Another trial, completed several years ago, is highly suggestive for dilution effects in aging humans, even though that wasn’t what the trial was designed to test.
Early in the last decade, Grifols — a global plasma products company — launched the AMBAR (Alzheimer’s Management by Albumin Replacement) trial to test albumin as a treatment for Alzheimer’s dementia of aging (AD). This was based on the facts that albumin is both a major extracellular antioxidant, and the carrier of about 90% of the beta-amyloid (Abeta) in the circulation — Abeta being one of the two key damaged proteins responsible for driving AD.
Previous research had shown that the pool of soluble Abeta in the brain exists in a kind of dynamic balance with the pool of Abeta in the blood. Therefore, lowering the level of circulating Abeta creates an osmotic force that draws soluble Abeta out of the brain, potentially offering protection against harmful effects. This “peripheral sink” approach had previously been demonstrated in animals using antibodies that trap Abeta in the blood, and was thought to be the mechanism for some of the passive antibodies targeting Abeta in human clinical trials.
In AMBAR, Grifols scientists hypothesized that AD patients’ albumin might be so saturated with Abeta that it would have lost its ability to draw out any more. Replacing that old, saturated albumin with fresh new protein would thus restore the youthful capacity to pull Abeta out of the brain and eliminate it via the liver.
The Grifols researchers also thought that patients would benefit from the fresh albumin’s antioxidant capacity. Albumin is a major antioxidant in blood plasma, but becomes more oxidized with age, and even more so in several diseases of aging — including AD, where albumin is more oxidized not only in plasma, but even more so in the cerebrospinal fluid.
Additionally, some patients in the trial were given Grifols’ intravenous immunoglobulin (IVIG) — a mixture of the antibodies in normal, non-infected people’s plasma, hypothesized to possibly contain natural antibodies targeting Abeta and thus further enhance the effect. IVIG had shown promise in several smaller clinical trials, but was largely abandoned after failing in a large one. Grifols scientists mostly included it to replace the antibodies that would be depleted by TPE, but also hoped that it might have some therapeutic effect of its own if combined with the effects of TPE and albumin itself.
The researchers also entertained the possibility that TPE itself would remove other toxic substances from AD patients’ plasma — but as a kind of haemodialysis, without imagining the sweeping effects seen in the Dilution Solution experiments (or in heterochronic parabiosis). Their real focus was on the albumin.
There were four groups in the trial. One group got a placebo treatment through every step of the trial, on the same schedule as the other groups: a yellowish fluid was circulated around the equipment, but was never actually connected to the patient’s circulation, giving the appearance of TPE without in any way changing a patient’s blood. All three of the remaining groups underwent six weekly sessions of conventional TPE — considered an intensive regime — and then, after a short break, received one session once a month of TPE ‘fortified’ with extra low- or high-dose albumin, with or without IVIG, for the next year.
The results were finally published this summer — and they look very promising. Overall, Therapeutic Plasma Exchange slowed AD patients’ decline in self-care ability by a remarkable 52% (see Figure (A)), and strongly appeared to slow cognitive decline — by an even larger two-thirds (Figure (G)) — but the pooled cognitive effects did not quite pass the standard test of statistical significance.
When you drill down one layer, both the cognitive effects and the activities of daily living were statistically significant when the moderate AD patients were considered separately (see Figures (B,H)). By contrast, there was no effect on either parameter in mild AD patients considered separately, seemingly for no other reason than the lack of any detectable decline in any of the mild AD groups over the course of the trial (Figures (C, I)).
Supposing that the effects in the moderate AD were real: what caused them? Was it the basic TPE that all treatment groups received, or was it the extra albumin added for all groups throughout the last twelve months of the trial? Did the IVIG have any effect at all? If TPE alone was the real driver, are we indeed seeing true dilution effects? There’s unfortunately no way to know for sure: all the treatment groups tend to bunch fairly closely together or to change relative positions throughout the trial ( Figures (D, E, J, and K)).
Overall, AMBAR offers some tantalizing clues about the benefits of the Dilution Solution in Alzheimer’s dementia of aging — but is far from proving or disproving the case.
