Therapeutic Plasma Exchange
Therapeutic plasma exchange (plasmapheresis with albumin or albumin plus immunoglobulin replacement)
Written by Aaron CuhaReviewed Sep 2026
Also known as: TPE, Plasmapheresis, Albumin exchange, AMBAR protocol, Plasma exchange
An established medical procedure that removes plasma and replaces it with albumin. A 347-patient randomised trial in Alzheimer disease met one of two co-primary endpoints, and two small 2025 randomised trials of ageing biomarkers reached opposite conclusions.
Overview
Therapeutic plasma exchange is not experimental as a procedure. It is a standard treatment used in neurology, haematology and nephrology, performed with cleared apheresis equipment, in which a volume of the patient's plasma is removed and replaced with albumin, or albumin plus intravenous immunoglobulin. What is investigational is using it against ageing rather than against a specific disease.
The largest controlled trial is AMBAR, a phase 2b/3 run by Instituto Grifols in mild to moderate Alzheimer disease. Three hundred and forty-seven patients were randomised into three plasma exchange arms with different albumin and immunoglobulin replacement doses or a sham procedure: six weeks of weekly conventional exchange, then twelve months of monthly low-volume exchange. At month 14 the treated patients declined less than sham on the activities of daily living co-primary endpoint, 52 percent less decline with p equal to 0.03, with a trend on the cognitive co-primary endpoint, 66 percent less decline with p equal to 0.06, which did not reach significance. Patients with moderate disease at baseline improved on both scales; patients with mild disease showed no change. The trial was funded by Grifols, which manufactures the albumin.
Two small randomised trials published in 2025 tested plasma exchange against ageing biomarkers directly and disagreed. In Aging Cell, 42 healthy adults over 50 were randomised to biweekly exchange with or without intravenous immunoglobulin, monthly exchange, or placebo. The authors reported that long-term exchange was safe, with two adverse events requiring discontinuation, and that 15 epigenetic clocks showed rejuvenation relative to placebo at a false discovery rate below 0.05, with the biweekly exchange plus immunoglobulin arm performing best. In Scientific Reports, a crossover randomised trial in healthy blood donors compared eight versus four plasmaphereses over 18 weeks without any young plasma or albumin replacement, and found no epigenetic rejuvenation; instead DNAmGrimAge, the Hannum clock and the Dunedin Pace of Aging all increased. The two trials used different protocols, and the second explicitly notes that its protocol omitted replacement fluid.
Mechanism of action
Two competing accounts, neither settled in humans. The dilution account, developed in mice, holds that removing a fraction of old plasma dilutes age-elevated autoregulatory proteins and resets systemic signalling, and that the replacement fluid is secondary; the 2020 mouse work found that saline plus albumin exchange matched the effects of young blood. The replacement account holds that the albumin itself matters, either by binding and carrying away circulating ligands or by restoring binding capacity; this is the rationale for the AMBAR protocol, in which albumin is the replacement product. The 2025 Scientific Reports trial, which removed plasma without replacing it with albumin and saw epigenetic clocks move in the wrong direction, is a data point against dilution alone being sufficient, though a single small crossover trial does not settle it.
Human evidence
Substantial by the standards of this catalogue: one 347-patient randomised controlled trial in Alzheimer disease with published results, and two small randomised trials in 2025 testing ageing biomarkers that reached opposite conclusions. This is more human data than almost anything else on this site claimed to affect ageing.
- AMBAR (NCT01561053, Alzheimer's and Dementia 2020): 347 patients with mild to moderate Alzheimer disease randomised 1:1:1:1 to three plasma exchange regimens or sham, triple masked, six weeks weekly then twelve months monthly. One of two co-primary endpoints was met. Activities of daily living declined 52 percent less than sham (p = 0.03); the cognitive co-primary showed 66 percent less decline but did not reach significance (p = 0.06). Manufacturer funded by Instituto Grifols.
- AMBAR subgroup detail, which cuts both ways: patients with moderate disease at baseline (Mini-Mental State Examination 18 to 21) scored better on both activities of daily living (p = 0.002) and cognition (p = 0.05), 61 percent less decline on each. Patients with mild disease (Mini-Mental State Examination 22 to 26) showed no change. Subgroup results from a trial that missed one co-primary are exploratory.
- AMBAR also reported better scores on the Clinical Dementia Rating Sum of Boxes (p = 0.002, 71 percent less decline) and the clinical global impression scale (p < 0.0001).
- Aging Cell 2025 (NCT06534450): 42 healthy adults over 50, randomised, single blinded, placebo controlled. Biweekly exchange with or without intravenous immunoglobulin, monthly exchange, or placebo. Reported safe over long-term use, two discontinuations for adverse events. Fifteen epigenetic clocks showed rejuvenation versus placebo at false discovery rate below 0.05, with the biweekly plus immunoglobulin arm strongest.
- Scientific Reports 2025: randomised crossover in healthy blood donors, 8 versus 4 plasmaphereses over 18 weeks with a minimum 14-day interval and no young plasma or albumin replacement. No epigenetic rejuvenation. DNAmGrimAge, the Hannum clock and the Dunedin Pace of Aging all rose. Serum total cholesterol, non-HDL cholesterol, triglycerides, apolipoprotein A, total protein and albumin fell.
What this does not tell you: AMBAR tested a disease population, not healthy ageing, it missed one of its two co-primary endpoints, and it was funded by the company that makes the albumin. The two 2025 biomarker trials are small, 42 and a crossover cohort of blood donors, and they used different protocols and different replacement fluids, which is the most likely reason they disagree. Epigenetic clocks are correlational measures; no human study has linked a clock change from plasma exchange to a health outcome, a disease event or survival. Plasma exchange also removes clotting factors, immunoglobulins and lipoproteins along with whatever is being targeted, which is why the Scientific Reports trial saw albumin and total protein fall.
Reading the research record
This page carries a live disagreement and this site does not resolve it. The Aging Cell trial reports rejuvenation across 15 epigenetic clocks against placebo; the Scientific Reports trial reports the clocks moving in the wrong direction. The differences that could explain it are concrete rather than rhetorical: the Aging Cell protocol replaced removed plasma with albumin and, in the strongest arm, added intravenous immunoglobulin, while the Scientific Reports protocol was plasmapheresis in healthy blood donors with no replacement fluid at all, and the authors say so explicitly. If the dilution hypothesis were sufficient on its own, the second trial should have shown benefit and did not. That is a real argument against dilution alone and it is being made by a small trial, which is how this field usually works.
The funding runs in the expected direction in one case and is worth naming. AMBAR was funded by Instituto Grifols, a plasma products company whose albumin is the replacement fluid in the protocol under test. That does not make the result wrong, and manufacturer funding is normal for a trial of this size, but it belongs on the page alongside the finding that one of two co-primary endpoints was missed. The 2025 Aging Cell trial's registry record lists an individual investigator as sponsor rather than a company and carries a registry status of unknown, which is a different kind of limitation.
A final point about what this procedure is. Unlike almost everything else in this batch, plasma exchange is available today, is performed routinely, and has a known safety profile from decades of use in neurological and haematological disease. The question is not whether it can be done but whether doing it in a healthy older person changes anything that matters. On that question there are two small randomised trials pointing in opposite directions and no outcome data at all.
The evidence, charted
Fig. 1 · evidence composition
7of 7 citations (100%) are in people
Every citation cited here is Human work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2012 to 2025, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2020
A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study
347 patients randomised 1:1:1:1 from 496 screened into three plasma exchange arms with different albumin and immunoglobulin replacement doses or sham, with six weeks of weekly conventional exchange then twelve months of monthly low-volume exchange. At month 14, treated patients had 52 percent less decline on activities of daily living (p = 0.03) and 66 percent less decline on the cognitive scale (p = 0.06, not significant). Moderate-disease patients improved on both; mild-disease patients did not change. Funded by Instituto Grifols, which manufactures the albumin used.
Alzheimer's and Dementia - Human2019
Plasma exchange for Alzheimer's disease Management by Albumin Replacement (AMBAR) trial: Study design and progress
The published design paper for AMBAR, describing the four-arm structure, the sham procedure and the endpoint plan before results were reported.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Human2022
Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer's disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study
Secondary analysis of the AMBAR randomised trial reporting the neuropsychological, neuropsychiatric and quality-of-life measures alongside the primary cognitive and functional endpoints.
Alzheimer's and Dementia - Human2025
Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange
42 healthy adults over 50 randomised to biweekly plasma exchange with or without intravenous immunoglobulin, monthly exchange, or placebo. Long-term exchange was reported safe, with two adverse events requiring discontinuation and one related to immunoglobulin. Fifteen epigenetic clocks showed rejuvenation versus placebo at a false discovery rate below 0.05, with biweekly exchange plus immunoglobulin performing best. Registered as NCT06534450.
Aging Cell - Human2025
Human clinical trial of plasmapheresis effects on biomarkers of aging (efficacy and safety trial)
A randomised crossover trial in healthy blood donors comparing 8 versus 4 plasmaphereses over 18 weeks, without young plasma or albumin replacement. No epigenetic rejuvenation was observed. DNAmGrimAge, the Hannum clock and the Dunedin Pace of Aging all increased, and the authors write that this protocol may accelerate epigenetic ageing. Serum lipids, total protein and albumin fell; red cell distribution width and mean corpuscular haemoglobin concentration rose.
Scientific Reports - Human2012
A Study to Evaluate Albumin and Immunoglobulin in Alzheimer's Disease (AMBAR)
Registry record for AMBAR. Sponsor Instituto Grifols S.A., phase 2/3, randomised parallel assignment, triple masked across participant, care provider and outcomes assessor, 347 participants enrolled, start April 2012, results first posted 31 July 2019.
ClinicalTrials.gov - Human2022
The Effects Of Therapeutic Plasma Exchange (TPE) On Age Related Biomarkers And Epigenetics
Registry record for the 2025 Aging Cell trial. Phase 3 designation, 40 participants enrolled, start 12 September 2022, sponsor listed as an individual investigator, registry status listed as unknown.
ClinicalTrials.gov
What users report
Self-reported experiences, not evidence. Nothing below was measured under controlled conditions, and reports like these cannot separate a real effect from placebo, from the training or diet change that accompanied it, or from what the product actually contained. They are here because knowing what people describe, including what goes wrong, is worth reading alongside the studies.
- Longevity clinics market therapeutic plasma exchange under names including plasmapheresis, albumin exchange and blood cleansing, typically in courses of several sessions, and typically citing epigenetic clock readouts as the endpoint. Clock readouts are the outcome being sold, which is exactly the endpoint the two 2025 randomised trials disagree about.
- The procedure itself is routine and its adverse event profile is documented in the trials rather than in anecdote: in the Aging Cell trial of 42 adults over 50, two adverse events required discontinuation, one attributed to the intravenous immunoglobulin component rather than the exchange.
- Measurable biochemical consequences of the procedure are reported in the published crossover trial and are worth knowing before booking one: total cholesterol, non-HDL cholesterol, triglycerides, apolipoprotein A, total protein and albumin all fell, and red cell distribution width and mean corpuscular haemoglobin concentration rose.
- Where the intervention is offered with intravenous immunoglobulin added, that addition is a separate product with its own risk profile, and it is the component to which the one discontinuation in the Aging Cell trial was attributed.
Sources: The published trial reports themselves, which is where the adverse event and laboratory-change numbers above come from: the AMBAR primary results in Alzheimer's and Dementia 2020, the Aging Cell 2025 randomised trial and the Scientific Reports 2025 crossover trial. The description of how the procedure is marketed reflects the endpoints those clinics advertise, which are the epigenetic clock measures named in the trials. No clinic, forum post or individual patient account is quoted or relied on.
Frequently asked questions
Does plasma exchange reduce biological age?
Two small randomised trials published in 2025 disagree. One, in 42 adults over 50 with albumin replacement and in one arm added immunoglobulin, reported rejuvenation across 15 epigenetic clocks against placebo. The other, a crossover trial in healthy blood donors with no replacement fluid, found no rejuvenation and reported that three clocks moved in the wrong direction. Neither trial measured a health outcome, only clocks.
What did the AMBAR trial show?
In 347 patients with mild to moderate Alzheimer disease, plasma exchange with albumin replacement produced 52 percent less decline on activities of daily living than sham at 14 months, which met one co-primary endpoint at p equal to 0.03. The cognitive co-primary showed 66 percent less decline but missed significance at p equal to 0.06. Patients with moderate disease improved on both measures; patients with mild disease did not change. The trial was funded by Grifols, which makes the albumin.
Is plasma exchange approved?
The procedure is an established medical treatment with recognised indications in neurological, haematological and renal disease, performed with cleared apheresis equipment. It is not approved anywhere for ageing, biological age reduction or Alzheimer disease. Being an approved procedure is not the same as being approved for this use.
Is it risky?
It is a routine procedure with a known profile rather than an unknown one, but it is not nothing. It removes clotting factors, immunoglobulins and lipoproteins along with everything else, and the published crossover trial documented falls in total protein, albumin, cholesterol and triglycerides. In the 42-person randomised trial, two participants discontinued for adverse events, one attributed to the added intravenous immunoglobulin.
How is this different from young plasma infusion?
Opposite directions. Young plasma infusion adds plasma from a young donor. Plasma exchange removes the person's own plasma and replaces the volume with albumin or albumin plus immunoglobulin, so nothing from a young donor is added. The mouse work that motivated the second approach found that saline plus albumin exchange matched the effects of young blood, which is the dilution hypothesis.