin.


Mercè Boada has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, Biogen, and Servier; and received fees for lectures and funds for research from Araclon, Esteve, Grifols, Janssen, Novartis, Nutricia, Piramal, Pfizer-Wyett,  Roche,  and  Servier.  Oscar  L.  Lo´pez  has been a consultant for Grifols and Lundbeck.  Laura Núñez,  Miquel  Barcelo´,  Carlota  Grifols,  and  Antonio P´aez   are   full-time   employees   of   Grifols.   Zbigniew

M. Szczepiorkowski has been on the board of directors or an advisory committee for, ICCBBA, Fenwal/Fresenius Kabi, Grifols, and Novartis; and has received grants and/or contract research for Fresenius Kabi, Erydel, Cell- phire, and Cytosorbents. Javier Olazar´an has been a con- sultant for Schwabe and Grifols; and received fees for lectures and funds for research from Esteve, Grifols, Nutricia, and Neuraxpharm. Other authors declare no conflict of interest.


The data that support the findings of this study are avail- able from the corresponding author upon reasonable request.


Institutional Review Boards or Ethics Committees from the sites and the health authorities approved the proto- col, the patient information sheets, and the informed consent form, in agreement with the Declaration of Hel- sinki as well as the standards of Good Clinical Practice.


Antonio Pa´ez



  1. Gauthier S, Rosa-Neto P, Morais J, Webster C. World Alzheimer Report 2021: Journey through the Diagnosis of Dementia. London, England: Alzheimer's Disease International; 2021.
  2. Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. World Alzheimer Report 2015: The Global Impact of Dementia. 2015.
  3. 2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021;17(3):327-406.
  4. Feldman HH, Jacova C, Robillard A, et al. Diagnosis and treat- ment of dementia: 2. Diagnosis. CMAJ. 2008;178(7):825-836.
  5. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease.

Lancet. 2006;368(9533):387-403.

  1. Ittner LM, Gotz J. Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011;12(2):65-72.
  2. Parsons CG, Danysz W, Dekundy A, Pulte I. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res. 2013;24(3): 358-369.
  3. Brody M, Liu E, Di J, et al. A phase II, randomized, double- blind, placebo-controlled study of safety,  pharmacokinetics, and biomarker results of subcutaneous bapineuzumab in patients    with    mild    to    moderate    Alzheimer's    disease. J Alzheimers Dis. 2016;54(4):1509-1519.
  4. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug- development pipeline: few candidates, frequent failures. Alzhei- mers Res Ther. 2014;6(4):37.
  5. Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzumab for mild to moderate Alzheimer's disease in two global, random- ized, phase 3 trials. Alzheimers Res Ther. 2016;8(1):18.
  6. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh  M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther. 2021;13(1):98.
  7. Klein G, Delmar P, Voyle N, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alz- heimer's disease: a PET substudy interim analysis. Alzheimers

Res Ther. 2019;11(1):101.

  1. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early Alzheimer's disease. N EnglJ Med. 2021;384(18):1691-1704.
  2. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double- blind, phase 2b proof-of-concept clinical trial in early Alzhei- mer's disease with lecanemab, an anti-Aβ protofibril antibody.

Alzheimers Res Ther. 2021;13(1):80.

  1. Boada M, Lopez O, Nunez L, et al. Plasma exchange for Alzhei- mer's disease management by albumin replacement (AMBAR) trial: study design and progress. Alzheimers Dement. 2019;5: 61-69.
  2. Kuo YM, Kokjohn TA, Kalback W, et al. Amyloid-beta peptides interact  with plasma proteins and erythrocytes:  implications for their quantitation in plasma. Biochem Biophys Res Commun. 2000;268(3):750-756.
  3. Roberts KF, Elbert DL, Kasten TP, et al. Amyloid-beta efflux from the central nervous system into the plasma. Ann Neurol. 2014;76(6):837-844.
  4. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-Abeta antibody alters CNS and plasma Abeta clearance and decreases brain Abeta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001;98(15):8850-8855.
  5. DeMattos RB, Bales   KR,   Cummins   DJ,   Paul   SM, Holtzman DM. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's dis- ease. Science. 2002;295(5563):2264-2267.
  6. DeMattos RB, Bales KR, Parsadanian M, et al. Plaque- associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium  in   a   mouse   model   of   Alzheimer's   disease. J Neurochem. 2002;81(2):229-236.

  1. Marques MA, Kulstad JJ, Savard CE, et al. Peripheral amyloid-beta levels regulate amyloid-beta clearance from the central nervous system. J Alzheimers Dis Rep. 2009;16(2): 325-329.
  2. Costa M, Ortiz AM, Jorquera JI. Therapeutic  albumin  bind- ing to remove amyloid-beta. J Alzheimers Dis. 2012;29(1): 159-170.
  3. Meca-Lallana JE, Rodriguez-Hilario H, Martinez-Vidal S, et al. Plasmapheresis: its use in multiple sclerosis and other demye- linating processes of the central nervous system. An observa- tion study. Rev Neurol. 2003;37(10):917-926.
  4. Biere AL, Ostaszewski B, Stimson ER, Hyman BT, Maggio JE, Selkoe DJ. Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J Biol Chem. 1996;271(51): 32916-32922.
  5. Costa M, Horrillo R, Ortiz AM, et al. Increased albumin oxidation in cerebrospinal fluid and  plasma  from  Alzhei- mer's disease patients. J Alzheimers Dis. 2018;63(4):1395- 1404.
  6. Ramos-Fernandez E, Tajes M, Palomer E, et al. Posttransla- tional nitro-glycative modifications of albumin in Alzheimer's disease: implications in cytotoxicity and amyloid-beta peptide aggregation. J Alzheimers Dis. 2014;40(3):643-657.
  7. Weinshenker BG, O'Brien PC, Petterson TM, et al. A random- ized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999;46(6): 878-886.
  8. Boada M, Ortiz P, Anaya F, et al. Amyloid-targeted therapeu- tics in Alzheimer's disease: use of human albumin in plasma exchange as a novel approach for Abeta mobilization. Drug News Perspect. 2009;22(6):325-339.
  9. 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, ran-

domized, controlled clinical trial. J Alzheimers Dis. 2017; 56(1):129-143.

  1. Cuberas-Borros G, Roca I, Boada M, et al. Longitudinal neuro- imaging analysis in mild-moderate Alzheimer's disease patients treated with  plasma  exchange  with  5%  human  albumin. J Alzheimers Dis. 2018;61(1):321-332.
  2. Boada M, Lopez O, Olazaran J, et al. A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: primary results of the AMBAR study. Alz- heimers Dement. 2020;16(10):1412-1425.
  3. Boada M, Lopez O, Olazaran J, et al. Neuropsychological, neu- ropsychiatric and quality-of-life assessments in Alzheimer's dis- ease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study. Alzheimers Dement. 2022;18:1314-1324.
  4. Bambauer R, Arnold A. Plasmapheresis with a substitution solu- tion of human serum protein (5%) versus plasmapheresis with a substitution solution of human albumin (5%) in patients suffering from autoimmune diseases. Artif Organs. 1999;23(12):1079-1087.
  5. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae- Grant A. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technol- ogy Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294-300.
  6. Dyck PJ, Litchy WJ, Kratz KM, et al. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demy- elinating polyradiculoneuropathy. Ann Neurol. 1994;36(6): 838-845.
  7. Mazzi G, Raineri  A,  Zucco  M,  Passadore  P,  Pomes  A, Orazi BM. Plasma-exchange in chronic peripheral neurological disorders. Int J Artif Organs. 1999;22(1):40-46.
  8. Nieto-Aristiz´abal I, Vivas A´ J, Ruiz-Montaño P, et al. Therapeu-

tic plasma exchange as a treatment for autoimmune neurologi- cal disease. Autoimmune Dis. 2020;2020:3484659.

  1. Connelly-Smith L, Dunbar NM. The 2019 guidelines from the American Society for Apheresis: what's new? Curr Opin Hema- tol. 2019;26(6):461-465.
  2. Alsina L, Mohr A, Montanes M, et al. Surveillance study on the tolerability and safety of Flebogamma® DIF (10% and 5% intra- venous immunoglobulin) in adult and pediatric patients. Phar- macol Res Perspect. 2017;5(5):e00345.
  3. McLeod BC. Therapeutic apheresis: use of human serum albu- min, fresh frozen plasma and cryosupernatant plasma in thera- peutic plasma exchange. Best Pract Res Clin Haematol. 2006; 19(1):157-167.
  4. Cortese I, Cornblath DR. Therapeutic plasma exchange in neu- rology: 2012. J Clin Apher. 2013;28(1):16-19.
  5. Henriksson MM, Newman E, Witt V, et al. Adverse events in apheresis: an update of the WAA registry data. Transfus Apher Sci. 2016;54(1):2-15.
  6. Basic-Jukic N, Kes P, Glavas-Boras S, Brunetta B, Bubic- Filipi L, Puretic Z. Complications of therapeutic plasma exchange: experience with 4857 treatments. Therap Apher Dial. 2005;9(5):391-395.
  7. Arslan O, Arat M, Tek I, Ayyildiz E, Ilhan O. Therapeutic plasma exchange in a single center: Ibni Sina experience. Transfus Apher Sci. 2004;30(3):181-184.
  8. Ataca P, Marasuna OA, Ayyildiz E, Bay M, Ilhan O. Therapeu- tic plasmapheresis in geriatric patients: favorable results. Transfus Apher Sci. 2014;51(3):64-67.
  9. Guptill JT, Oakley D, Kuchibhatla M, et al. A retrospective study of complications of therapeutic plasma exchange in myasthenia. Muscle Nerve. 2013;47(2):170-176.
  10. Yücesan C, Arslan O, Arat M, et al. Therapeutic plasma exchange  in  the  treatment  of  neuroimmunologic   disor- ders: review of 50 cases. Transfus Apher Sci. 2007;36(1): 103-107.
  11. Plasma Protein Therapeutics Association. United States Total Plasma Collections 2009–2018. Annapolis, MD. 2019.
  12. Schulzki T, Seidel K, Storch H, et al. A prospective multicentre

study on the safety of long-term intensive plasmapheresis in donors (SIPLA). Vox Sang. 2006;91(2):162-173.

  1. McLeod BC, Price TH, Owen H, et al. Frequency of immediate adverse effects associated with apheresis donation. Transfusion. 1998;38(10):938-943.
  2. GRIFOLS. Albutein 20% Albumin (Human) U.S.P. Injection, Solution. Los Angeles, CA: Grifols Biologicals, LLC. 2019. https://www.grifols.com/documents/10192/58284/ft-albutein- 5-usa-en/9272eef7-67db-45f1-9fb9-68a6b1c83ecb. Accessed October 29, 2021.
  3. GRIFOLS. Flebogamma 10% DIF: Immune Globulin Intrave- nous (Human) Solution for Intravenous Administration. Barce- lona, Spain: Instituto Grifols, S.A.; 2019. https://www.grifols.

com/documents/10192/63615/flebo10-ft-us-en/f477695f-32d7- 4d2b-bdb6-85f49d8eab67. Accessed October 29, 2021.


Additional supporting information can be found online in the Supporting Information section at the end of this article.

How to cite this article: Boada M, Kiprov D, Anaya F, et al. Feasibility, safety, and tolerability of two modalities of plasma exchange with albumin replacement to treat elderly patients with Alzheimer's disease in the AMBAR study. J Clin

Apher. 2022;1‐10. doi:10.1002/jca.22026


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