14 Dec 2017

In mice, infusing young blood rejuvenates the old, and even staves off some of the changes linked to Alzheimer’s. It’s too early to say if the same is true in people, but first results look encouraging. At the 2017 Clinical Trials on Alzheimer’s Disease meeting, held November 1–4 in Boston, Sharon Sha of Stanford University in Palo Alto, California, presented results of a small Phase 1 trial in which patients with mild to moderate AD received infusions of plasma donated by young men. The treatment appeared safe, and gave recipients a small boost on tests of everyday functioning. In a press release, Karoly Nikolich, from the trial sponsor, Alkahest, Inc., San Carlos, California, wrote that the data support “the ability of plasma compositions to counteract the biological processes underlying neurodegeneration.” The company has since made a proprietary plasma fraction to be its lead clinical candidate, and will evaluate it as a potential treatment for mild to moderate Alzheimer’s disease, Nikolich wrote.

In another plasma-based approach, Montserrat Costa, who works at the blood products company Grifols in Barcelona, Spain, presented data from that company’s ongoing testing of repeated plasma exchange and albumin replacement to treat symptoms of AD. The idea is that albumin’s propensity to bind Aβ creates a peripheral “sink” that coaxes the toxic protein from the brain, though results from ongoing trials suggest the treatment could also augment antioxidant defenses.

The Alkahest trial was inspired by work in Tony Wyss-Coray’s lab at Stanford. Back in 2011, Wyss-Coray and colleagues demonstrated that parabiotic joining of the blood supplies of a young and an old mouse reversed the effects of aging on the brain (Aug 2011 news). Subsequently, the researchers bypassed the need to conjoin the animals and succeeded in boosting neurogenesis, synaptic activity, and memory in old mice by simply injecting young plasma (May 2014 conference news). Young plasma even improved memory in mouse models of AD (Sep 2016 news). 

Intravenous administration of plasma—the soluble portion of blood sans its cells—is routine during surgery and trauma, and as a treatment for clotting factor deficiencies. In the Plasma for Alzheimer Symptom Amelioration study (PLASMA), Sha assessed the safety and feasibility of plasma infusions in people with AD. 

For the trial, Sha enrolled 18 patients with mild to moderate AD, with an average age in the early 70s and average MMSE score around 19. For the first nine patients, she used a double-blind, placebo-controlled crossover design: After baseline cognitive testing, patients received four weekly infusions of either one unit, i.e. 250 ml, of plasma from men betweem the ages of 18 and 30, or one bag of saline. Then all cognitive tests were repeated. After a six-week washout period, the patients repeated the same sequence but received the opposite treatment from the first block. Of the nine who went through the first round, two left the trial before beginning the second round of treatment. Sensing study fatigue, the investigators switched to open-label, treatment-only infusion for the remaining nine subjects. In total, 13 completed active treatment and nine received placebo.

The treatment appeared safe, with no serious adverse events associated with plasma infusion. One person dropped out due to hives, and one due to an unrelated stroke.

In treated participants, Sha saw a statistically significant change in function, with a 4.5-point improvement on the Functional Activities Questionnaire and an increase of 3.2 points on the ADCS-Activities of Daily Living over those who got placebo. There was no improvement in the CDR-SB, a combined clinical-functional endpoint. Sha also detected no improvement in overall cognition measured by the ADAS-Cog or Trails test. Some domains of the ADAS-Cog shifted slightly: Commands were improved, while word recognition and comprehension declined. Participants had no changes in mood assessed by two methods.

Did the improvement reflect a placebo effect? Sha does not think so. Individual patients’ scores indicated that four of six participants treated in the crossover (blinded) arm improved on the ADCS-ADL, while only two of the seven open-label patients did. This makes it unlikely that responders in the open-label arm drove the improvement in average scores, she said, though others noted that the numbers are so small as to render the results vulnerable to chance.

Anecdotally, Sha told Alzforum that study partners commented that their participant seemed “brighter and more engaged” after treatment, and there was a trend for improvement on memory. “Some study partners planned outings and museum visits for the days after a treatment visit, because they expected dad will be more lucid and energetic,” Nikolich told Alzforum. The results warrant exploration in a larger, longer study, the scientists concluded

Future efforts will focus on a proprietary plasma fraction of some 400 proteins that Alkahest is developing, rather than whole plasma, Sha said. The fraction is easier to use, as it requires no matching of blood type. To produce this fraction in large batches, Alkahest is partnering with Grifols, one of the world’s largest producers of plasma products, which invested US$50 million in the company in 2015.

Separately, Grifols is also working on its own plasma-based therapy. Called PE-A, the treatment comprises a total plasma exchange and albumin replacement. Albumin, one of the body’s most abundant proteins, binds 90 percent of circulating Aβ, and provides the predominant antioxidant activity in plasma. PE-A aims to remove Aβ-laden, oxidized albumin and replace it with fresh protein, thereby lowering amyloid levels, offering binding capacity for additional Aβ, and boosting protection against oxidative stress.

The idea was put to the test in a placebo-controlled Phase 2 trial that treated 42 patients with 18 plasma exchanges over the course of six months (Boada et al., 2017). The exchanges decreased plasma Aβ42, and caused a borderline increase in CSF Aβ42 at the end of treatment that reversed after treatment stopped. Two cognitive measures, the Boston naming test and a semantic verbal-fluency test, improved from baseline in treated patients, and the ADAS-Cog and MMSE showed a trend in the right direction.

At CTAD, Costa presented data on the characterization of albumin from patients in the trial, looking at the state of oxidation and other post-translational modifications. She found that plasma or CSF albumin was more oxidized at baseline in AD patients compared to healthy controls, suggesting it was less able to buffer oxidative stress. The difference in CSF was large and consistent enough that it clearly distinguished patients from controls.

In the Phase 2 study, Costa found no significant change in albumin’s oxidation status after treatment. However, treatment did cause a reduction in glycated albumin, a sugar-modified form of the protein that has been reported to have toxic properties (Ramos-Fernandez et al., 2014). 

Overall, there was a trend toward higher plasma levels of native, unmodified albumin at the end of treatment, at the same time point when CSF Aβ42 was slightly higher. Costa suggested that if this relationship can be confirmed in a larger cohort, albumin modification could serve as a biomarker, and possibly a therapeutic target for treatment. Grifols is now running a randomized, multicenter Phase 2b/3 trial in nearly 500 patients. It will finish in 2018, hopefully with a definitive answer, Costa said.—Pat McCaffrey and Gabrielle Strobel

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References

News Citations

1. Paper Alert: Do Blood-Borne Factors Control Brain Aging? 31 Aug 2011
2. In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition 5 May 2014
3. Young Blood a Boon for APP Mice 14 Sep 2016

Paper Citations

1. Boada M, Anaya F, Ortiz P, Olazarán J, Shua-Haim JR, Obisesan TO, Hernández I, Muñoz J, Buendia M, Alegret M, Lafuente A, Tárraga L, Núñez L, Torres M, Grifols JR, Ferrer I, Lopez OL, Páez A. 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(1):129-143. PubMed.
2. Ramos-Fernández E, Tajes M, Palomer E, Ill-Raga G, Bosch-Morató M, Guivernau B, Román-Dégano I, Eraso-Pichot A, Alcolea D, Fortea J, Nuñez L, Paez A, Alameda F, Fernández-Busquets X, Lleó A, Elosúa R, Boada M, Valverde MA, Muñoz FJ. Posttranslational nitro-glycative modifications of albumin in Alzheimer's disease: implications in cytotoxicity and amyloid-β peptide aggregation. J Alzheimers Dis. 2014;40(3):643-57. PubMed.

External Citations

1. PLASMA
2. Phase 2 trial

Further Reading

No Available Further Reading