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Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Müller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54. PubMed.
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Institute of Neurology, UCL
This an extremely interesting preliminary report. The editorial by Winblad and Blum is very careful in conveying both the excitement this data causes,
View all comments by John Hardyand also the caution that needs to be exercised in its interpretation. Hock and his colleagues are to be congratulated for their astuteness in taking
part in the Elan trial, but negotiating themselves some freedom in using their own data from their trial subjects. Let's hope that when Elan releases the data on the whole trial, the overall results confirm these
preliminary data. Even if immunization turns out not to be the way forward for safety reasons, such an outcome would imply that other Aβ-reducing
strategies have every chance of clinical success.
Washington University
It is encouraging that in a subset (n=30) of the more than 300 subjects enrolled in the Elan study who were analyzed, there is preliminary evidence that there may be a positive response. This preliminary analysis suggests that further, more conclusive studies of the immunization approach (active and passive) should continue. Though the analysis argues for more studies, the title and some of the conclusions of this study are
View all comments by David Holtzmannot yet justified. As pointed out in the accompanying commentary by Winblad and Blum, the control group, which is really N=6 who received placebo or N=10 total who did not generate "antibodies," is very small. More importantly, not only is the control group small, that group deteriorated at a much faster rate than subjects with mild to moderate Alzheimer's disease normally worsen. The amount of MMSE decline in the group treated with immunization is actually what is described in patients with Alzheimer's who are on cholinesterase inhibitors, (which many of these patients were on), namely about one to three points in the first year
of follow-up. It would have been very useful if this study included all of the subjects in the Elan trial over the first year. One comment about the measurement of Aβ levels in plasma and CSF is warranted. The study measured Aβ by ELISA. If these subjects generated antibodies, they were polyclonal antibodies. These antibodies can bind to Aβ in the plasma (or CSF) and, if they are present, can potentially block binding of other antibodies used in the ELISA. No methods were used to account for this. Thus, the plasma and CSF Aβ levels are not
interpretable with the technique used here. Also, there appears to be an error in Fig. 4B for CSF Aβ42. It is listed
as ng/ml, but presumably is pg/ml. In the legend for Fig. 4, it appears A and B are reversed. In summary, while this clinical report is encouraging, it is preliminary.
Yale University School of Medicine
Since this is a clinical study involving human subjects, one cannot expect it to be without unavoidable limitations. The numbers of patients are small, the follow-up is of relatively short duration, and these are both problems, as Winblad and Blum point out. The mental state of AD patients can fluctuate widely, so I think more specific functional tests will have to be done to strengthen the case for a positive effect.
Let's assume that some of the patients show improvement and this is correlated with antibody levels. Can we rule out some nonspecific immunological reactions that cause improvement independent of the ability of the antibodies to bind to Aβ? If these were experimental animals, one would be able to test the effects of immunizing with different forms of synthetic peptides. This is clearly not possible with human subjects. I am also concerned about the different results that are reported for the ELISA tests and the authors' tissue amyloid plaque assay. It is possible that they are looking at different conformational epitopes, as the authors suggest, but one should not overlook the fact that the tissue assay involves "fixed" tissue (they don't specify how) that is embedded in paraffin. It is not stated whether the Aβ peptides were similarly treated. If they were not, I would look first at the differences in antigenicity related to antigen preparation before concluding that conformational differences explain differences in immunoreactivity.
I find it puzzling that serum antibodies against Aβ remain high in the patients, without changes in circulating Aβ levels.
View all comments by Vincent MarchesiMichigan State University
This paper continues the rollercoaster of emotion regarding the use of amyloid vaccines to treat Alzheimer's disease. The identification that Aβ vaccination could dramatically reduce amyloid deposition in the PDAPP mouse (Schenk et al., 1999), followed by demonstration that the vaccine also protected mice from learning and memory deficits (Janus et al., 2000; Morgan et al., 2000), led to early trials of the vaccine in humans.
Although Phase I trials found no adverse consequences, six percent of the Phase II trial patients developed aseptic meningoencephalitis (Schenk, 2002), which in some cases was severe (Nicoll et al., 2003). This led to premature termination of the trial, with cessation of any further inoculations with the Aβ peptide. Thus, as rapidly as hope was raised by the early successes in animal models, all the enthusiasm for the vaccine as a potential therapy crashed, leading some to accuse Elan of proceeding too rapidly into human trials in spite of the safety testing performed in Phase I.
For the last year, very few grants were supported that proposed to investigate the amyloid vaccine, even if it was only used as a tool to reduce Aβ deposits. Several other reports appeared suggesting that Aβ vaccination would have adverse consequences, such as hemorrhage (Pfeifer et al., 2002) or invasion of T cells into the CNS (Furlan et al., 2003). It seemed increasingly unlikely that the scientific community could be convinced that anti-Aβ immunotherapy should continue to be investigated.
Now, this manuscript by Hock et al., reporting on their subset of patients from the Elan clinical trial, shows (by some measures) a significant slowing of cognitive deterioration in those patients with plaque-reactive antibodies. Moreover, the patients with the highest antibody titers have remained stable or even improved their cognitive functions over a year's time.
Thus, the immunotherapy rollercoaster begins another climb up the track. It has risen, phoenix-like, to again generate hope among the millions with relatives suffering from end-of-life dementias. It will be important in this swing of the pendulum to avoid hype and promotion, and to maintain a sober outlook while investigating the advantages and disadvantages of this approach to dementia therapy.
At the AD-PD meeting in Seville in early May 2003, where the Hock et al. data were presented, the representatives from Elan were quick to point out that this is a subset of patients from their trial. They also indicated that, at least based upon intention to treat (i.e., comparing the group receiving the vaccine vs. placebo), there was no benefit in the ADAS-COG scores in the complete dataset.
It remains to be determined if, overall, the subset of patients with plaque-reactive anti-Aβ antibodies do still show benefit from the vaccination. The 12-month decline in cognitive function in the group lacking anti-Aβ antibodies in the Hock et al. study is greater than is typically observed over this period (see commentary by Winblad). However, this report will once again encourage the investigation of anti-Aβ immunotherapy as a treatment for dementias, and will permit neuroscientists and immunologists to develop alternative methods of increasing anti-Aβ titers while avoiding meningoencephalitis and other potential problems associated with this once-again promising avenue of therapy.
References:
Furlan R, Brambilla E, Sanvito F, Roccatagliata L, Olivieri S, Bergami A, Pluchino S, Uccelli A, Comi G, Martino G. Vaccination with amyloid-beta peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain. 2003 Feb;126(Pt 2):285-91. PubMed.
Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):979-82. PubMed.
Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. PubMed.
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. PubMed.
Schenk D. Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci. 2002 Oct;3(10):824-8. PubMed.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999 Jul 8;400(6740):173-7. PubMed.
View all comments by Dave MorganUniversity of Texas Medical School at Houston
During the last 10 years, much evidence has been reported in support of the amyloid hypothesis for the progression of AD. However, the key finding of whether inhibitors of Aβ amyloidogenesis would lead to a cognitive improvement was missing. In this very interesting article, Hock et al. report for the first time preliminary results indicating that this may be the case. In addition to the practical implications for treatment, in my opinion the great importance of this study, as well as the previous publication by Nicoll et al., is that it provides crucial data to understand the molecular mechanism of AD pathogenesis in humans. It should also boost the race to develop safer immunization strategies and other anti-Aβ production, misfolding, and aggregation approaches for AD treatment. I concur with Winblad and Blum's caution on the interpretation of results with very small number of patients, but Hock, Nitsch, and colleagues should be congratulated for making these results public and imitated by the rest of the centers involved in the Elan Phase II trial.
References:
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
View all comments by Claudio SotoUniversity of Minnesota
This paper shows that immunization with Aβ may slow the progression of Alzheimer’s disease, but does not restore cognitive function. These results contrast with studies of immunoneutralization of Aβ in AβPP-transgenic mice, which demonstrate reversal of memory loss and restoration of cognitive function (Kotilinek et al., 2002; Dodart et al., 2002). The most likely explanation for this discrepancy is that important differences in pathology exist between AβPP-transgenic mice and Alzheimer’s disease.
During the first year following the appearance of memory deficits in Tg(APPNL)2576 mice, neurons and synapses are largely intact (Irizarry et al., 1997). During the second year, postsynaptic markers decline, while presynaptic markers and neurons remain unchanged (G. Cole and B. Hyman, personal communication). We have proposed that soluble Aβ assemblies impair memory in Tg(APPNL)2576 mice (Ashe, 2001; Westerman, 2002), and have suggested that the rapid restoration of memory by passive immunization against Aβ indicates that Aβ assemblies disrupt memory by altering neuronal function, but not neuronal structure.
Patients with Alzheimer’s disease differ from Tg(APPNL)2576 mice because they have substantial plaque and tangle deposition as well as significant cell loss in vulnerable brain regions important for memory. The relative benefit conferred by Aβ immunization in the Hock et al. paper may reflect the inhibition of the disruptive effects of Aβ assemblies on cognitive function or the improvement of certain aspects of amyloid pathology taking place in the setting of ongoing neurodegeneration. Achieving in humans the dramatic results observed in mice is more likely to occur if interventions are administered in earlier stages of disease. Understanding how to improve cognitive function in later stages of Alzheimer’s disease will require a new generation of mouse models to study.
References:
Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci. 2002 Aug 1;22(15):6331-5. PubMed.
Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002 May;5(5):452-7. PubMed.
Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol. 1997 Sep;56(9):965-73. PubMed.
Ashe KH. Learning and memory in transgenic mice modeling Alzheimer's disease. Learn Mem. 2001 Nov-Dec;8(6):301-8. PubMed.
Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1858-67. PubMed.
View all comments by Karen Hsiao AsheTel Aviv University
One of the critical questions in β-amyloid immunotherapy is whether depletion of the amyloid plaques is accompanied by improvement in behavioral/neurophysiological impairments and in a reduction in the nerve cell death of Alzheimer’s disease. In other words, does immunization with Aβ simply clear a neuropathological byproduct, or can it cure the disease? Anti-β-amyloid immunization of the AD mouse model showed remarkable efficacy in reducing amyloid and restoring cognitive function. The present data is the first attempt to compare cognitive test results in human AD patients—a small number so far—before and one year after vaccination. Indeed, patients with serum antibodies against β-amyloid plaques showed diminished cognitive decline and slowed disease progression, and the "dose-response" relationship between antibody levels and clinical effects constitutes evidence that amyloid proteins are indeed a primary cause of Alzheimer’s symptoms. The treated patients, suffering mild or moderate dementia, received only two injections and throughout the year were dosed with antiinflammatory and antioxidant protection drugs. Finding the antibodies 12 months after the last administration suggests an impressive long-lasting immunization effect induced by a relatively small amount of antigen. Moreover, data suggest that a low titer of antibodies is enough to affect plaque development.
Site-directed antibodies induced by various immunological approaches are aimed at treatment of a disease that is caused by abnormal conformational changes or folding of a peptide or protein, as presented in Alzheimer’s disease and other amyloidosis disorders (Solomon, 2002). However, any effective immunization strategy must identify not only the specific nature of the antigen or the epitope, but also address the formulation and method of delivery of the antigen or antibodies as a major and critical parameter.
Unfortunately, humans may develop self-antibodies when immunized with whole or fragments of AβPP. These antibodies are capable of binding to a variety of Aβ species in the brain; thus, immunization could have beneficial effects, such as inhibition of amyloid fibril formation, while microglial overactivation may lead to neuroinflammation. The consequence of this on inflammatory pathology in AD brains needs to be considered before immunization is used as a strategy for treating AD. As recently reported, interactions of human microglia with antibody-opsonized amyloid showed increased inflammation (Lue et al., 2002).
Several strategies directed towards prevention of neuroinflammation are under investigation. Active immunization with synthetic Aβ1-42 peptide reduces β-amyloid plaques in AβPP-transgenic mice without detectable toxicity, but the extension of this approach to AD patients induced a neuroinflammatory reaction in some of the study subjects, precluding further testing of the preparation. Vaccination with nontoxic, small antiaggregating epitopes of AβPP may partially avoid the undesirable effects of neuroinflammation, e.g., by preventing T cell activation (Frenkel et al., 2003).
Administration of intravenous immunoglobulin (IVIG), which has well-recognized antiinflammatory activities independent of the antigen-specific effect, may modulate the inhibitory FcR pathway, thus controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD. Another approach may be passive immunization with antibodies devoid of Fc, which may prevent overactivation of microglia and, thus, attenuation of autoantibody-triggered neuroinflammation. Progress in vector development for brain delivery of such antibodies, as well as clearance of immunocomplex devoid of Fc region, was recently reported (Frenkel and Solomon, 2002).
Many important questions remain open. Is the reported improvement in the behavior of AD patients caused by dissolving existing plaques or preventing formation of new plaques, or is it caused by sequestration of soluble AβPP? How many antibodies are required? How can inflammation and/or overactivation of microglia be prevented? In spite of these questions, the immunotherapeutic approach towards amyloid peptide remains the most fascinating therapeutic target for generating agents potentially able to modify the natural history of AD.
References:
Solomon B. Immunological approaches as therapy for Alzheimer's disease. Expert Opin Biol Ther. 2002 Dec;2(8):907-17. PubMed.
Lue LF, Walker DG. Modeling Alzheimer's disease immune therapy mechanisms: interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide. J Neurosci Res. 2002 Nov 15;70(4):599-610. PubMed.
Frenkel D, Dewachter I, Van Leuven F, Solomon B. Reduction of beta-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization. Vaccine. 2003 Mar 7;21(11-12):1060-5. PubMed.
View all comments by Beka SolomonUK Dementia Research Institute@UCL and VIB@KuLeuven
These are really exciting results, and we are likely looking at a historical crucial manuscript providing the proof-of-principle that a cure for AD is possible, and definitively establishing the amyloid hypothesis for AD.
HASTA LA VISTA, AMYLOID CASCADE HYPOTHESIS, OR WILL ACADEMIC DISHONESTY YIELD ALZHEIMER'S CURE?
Please see my letter to Neuron editor regarding the article by Hock et al. Science SAGE KE (26 May 2003) [ Full Text ] [ No-registration access link ] .
Editor, <a href="http://www.Cholesterol-And-Health.com">Cholesterol-And-Health.com</a>
This paper was interesting, but I find several problems with it.
First, there was no control group that was not immunized, and the rate of increase in antibody levels was not studied in the patients prior to baseline. Thus, since some patients had endogenous antibodies to β amyloid, there was no evidence that the immunizations actually caused the increase in antibodies.
Since a large portion of the patients did not generate a significant increase in antibody levels, and these patients did worse than the literature average on some cognitive tests, this calls into question several things:
1) Perhaps the immunization is doing harm in some and is benefiting others,
or, what I consider more likely:
2) The level of antibody increase may simply be gauging the health of the immune system, and thereby gauging general health. Those who have the lowest response, then, have worse-than-average general health and thus would suffer a worse-than-average cognitive decline.
A control of non-immunized subjects is absolutely necessary to judge how the immunization actually influenced antibody levels.
Finally, the authors conclude that there is no evidence that the β amyloid was being bound and transported out of the brain; therefore, it is quite clearly not a clinical confirmation that β amyloid has a central role in AD, as they write.
In fact, it seems to be suggestive that a third factor not involving β amyloid was causing the rise in antibodies as well as the increased performance—namely, the multiplicity of factors involved in immune function that are also involved in general health.
I cite this study and discuss it in my article "Myth: Cholesterol Causes Alzheimer's Disease | Part I: Debunking the Myth."
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