Dr. Norman Relkin and colleagues presented data at this year’s American Academy of Neurology meeting on the use of intravenous immunoglobulin (IVIG) in patients with Alzheimer disease. IVIG is utilized to treat several neurological disorders that have an immune-mediated basis such as acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome). The reason that IVIG is effective in these disorders is unknown. It has been shown that most humans have some immunoglobulins in their plasma that are directed against Aβ. It was rationalized that, given IVIG is pooled from many individuals, it would contain anti-Aβ antibodies and that its administration might mimic the effects of passive immunization with anti-Aβ antibodies.

Seven patients diagnosed with mild to moderate AD were given IVIG over 6 months. There was no decline and was an actual improvement on some neuropsychological test scores in these patients over this time. There was also an increase in plasma Aβ in patients given IVIG. The reason for the increase in detectable plasma Aβ still...  Read more

Dr. Norman Relkin and colleagues presented data at this year’s American Academy of Neurology meeting on the use of intravenous immunoglobulin (IVIG) in patients with Alzheimer disease. IVIG is utilized to treat several neurological disorders that have an immune-mediated basis such as acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome). The reason that IVIG is effective in these disorders is unknown. It has been shown that most humans have some immunoglobulins in their plasma that are directed against Aβ. It was rationalized that, given IVIG is pooled from many individuals, it would contain anti-Aβ antibodies and that its administration might mimic the effects of passive immunization with anti-Aβ antibodies.

Seven patients diagnosed with mild to moderate AD were given IVIG over 6 months. There was no decline and was an actual improvement on some neuropsychological test scores in these patients over this time. There was also an increase in plasma Aβ in patients given IVIG. The reason for the increase in detectable plasma Aβ still needs to be worked out. This was a small, open-label study in which all patients received IVIG. From a clinical perspective, the small study is interesting and will need follow-up with a randomized trial to understand whether this treatment has the potential to be beneficial. The amount of anti-Aβ antibodies and their titer in IVIG is likely much lower than what has been given to animal models of AD or what was generated in many humans who were actively immunized with Aβ42. It will be important to further characterize the anti-Aβ antibodies that are present in IVIG preparations, as well as their effect on plasma and CSF Aβ. If in the long run, it turns out that there is an effect of IVIG on cognition in AD, it may or may not have to do with its effects on Aβ. It is interesting that despite the fact that IVIG is effective for certain inflammatory neurological diseases, we still do not completely understand its mechanism of action.

View all comments by David Holtzman

The work by Norman Relkin is an intriguing approach to passive immunotherapy. IVIG has been safely administered to thousands of patients and has a good safety record. It is readily available and FDA-approved for other indications. The study presented is open-label and quite preliminary. The conclusion must be that in a small number of patients with AD, IVIG could be administered safely. There are many developmental issues that need to be explored, including dose, frequency, and antibody content of the preparation, before definitive phase 2-3 trials can be undertaken.

View all comments by Leon Thal

I know where you can buy Immunoglobulin in capsule form. Let me know if you are interested. Richard

View all comments by Richard Novara

Dr. Norman Relkin and colleagues reported about the use of intravenous immunoglobulin (IVIG) in patients with AD. Unfortunately, the amount of anti-Aβ antibodies in the IVIG is difficult to measure and it should be very low. At the same time it is important to mention that the level of mouse anti-Aβ antibodies, required to provide therapeutic benefits, has not been clearly defined in the majority of active and passive immunizations studies. Determining the minimal therapeutic concentrations of anti-Aβ antibodies in mouse model of AD may help to design new passive immunizations clinical trials and better understand the mechanisms of clearance of Aβ from the brain. Thus, it likely will be very important to further characterize the specificity and determine the exact concentrations of anti-Aβ antibodies that are present in IVIG preparations in future pre-clinical and clinical trials.

View all comments by Michael G. Agadjanyan

This paper shows that immunization of aged monkeys against the Aβ peptide produces measurable antibody titers and sizeable increases in circulating Aβ levels. These data are consistent with the argument that anti-Aβ immunotherapy may reduce brain amyloid by sequestering Aβ in the plasma. Somewhat surprisingly, the results with protein G imply that even though much of the increased circulating Aβ found after immunization is associated with antibody, some of the increase in Aβ remains even after removal of antibodies.

These results differ from those reported by Hock et al., where humans vaccinated against Aβ did not reveal detectable increases in circulating Aβ, suggesting that the antibodies generated in humans did not create a peripheral sink for Aβ. However, it is important to recognize that measurement of serum Aβ and anti-Aβ antibodies may be complicated when both agents are present in the sample to be evaluated. Certainly, if an antibody against...  Read more

This paper shows that immunization of aged monkeys against the Aβ peptide produces measurable antibody titers and sizeable increases in circulating Aβ levels. These data are consistent with the argument that anti-Aβ immunotherapy may reduce brain amyloid by sequestering Aβ in the plasma. Somewhat surprisingly, the results with protein G imply that even though much of the increased circulating Aβ found after immunization is associated with antibody, some of the increase in Aβ remains even after removal of antibodies.

These results differ from those reported by Hock et al., where humans vaccinated against Aβ did not reveal detectable increases in circulating Aβ, suggesting that the antibodies generated in humans did not create a peripheral sink for Aβ. However, it is important to recognize that measurement of serum Aβ and anti-Aβ antibodies may be complicated when both agents are present in the sample to be evaluated. Certainly, if an antibody against Aβ is bound to circulating Aβ peptide before placing the serum into an ELISA assay, the antibody cannot bind to additional Aβ tethered to the ELISA plate. For high-affinity antibody-antigen interactions, the off rate may be too slow for dissociation to occur during the period of incubation on the ELISA plate, and the antibody concentration will be underestimated. We have evidence that this sort of antibody masking does occur in transgenic mice when antibody titers are not in excess of circulating Aβ (Li et al., in review).

Conversely, measurement of Aβ may also be modified in sandwich ELISA assays by the presence of anti-Aβ antibodies derived from the serum. First, if the circulating anti-Aβ antibody and the capture antibody have overlapping epitopes, they may compete and prevent the Aβ from being captured and thus detected by the ELISA. However, if the two epitopes do not overlap, permitting capture of Aβ still bound to the circulating host antibody, and the detection antibody can also bind the Aβ, there is an opportunity for magnification of the signal. Assuming a secondary antibody binding the detection antibody can cross-react with the circulating host antibody, the apparent signal may be doubled, relative to a standard curve made from Aβ without attached antibody.

These complications make direct comparisons between papers difficult. Often, manuscripts do not provide the detailed steps used for the ELISAs measuring Aβ and anti-Aβ antibodies, as these are viewed as standard techniques within the respective laboratories. However, the antibodies used and their extent of cross-reactivity and epitope overlap may be important to the overall results obtained. Even the time that sera are in a diluted state may influence the results, depending upon antibody-Aβ dissociation rates To avoid these problems, we have recently started dissociating serum antibody-bound Aβ with a mild acid denaturation step (pH 2.5) followed by centrifugation through a size sieving filter to separate Aβ and antibody prior to ELISA. Obviously, other techniques may be used that accomplish the same result.

Thus, the question regarding a peripheral sink for Aβ remains with regard to humans vaccinated against Aβ. Our view of the literature, coupled with our own data, finds support for at least three mechanisms by which immunotherapy lowers Aβ in transgenic mouse models of amyloid deposition (Wilcock et al., 2003; Wilcock et al., 2004) It would be surprising if all three were not also at work in humans vaccinated against Aβ. The work from Gandy et al. would suggest that more detailed and controlled analyses will be needed to reach a final conclusion.

View all comments by Dave Morgan

This paper deals with immunization of healthy old monkeys with fibrillar Aβ42. These animals showed age-related cerebral amyloidosis but no Alzheimer's disease pathology (1) like plaques and gliosis. I wonder if vaccination of healthy old monkeys could be a good model for treatment of AD, as apart from aging they showed no sign of the disease (or cognitive impairment?).

The changes in treated monkeys of plasma levels of Aβ, similar to those found in young AD transgenic mice before plaque appearance, may support the peripheral sink theory (2). Treatment with intravenous immunoglobulin (IVIG), containing natural anti-Aβ antibodies, of elderly people suffering from neurological diseases other than AD (such as multiple sclerosis, peripheral neuropathy, LEMNS, dermatomyositis) showed a similar pattern of reduction of CSF Aβ and Aβ42 and an increase of CSF anti-Aβ antibodies as compared to the baseline. Total serum Aβ and anti-Aβ antibodies both increased, with a nonsignificant trend toward increased serum Aβ42 after treatment,...  Read more

This paper deals with immunization of healthy old monkeys with fibrillar Aβ42. These animals showed age-related cerebral amyloidosis but no Alzheimer's disease pathology (1) like plaques and gliosis. I wonder if vaccination of healthy old monkeys could be a good model for treatment of AD, as apart from aging they showed no sign of the disease (or cognitive impairment?).

The changes in treated monkeys of plasma levels of Aβ, similar to those found in young AD transgenic mice before plaque appearance, may support the peripheral sink theory (2). Treatment with intravenous immunoglobulin (IVIG), containing natural anti-Aβ antibodies, of elderly people suffering from neurological diseases other than AD (such as multiple sclerosis, peripheral neuropathy, LEMNS, dermatomyositis) showed a similar pattern of reduction of CSF Aβ and Aβ42 and an increase of CSF anti-Aβ antibodies as compared to the baseline. Total serum Aβ and anti-Aβ antibodies both increased, with a nonsignificant trend toward increased serum Aβ42 after treatment, suggesting the possibility of increased antibody-mediated clearance of Aβ from CSF to serum (3) unrelated to Alzheimer's disease.

In the absence of AD brain pathology, antibodies bind to soluble Aβ and may interfere with the equilibrium between the brain and peripheral Aβ peptide, which supports the sink theory. However, immunotherapy of AD patients who show plaque pathology did not support this theory (4). Therefore, it seems that this research, done on only four monkeys exhibiting no signs of AD, cannot support the sink theory, as appealing as it is.

References
1. Walker LC, Cork LC. The neurobiology of aging in nonhuman primates. In: Terry RD, et al., eds. Alzheimer's Disease. Philadelphia: Lippincott Williams and Wilkins, 1999: 233-243.

2. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A β antibody alters CNS and plasma A β clearance and decreases brain A β burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001:98(15):8850-5. Abstract

3. Dodel R, Hampel H, Depboylu C et al. Human antibodies against amyloid β peptide: a potential treatment for Alzheimer's disese. Annal Neurol, 2002: 52(2) 253-256. Abstract

4. Hock C, Konietzko U, Streffer JR et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003: 38(4) 547-54. Abstract

View all comments by Beka Solomon