The authors should cite the literature on CSF levels of amyloid-β (total and 1-42). Without having a comparison and seeing a discussion of previous CSF studies, I do not know whether the reduced level in CSF is good, bad, or a chance event. Antibodies to amyloid-β could opsonize amyloid-β deposits for phagocytosis by macrophages, which are probably the critical cells for phagocytosis of amyloid-β deposits in human brain (Fiala et al., submitted for publication).

View all comments by Milan Fiala

This pilot study by Dodel et al. demonstrates the effect of passive immunization in Alzheimer’s patients with the intravenous immunoglobulin prepared from the plasma pools of normal, healthy donors, based on the fact that healthy individuals have circulating auto-antibodies against Aβ peptide.

They found that the immunization performed in five patients reduced CSF Aβ, while the levels of serum Aβ were increased. There was no significant change found in Aβ42 levels. Given the fact that Aβ42 is a pathogenic “seeding” peptide, it is interesting as to how unchanged levels of Aβ42 following passive immunization would be effective. The authors themselves speculate “whether the observed reduction may have an impact on plaque formation”! This might be the explanation why MMSE scores were not affected after the treatment.

Secondly, the observed increase in the levels of serum Aβ is highly likely to trigger vasculopathy and microhemorrhage.

Thirdly, this study has been performed only in five patients. Out of these, one patient was excluded since he refused to get a lumbar...  Read more

This pilot study by Dodel et al. demonstrates the effect of passive immunization in Alzheimer’s patients with the intravenous immunoglobulin prepared from the plasma pools of normal, healthy donors, based on the fact that healthy individuals have circulating auto-antibodies against Aβ peptide.

They found that the immunization performed in five patients reduced CSF Aβ, while the levels of serum Aβ were increased. There was no significant change found in Aβ42 levels. Given the fact that Aβ42 is a pathogenic “seeding” peptide, it is interesting as to how unchanged levels of Aβ42 following passive immunization would be effective. The authors themselves speculate “whether the observed reduction may have an impact on plaque formation”! This might be the explanation why MMSE scores were not affected after the treatment.

Secondly, the observed increase in the levels of serum Aβ is highly likely to trigger vasculopathy and microhemorrhage.

Thirdly, this study has been performed only in five patients. Out of these, one patient was excluded since he refused to get a lumbar puncture. As the authors themselves suggest, “this study requires detailed clinical assessment.”

In summary, although this study provides an additional proof for pursuing immunization in treating AD, it is inconclusive.

The inconclusiveness of this study could be due to:

1. Very small sample size;
2. Unchanged levels of a key pathogenic Aβ42;
3. Unchanged MMSE scores;
4. Projected risk of vasculopathy and hemorrhage due to elevated serum Aβ levels.

View all comments by Neelima Chauhan

I think that this is an interesting paper, and new for the future. The study in this paper was not blinded, had no group with placebo, and the groups were too small. I think that the authors of the paper should continue their study using intravenous immunoglobulins in the treatment of Alzheimer disease. The authors are changing the method of investigating Alzheimer disease.

View all comments by Ryszard Pluta

First off, I’d like to disclose that I am lead investigator in the GAP 160701 Study, which is the NIA- and Baxter-supported Phase 3 pivotal study of Gammagard® IVIG in AD that has been conducted at 45 ADCS sites in the U.S. and Canada. It employed a placebo-controlled, double-blind randomized design in which infusions of either IVIG or placebo were administered every two weeks for 18 months to 390 patients with mild to moderate Alzheimer’s disease. Results will be announced in the second quarter of 2013.

The interim results presented by Dr. Kile and colleagues at the 2013 AAN meeting are encouraging, albeit preliminary. I am particularly gratified to see an independent replication of the finding I first reported at the AAN meeting in 2010 of a significantly reduced rate of brain atrophy following IVIG treatment of Alzheimer's patients. The current study used the same dose of IVIG (0.4 g/kg every two weeks) for each infusion that we found worked best in our Phase 1 and 2 studies of IVIG in Alzheimer's patients, but they gave fewer infusions. The magnitude of the effect they...  Read more

First off, I’d like to disclose that I am lead investigator in the GAP 160701 Study, which is the NIA- and Baxter-supported Phase 3 pivotal study of Gammagard® IVIG in AD that has been conducted at 45 ADCS sites in the U.S. and Canada. It employed a placebo-controlled, double-blind randomized design in which infusions of either IVIG or placebo were administered every two weeks for 18 months to 390 patients with mild to moderate Alzheimer’s disease. Results will be announced in the second quarter of 2013.

The interim results presented by Dr. Kile and colleagues at the 2013 AAN meeting are encouraging, albeit preliminary. I am particularly gratified to see an independent replication of the finding I first reported at the AAN meeting in 2010 of a significantly reduced rate of brain atrophy following IVIG treatment of Alzheimer's patients. The current study used the same dose of IVIG (0.4 g/kg every two weeks) for each infusion that we found worked best in our Phase 1 and 2 studies of IVIG in Alzheimer's patients, but they gave fewer infusions. The magnitude of the effect they observed on brain appears to be commensurately smaller than what we observed. Nevertheless, if their final results prove to be consistent with these interim findings, it will likely spark a lively discussion about whether a short duration of IVIG is sufficient to obtain a meaningful therapeutic response in very mildly affected dementia patients. This is an important consideration because IVIG is costly and supplies are limited.

MCI patients are by definition more mildly affected than persons with actual dementia due to Alzheimer’s, so studies of MCI typically require larger numbers of subjects and longer periods of observation. Dr. Kile and his colleagues took a calculated risk in studying only 51 subjects and using a very short exposure to IVIG, both of which might be expected to reduce the likelihood of a successful study outcome. A much larger study will be needed to draw firm conclusions about the use of IVIG in MCI.

In the meantime, it’s important to point out that IVIG is not approved for use in treating MCI or AD at this time.

View all comments by Norman Relkin

The clinical study of using IVIG in MCI as reported above by Kile is encouraging to those supporters of the "emerging role of pathogens in Alzheimer’s disease." Hopefully, the larger clinical trial of IVIG, as mentioned by Norman Relkin in 390 patients, will also slow shrinkage of the brain in the treated group as compared to the controls on imaging studies.

Since IVIG uses pooled γ globulin, the treatment as mentioned will never have the resources and availability that a treatment engineered by biotech or big pharmacological companies. Such companies could narrow down the therapeutic response to more defined molecules such as TNFα, interleukins, macrophage inhibition, etc. Eventually, then, antiviral, antibiotic, and other early interventional measures will be implemented before brain shrinkage due to amyloid plaques and tau tangles occurs.

However, any success now in Alzheimer's therapeutics is highly encouraged, as the economic burden to the healthcare system is out of control. The newspaper yesterday reported 15.4 million caregivers provided more than 17.5 billion...  Read more

The clinical study of using IVIG in MCI as reported above by Kile is encouraging to those supporters of the "emerging role of pathogens in Alzheimer’s disease." Hopefully, the larger clinical trial of IVIG, as mentioned by Norman Relkin in 390 patients, will also slow shrinkage of the brain in the treated group as compared to the controls on imaging studies.

Since IVIG uses pooled γ globulin, the treatment as mentioned will never have the resources and availability that a treatment engineered by biotech or big pharmacological companies. Such companies could narrow down the therapeutic response to more defined molecules such as TNFα, interleukins, macrophage inhibition, etc. Eventually, then, antiviral, antibiotic, and other early interventional measures will be implemented before brain shrinkage due to amyloid plaques and tau tangles occurs.

However, any success now in Alzheimer's therapeutics is highly encouraged, as the economic burden to the healthcare system is out of control. The newspaper yesterday reported 15.4 million caregivers provided more than 17.5 billion hours of unpaid care valued at $216 billion for Alzheimer's patients in 2012!

View all comments by Trent Nichols

This result makes me wonder if there is overlap between IVIG and colostrum, because the latter contains many antibodies, and in the case of Colostrinin®, also proline-rich peptides (PRP). Researchers at the University of Texas Medical Branch at Galveston have shown that PRP has multiple effects in models of AD pathogenesis, at biochemical and genetic levels as well as in live mice and clinical trials in humans.

References:
Szaniszlo P, German P, Hajas G, Saenz DN, Kruzel M, Boldogh I. New insights into clinical trial for Colostrinin in Alzheimer's disease. J Nutr Health Aging. 2009 Mar;13(3):235-41. Abstract

View all comments by Andrew Sutton