Fillit H, Hess G, Hill J, Bonnet P, Toso C.
IV immunoglobulin is associated with a reduced risk of Alzheimer disease and related disorders.
Neurology. 2009 Jul 21;73(3):180-5.
PubMed.
This interesting retrospective case-control study by Fillit and coauthors finds that treatment with IVIg lowers the risk to develop Alzheimer disease (AD) and related disorders by 42 percent for patients with immunodeficiency, inflammatory conditions, or various forms of cancer, in comparison to healthy untreated people. IVIgs are currently tested as a potential treatment for AD (Relkin et al., 2008), and in this light the beneficial outcome of IVIg therapy in non-AD patients is most intriguing. There are many potential pitfalls in interpreting the type of data analyzed in the current study, but the authors took great care discussing confounding factors in a clear and unbiased fashion.
They discuss, for example, the possibility that AD is underdiagnosed in the IVIg treated cancer patients because a sizable number of them have also undergone chemotherapy treatment which can result in cognitive deficits. Another interesting factor in the interpretation of the findings is that many of the IVIg treated patients suffer from severe deficiencies of the adaptive immune response, and these patients have likely a different overall immune status than the healthy controls. It is interesting to speculate that some of these changes in immune function could help in reducing the risk of AD independent of the immunoglobulin therapy. It would also be interesting to assess the role of APOE genotype given the dominant role of this gene not only for AD risk in general put possibly also for its role in therapeutic efficacy of Aβ monoclonal antibodies in immunotherapy in AD patients.
IVIgs are isolated and purified from human blood, and some of the immunoglobulins bind to Aβ and can neutralize its neurotoxic effects. We have recently demonstrated that blood contains a broad repertoire of IgGs that bind to toxic Aβ peptides and oligomeric assemblies (see Britschgi et al., 2009). Importantly, we detected lower levels of such antibodies in healthy individuals older than 70 years of age compared with 21-44-year-old people, and found that antibody levels to oligomeric Aβ are even more reduced in later stages of AD. It is interesting in this context that the current epidemiological study found that IVIg was more effective in reducing the risk for AD in patients at the relatively younger age of 65-74 years compared with older patients. One would maybe expect a stronger effect of IVIg in the older group with presumably lower levels of endogenous Aβ autoantibodies, but the degenerative processes in the aging brain may have advanced too much already for the IVIg to be effective.
If IVIgs can be confirmed to reduce AD risk, the question remains whether Aβ autoantibodies are responsible for this effect and if so, whether they act in the periphery or in the CNS. It is possible that Aβ unrelated antibodies can neutralize age-related toxic factors or stimulate immune cells and thus boost immune functions. In any case, we feel the current study provides an exciting piece of evidence in support of Aβ as a target in AD, and thus for Aβ immunotherapy and potentially for monitoring Aβ autoantibody levels in people.
References:
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME.
18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease.
Neurobiol Aging. 2009 Nov;30(11):1728-36.
PubMed.
Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, Lemieux MC, Rufibach K, Rajadas J, Zhang H, Tomooka B, Robinson WH, Clark CM, Fagan AM, Galasko DR, Holtzman DM, Jutel M, Kaye JA, Lemere CA, Leszek J, Li G, Peskind ER, Quinn JF, Yesavage JA, Ghiso JA, Wyss-Coray T.
Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50.
PubMed.
Previous studies on small groups of patients have indicated that IVIg treatment may have therapeutic benefit for AD (Dodel et al., 2004; Relkin et al., 2008). This report by Fillit et al. appears to be the broadest test of the effectiveness of IVIg treatment for AD to date. In this retrospective case-control study of 847 patients who received IVIg, the authors report that the incidence of AD is reduced by 42 percent. These results are complementary to the report in PNAS last week by Britschgi et al., 2009 that showed that high levels of circulating antibodies directed against conformation-dependent, aggregation-specific, sequence-independent epitopes decline with aging and seem to protect against amyloid toxicity. Taken together, these results seem to indicate that these naturally occurring oligomer-specific antibodies may be responsible for the therapeutic benefits of IVIg. Perhaps these types of antibodies would be worthy of more extensive human clinical trials. Currently, only antibodies directed against linear Aβ sequence epitopes are in clinical trials.
References:
Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH.
Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease.
J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1472-4.
PubMed.
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME.
18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease.
Neurobiol Aging. 2009 Nov;30(11):1728-36.
PubMed.
Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, Lemieux MC, Rufibach K, Rajadas J, Zhang H, Tomooka B, Robinson WH, Clark CM, Fagan AM, Galasko DR, Holtzman DM, Jutel M, Kaye JA, Lemere CA, Leszek J, Li G, Peskind ER, Quinn JF, Yesavage JA, Ghiso JA, Wyss-Coray T.
Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50.
PubMed.
Comments
F. Hoffmann-La Roche AG
This interesting retrospective case-control study by Fillit and coauthors finds that treatment with IVIg lowers the risk to develop Alzheimer disease (AD) and related disorders by 42 percent for patients with immunodeficiency, inflammatory conditions, or various forms of cancer, in comparison to healthy untreated people. IVIgs are currently tested as a potential treatment for AD (Relkin et al., 2008), and in this light the beneficial outcome of IVIg therapy in non-AD patients is most intriguing. There are many potential pitfalls in interpreting the type of data analyzed in the current study, but the authors took great care discussing confounding factors in a clear and unbiased fashion.
They discuss, for example, the possibility that AD is underdiagnosed in the IVIg treated cancer patients because a sizable number of them have also undergone chemotherapy treatment which can result in cognitive deficits. Another interesting factor in the interpretation of the findings is that many of the IVIg treated patients suffer from severe deficiencies of the adaptive immune response, and these patients have likely a different overall immune status than the healthy controls. It is interesting to speculate that some of these changes in immune function could help in reducing the risk of AD independent of the immunoglobulin therapy. It would also be interesting to assess the role of APOE genotype given the dominant role of this gene not only for AD risk in general put possibly also for its role in therapeutic efficacy of Aβ monoclonal antibodies in immunotherapy in AD patients.
IVIgs are isolated and purified from human blood, and some of the immunoglobulins bind to Aβ and can neutralize its neurotoxic effects. We have recently demonstrated that blood contains a broad repertoire of IgGs that bind to toxic Aβ peptides and oligomeric assemblies (see Britschgi et al., 2009). Importantly, we detected lower levels of such antibodies in healthy individuals older than 70 years of age compared with 21-44-year-old people, and found that antibody levels to oligomeric Aβ are even more reduced in later stages of AD. It is interesting in this context that the current epidemiological study found that IVIg was more effective in reducing the risk for AD in patients at the relatively younger age of 65-74 years compared with older patients. One would maybe expect a stronger effect of IVIg in the older group with presumably lower levels of endogenous Aβ autoantibodies, but the degenerative processes in the aging brain may have advanced too much already for the IVIg to be effective.
If IVIgs can be confirmed to reduce AD risk, the question remains whether Aβ autoantibodies are responsible for this effect and if so, whether they act in the periphery or in the CNS. It is possible that Aβ unrelated antibodies can neutralize age-related toxic factors or stimulate immune cells and thus boost immune functions. In any case, we feel the current study provides an exciting piece of evidence in support of Aβ as a target in AD, and thus for Aβ immunotherapy and potentially for monitoring Aβ autoantibody levels in people.
References:
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009 Nov;30(11):1728-36. PubMed.
Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, Lemieux MC, Rufibach K, Rajadas J, Zhang H, Tomooka B, Robinson WH, Clark CM, Fagan AM, Galasko DR, Holtzman DM, Jutel M, Kaye JA, Lemere CA, Leszek J, Li G, Peskind ER, Quinn JF, Yesavage JA, Ghiso JA, Wyss-Coray T. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50. PubMed.
University of California, Irvine
Previous studies on small groups of patients have indicated that IVIg treatment may have therapeutic benefit for AD (Dodel et al., 2004; Relkin et al., 2008). This report by Fillit et al. appears to be the broadest test of the effectiveness of IVIg treatment for AD to date. In this retrospective case-control study of 847 patients who received IVIg, the authors report that the incidence of AD is reduced by 42 percent. These results are complementary to the report in PNAS last week by Britschgi et al., 2009 that showed that high levels of circulating antibodies directed against conformation-dependent, aggregation-specific, sequence-independent epitopes decline with aging and seem to protect against amyloid toxicity. Taken together, these results seem to indicate that these naturally occurring oligomer-specific antibodies may be responsible for the therapeutic benefits of IVIg. Perhaps these types of antibodies would be worthy of more extensive human clinical trials. Currently, only antibodies directed against linear Aβ sequence epitopes are in clinical trials.
References:
Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1472-4. PubMed.
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009 Nov;30(11):1728-36. PubMed.
Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, Lemieux MC, Rufibach K, Rajadas J, Zhang H, Tomooka B, Robinson WH, Clark CM, Fagan AM, Galasko DR, Holtzman DM, Jutel M, Kaye JA, Lemere CA, Leszek J, Li G, Peskind ER, Quinn JF, Yesavage JA, Ghiso JA, Wyss-Coray T. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50. PubMed.
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