Two papers in the 19 July Lancet bring both dismay and hope to the ongoing quest for more effective Alzheimer disease treatments. One study—a six-year follow-up of eight patients from Elan’s original AN1792 active immunization trial—confirmed that vaccination with full-length Aβ42 can clear amyloid plaques but showed that this clearance did not slow disease progress. The pages immediately preceding the report of this AD immunotherapy setback carry more promising news: in a six-month Russian trial of 183 patients, Dimebon—a weak inhibitor of cholinesterase and NMDA receptors with neuroprotective properties—improved mild to moderate AD patients in all five of the study’s outcome measures (four cognitive, one global). What’s more, Dimebon’s benefits seemed to hold, and by some measures even increase, through the trial’s six-month blinded extension. The authors note that these persistent benefits distinguish the small-molecule drug from existing approved therapies for mild to moderate AD—none of which have shown increasing improvement past 12 months.

A perplexing mix of evidence from Aβ immunization studies in humans and animal AD models has led researchers in the AD immunotherapy field to a central question: does the immune system help or harm in a person’s fight against AD? The emerging answer is, of course, multi-faceted and situational (for a review of recent evidence, see Boche and Nicoll, 2008).

AN1792’s storied history provides a case in point. Phase 1 trials of this AD vaccine—the first to be tested in people—began in September 2000. In early 2002, Elan Corporation discontinued clinical testing of the vaccine during Phase 2 trials because 6 percent of immunized patients developed cerebral inflammation (see ARF live discussion). Follow-up analysis revealed that among AD patients who got the vaccine, those who made antibodies against the injected Aβ42 preparation seemed to fare better or at least decline less on several measures of cognitive function and daily living (see Hock et al., 2003 and ARF related news story). Another study (Gilman et al., 2005) found no improvement in AN1792-treated subjects using a handful of outcome measures (ADAS-cog, Disability Assessment for Dementia, Clinical Dementia Rating, Mini-Mental State Examination [MMSE], or Clinical Global Impression of Change) but did show some benefits (better neuropsychological test battery (NTB) scores and lower CSF tau levels). More recent studies looking at how AN1792-treated patients were faring four and a half years after the start of the trial have also delivered somewhat hopeful but tentative results (see ARF Madrid news story and ARF Washington news story).

In the new study, James Nicoll at the University of Southampton, UK, with collaborators there and elsewhere, set out to determine how Aβ42 immune response correlated with extent of amyloid plaque removal and longer-term clinical outcomes. Due to patient deaths before and during follow-up, as well as limited numbers offering consent for postmortem analysis, first author Clive Holmes and colleagues were left with eight AN1792 trial participants, all in the treatment group, to analyze. In these patients and an age-matched control group of non-immunized AD patients, the researchers assessed Aβ load by determining the percent of cortical area with Aβ immunoreactivity (clone 6F/3D) and scoring specific histological evidence for plaque removal. For each patient, Aβ load was compared with mean anti-AN1792 antibody titers and longer-term outcomes (survival time and MMSE score before death). A morsel of good news came from the study’s confirmation that the Aβ immunization procedure generally works. Mean Aβ load was lower in the vaccinated patients (2.1 versus 5.1 percent in controls), and though the extent of plaque removal varied greatly, it did correlate to some degree with serum anti-Aβ antibody titers, the researchers found.

The bottom-line news, unfortunately, was grim. In the small cohort they were able to analyze, the researchers saw no measurable clinical gains in the AN1792-treated group. In fact, two patients with near complete clearance of amyloid plaques still succumbed to profound end-stage dementia before they died. Overall, the immunized patients did not live longer, nor did they take longer to reach severe dementia, compared with controls. “Although our findings are based on small numbers of patients, they seem to demonstrate that the presence of plaques is not a prerequisite for progressive cognitive impairment in AD,” wrote Nicoll in an e-mail to ARF.

Donna Wilcock of Duke University in Durham, North Carolina, noted that the authors did not specifically address the possibility that cerebral amyloid angiopathy (CAA) and associated microhemorrhage contributed to the clinical progression of the study patients. She pointed out a recent report (Schroeter et al., 2008) suggesting that even low doses of anti-Aβ antibody, which resulted in virtually no amyloid removal, were associated with subtle increases in microhemorrhage. (See full comment below.)

Based on the new findings, Nicoll expects other immunization strategies (e.g., passive immunization and active immunization with truncated versions of Aβ) to be effective at clearing plaques but predicts that these changes will not correlate well with cognitive improvement. However, he noted that newer protocols may have differential effects on the various forms of Aβ (e.g., plaque, soluble, oligomeric, intraneuronal), which could in turn lead to different cognitive effects. Nicoll expressed cautious hope in using immunization to prevent AD rather than treat it. “A study to determine if Aβ immunization at a young age could prevent the development of AD later in life would be the ultimate test of the Aβ hypothesis,” he wrote. (See full comment below.) Preventive AD vaccines have not yet entered clinical trials, but a recent study (see Movsesyan et al., 2008 and ARF related news story) describes a DNA-based, preventive vaccination approach that seems to work in an AD mouse model.

As the field ponders new avenues for immunotherapy, AD researchers and patients are likely to take heart in the report on Dimebon. Rachelle Smith Doody of Baylor College of Medicine in Houston, Texas, with collaborators elsewhere, led the new study of this small-molecule compound—marketed in Russia as an antihistamine decades ago and repurposed as an AD drug when its anti-cholinesterase and NMDA receptor inhibitory properties were discovered. Studies have shown that Dimebon has neuroprotective effects in rodents, and that this benefit may stem from its ability to stabilize and enhance mitochondrial function (Bachurin et al., 2001; Bachurin et al., 2003). David Hung, CEO of San Francisco-based Medivation, Inc., will discuss evidence for the drug’s novel mitochondrial mechanism of action at ICAD on 30 July. Medivation is developing Dimebon as a treatment for Alzheimer and Huntington diseases.

Much of the newly published data on the Russian trial of Dimebon has been presented previously (see ARF Boston news story, ARF Washington news story, and ARF related news story). In short, the cohort receiving oral Dimebon (20 mg three times a day) showed significant improvement in all cognitive outcome measures (ADAS-cog, MMSE, neuropsychiatric inventory, the Alzheimer’s Disease Cooperative Study—activities of daily living [ADCS-ADL]) as well as in a global measure (Clinician’s Interview-based Impression of Change plus Caregiver Input [CIBIC-plus]). “The interesting thing about those differences is that there was both significant improvement over baseline in all measures and significant decline in the placebo group, and the benefit was driven both by improvement and decline,” noted Doody in an Alzforum interview. Most AD drugs that have shown benefit in clinical trials have only done so compared with placebo groups that declined more sharply. “In the Dimebon case, even if the placebo group was flat, we’d still have a positive study,” Doody said.

Because 86 percent of those who completed the trial chose to enroll in the six-month blinded extension, which retained each person’s original treatment assignment, the researchers essentially got a one-year look at Dimebon, Doody said. “What we saw was continued benefit above baseline and further decline in the placebo group on all of the outcomes, leading to statistical significance for all the measures.” The Dimebon-placebo difference was greater at week 52 than at week 26 for the ADAS-cog, ADCS-ADL, and CIBIC-plus measures.

In this Russian trial, Dimebon was safe and well tolerated. At week 26, dry mouth and depressed mood were the most common adverse events (14 percent for each symptom, versus 5 percent of placebo patients).

“It's very important that the field be investigating non-amyloid-based interventions as well as amyloid-based interventions,” said Jeff Cummings of the University of California, Los Angeles, who serves on the steering committee to help design Dimebon trials. “This non-amyloidogenic pathway involving unique mechanisms of action appears to result, in this first pivotal trial, in a good effect size, a consistent effect across measurement instruments, and a more persistent effect than we have seen in previous trials.”

In May, Medivation launched a multinational Phase 3 Dimebon trial with an anticipated enrollment of 525 patients in the U.S., Europe, and South America. Like the newly published study, the global trial excludes patients who are taking other anti-dementia drugs, including cholinesterase inhibitors and NMDA receptor antagonists.—Esther Landhuis


  1. The paper by Holmes et al. examines pathology and cognition of eight patients from the AN1792 Aβ vaccination trial. Despite the suspension of this trial in 2002, the patients continued to be followed clinically. Two patients showed almost complete removal of amyloid in the brain. The important finding of the current report is that cognitive decline was identical to placebo-treated patients despite the pronounced removal of amyloid. While these data contrast with the many mouse studies showing cognitive improvement and indeed suggest a more limited role for Aβ in the progression of Alzheimer disease, extensive speculation from such a small cohort should be avoided. In contrast to the current report, the 2003 report from Hock et al. showed slowed cognitive decline in a group of 30 patients over a year following treatment; however, this was correlated with a modified antibody titer; the TAPIR assay (tissue amyloid plaque immunoreactivity; the ability of circulating antibodies to bind to amyloid plaques on tissue) (Hock et al., 2003). In the current study the authors suggest several scenarios for the lack of clinical efficacy: 1) amyloid plaques initiate but do not maintain progressive neurodegeneration, 2) very slow plaque removal, 3) inability to remove oligomeric Aβ, and 4) overactivation of the innate immune system.

    An important effect of immunization that has not been reported on in the current study is cerebral amyloid angiopathy (CAA) and microhemorrhage. It has been shown that passive immunotherapy increases CAA in transgenic mice (Wilcock et al., 2004) and causes increased incidence of microhemorrhage (Pfeifer et al., 2001, Wilcock et al., 2004, Racke et al., 2005). We also reported that these adverse events occurred with active vaccination (Wilcock et al., 2007). Indeed, the authors of the current report use CAA and Aβ accumulation around capillaries as histopathological factors used to determine the degree of amyloid clearance. It also seems the microhemorrhage occurrence will be difficult to overcome. The recent report from Schroeter et al. showed that even low doses of antibody, which were associated with essentially no amyloid removal, resulted in an apparent subtle increase in microhemorrhage (Schroeter et al., 2008; control mice had no animals with microhemorrhage rated 2 or 3 while the lowest dose of 3D6 had three mice rated 2 or 3). Accumulation of CAA and associated microhemorrhage likely contributes significantly to the clinical progression of disease. Additionally, as the authors suggest, a change in inflammatory state could certainly contribute to further cognitive decline. Recent data show that the inflammatory profile of Alzheimer’s and transgenic mouse brain is highly complex (Colton et al., 2006). It is likely that Fcγ receptor activation affects the inflammatory state.

    These data highlight the significant differences between human and mouse studies. Since neurodegeneration is not abundant in the majority of mouse models, it has not been possible, to date, to study this. It is likely that while amyloid may initiate the cascade, neurodegeneration may be self-perpetuating and neuroprotection may also be critical for successful anti-amyloid therapeutics. It has been suggested that passive immunization will overcome some of the limitations of active vaccination, and we certainly eagerly anticipate the data from Elan’s passive immunization trial of bapineuzumab.


    . Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation. 2006;3:27. PubMed.

    . Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54. PubMed.

    . Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. PubMed.

    . Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005 Jan 19;25(3):629-36. PubMed.

    . Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008 Jul 2;28(27):6787-93. PubMed.

    . Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004 Dec 8;1(1):24. PubMed.

    . Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid. Neuroscience. 2007 Feb 9;144(3):950-60. PubMed.

  2. Our study was a six-year follow-up of patients in the original Elan AN1792 study of active immunization of AD patients with full-length Aβ42 peptide. We have confirmed that Aβ immunization can result in plaque removal from the AD brain. The extent of plaque removal is quite variable—ranging from no demonstrable plaque removal to essentially complete removal of plaques from the brain. The extent of plaque removal correlated at least to some extent with the titers of antibodies to Aβ in the serum. Two patients had almost complete removal of plaques from the brain, and yet they still had a progressive decline in cognitive function to profound end-stage dementia shortly before they died. All patients who had postmortem neuropathology had extensive tangles—Braak stages V/VI, consistent with AD. Although our findings are based on small numbers of patients, they seem to demonstrate that the presence of plaques is not a prerequisite for progressive cognitive impairment in AD.

    We suggest a number of possible explanations for our findings:

    1. The presence of Aβ plaques is required to initiate, but not to maintain the progressive neurodegeneration in AD.

    2. Amyloid plaques are an epiphenomenon, and extracellular soluble/oligomeric or intraneuronal forms of Aβ are responsible for the neurodegeneration in AD.

    3. Immunization activates microglia, which may be beneficial (by removing plaques) but at the same time neurotoxic.

    4. The plaques could have been removed shortly before the patients died, after their cognitive function had declined—this seems rather unlikely.

    A major driver of the immunization strategies currently in clinical trials has been to avoid a T lymphocyte reaction in the belief that this is what underlay the side effect noted in the second study of AN1792. Passive immunization, in particular, should theoretically not be able to provoke a T cell response and has the additional benefit that the bioavailability of the antibodies can be controlled. However, it is not clear by what mechanism lymphocytes in the leptomeninges, identified in patients with the side effect, can cause changes in the cerebral white matter (a consistent feature on brain imaging of the affected patients). An alternative explanation for the side effect is that it was due to disaggregation and solubilization of plaque Aβ which then tracks to the cerebral vasculature, increasing the severity of cerebral amyloid angiopathy (CAA). We know from previous studies that severe cerebral amyloid angiopathy is associated with abnormalities in the white matter. Interestingly, the new information from the current Elan trial of passive immunization (bapineuzumab) seems to be showing evidence of white matter abnormalities which are occurring more frequently in patients with ApoE4—known to be associated with more severe CAA.

    On the basis of our findings, we would predict that other immunization protocols (e.g., passive immunization and active immunization with truncated versions of the Aβ peptide) will also be effective in clearance of plaques. A number of current studies have before and after immunization in vivo plaque imaging, for example, with PIB, built into their design. We would predict that these will demonstrate plaque clearance following immunization. However, on the basis of our findings, we would speculate that plaque removal will not correlate well with any changes in cognitive function.

    It is possible that some of the new immunization protocols will have a different balance of effects on the different forms of Aβ (e.g., plaque, soluble, oligomeric, intraneuronal) and may therefore have different effects on cognitive function. One of the approaches being trialled involves passive immunization with an Fc-truncated antibody, and this may have the potentially beneficial effect of not provoking microglial activation.

    Using immunization as prevention rather than treatment would likely avoid these complications which seem to be due to the presence of substantial quantities of Aβ already being present in the brain. On the basis of the animal studies, immunization at a young age can prevent the formation of plaques in later life. Of course, we don’t yet know if this can be done safely in humans—we don’t know the physiological function of Aβ and if immunization might interfere with this function. A study to determine if Aβ immunization at a young age could prevent the development of AD later in life would be the ultimate test of the Aβ hypothesis.

  3. Comment by Rudy J. Castellani, George Perry, Xiongwei Zhu, Hyoung-gon Lee, Mark A. Smith

    The Next Phase: Prevention. Where Do I Sign Up?
    The Aβ vaccination strategy failed because it was not used early enough in the course of the disease.

    Come again?

    We know this apparently because Aβ oligomers, which are artifacts of ultracentrifugation, when injected into the ventricles of mice, cause mice to navigate water mazes poorly, and press levers inappropriately. We know this because when hippocampal slices are bathed in a suspension of the artifact, they demonstrate electrophysiological abnormalities. And we know this because transgenic mice, which are engineered to overproduce Aβ, and then administered antibodies against it, improve in their ability to navigate water mazes and press the appropriate levers.

    We apparently also must set aside the ad hoc revisions and contortions of the amyloid cascade hypothesis over the years (1-3), and the plethora of problems with experimental AD models, from lack of cognitive dysfunction, to lack of neuronal loss, to necessity of multiple mutations, to hyperphysiologic production of a target protein. We set this aside because we apparently now know that synaptic damage, a process never directly assessed, and which probably has the same specificity as gliosis, is the pathological substrate for this laboratory artifact in AD (1).

    So a strategy, founded in the analysis of a pathological lesion (once said to be toxic and now discarded as a distraction, except of course for the two subjects who found to be “cleared” of plaques at autopsy), based on an ad hoc modification of a hypothesis that a laboratory artifact specifically causes nonspecific damage that has never been analyzed directly, verified in a transgenic mouse construct that generally does not lose neurons, and which was tested and failed in human disease subjects, must now be used on normal people. Where do I sign up?


    . Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol. 2008 Jun;67(6):523-31. PubMed.

    . Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol. 2006 Jun;111(6):503-9. PubMed.

    . Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. PubMed.

  4. The recent follow-up to the AN1792 study by Holmes et al. is a thought-provoking study that reinforces but certainly does not prove speculation by many in the field, including myself (Golde, 2006; Golde, 2003), that therapeutic targeting of Aβ may have limited impact on the clinical disease (Golde, 2006; Golde, 2003). Because of the small number of subjects and the unknown possible untoward consequences of an active vaccination targeting an auto-epitope, I think that this data is simply provocative but certainly not definitive.

    I have often used the analogy that anti-Aβ therapy for AD is analogous to treating patients whose coronary arteries are 99 percent clogged with a statin and hoping for a clinical effect. These new data raise the possibility that anti-Aβ immunotherapy is more like trying to treat somebody with massive myocardial contraction deficits following multiple MIs with a statin and a bypass. So much damage has been done that targeting the trigger, by itself, is simply too little too late. Indeed, we would not approach the treatment of a patient in severe cardiac dysfunction that has resulted from multiple MIs as a result of long-standing atherosclerotic disease with a statin alone. It simply is not going to work, though it might have some benefit in combination with other therapeutic agents.

    Though a small and vociferous group of colleagues are publicly using such data to refute the role of Aβ aggregation in AD and thus indirectly attempting to invalidate it, Aβ or Aβ aggregates, as a target, I think a more parsimonious approach and one discussed to an extent by the authors is to really think carefully about these data and how we as a field might modify our approach to AD therapy and research based on such studies. Although there are numerous potential implications of these data, I will limit myself to a few issues that I see as most important. Obviously, the following comments may be tempered somewhat by any future demonstration of efficacy in Phase 3 studies of anti-Aβ therapies, but I think they will likely hold even in that event.

    From a basic research point of view, this ups the ante on two critical issues.

    In order to enable better preclinical studies, we still need better animal models of AD that fully recapitulate all the features of the human disease—especially neuronal loss. Given that this appears very difficult to do in APP mice, we probably need to consider looking at other species. Indeed, this report suggests the AN1792 trial appears to have “worked” in humans as it did in mice. Of course, APP mice are good models of Aβ deposition but not real models of AD. If we had a complete animal model of AD, we might be better able to evaluate therapeutic paradigms for impact on neurodegeneration. Tau mice might be better predictors for effects on neuronal loss, but obviously aren’t much use for testing anti-Aβ therapies. Hopefully they will be predictive of clinical outcomes when novel anti-tau therapies are moved into the clinic.

    We need a real understanding of why neurons die in AD, and we need to identify additional therapeutic targets that will protect or restore neuronal function. Indeed, though my own research is Aβ-centric, I believe it is of paramount importance to identify targets beyond Aβ and, for that matter, tau. I think that it is more important to explicitly state that we need additional targets than to try and invalidate current ones.

    From a clinical perspective, I think this reinforces our need to figure out how to prophylactically treat AD. We need to directly confront and overcome the challenges that distinguish therapeutic trials from prevention trials. We also need to figure out whether a trial of MCI of the AD type to AD conversion is really a prevention trial or just a very early therapeutic trial. Current predictive AD biomarker initiatives will certainly help to frame and define some aspects of the problem in more detail, but we also need to find common ground on how to actually execute a prophylactic trial that is economically feasible, ethical, and appropriately powered. Such trials will almost certainly require the joint efforts of academic, government, and commercial sectors, and of course, “safe agents.” Indeed, the true test of the Aβ “aggregate/amyloid” hypothesis of AD is a trial to prevent Aβ deposition in humans, not a therapeutic treatment of patients with clinical symptoms.

    On a final, more technical note, following the initial report (Nicoll et al., 2003) of plaque clearance in one patient, I was less than convinced that there was clearance. The new data do make me more convinced. However, I would like to see some rigorous biochemical analysis of Aβ levels in the brains of these subjects. Even in mouse models, “plaque loads” seem to overestimate reductions in Aβ as compared to biochemical measures. I am also struck by what appears to be patchy clearance. I find it hard to rationalize how patchy clearance can occur with an antibody-mediated mechanism and wonder whether cellular immune responses play some role in the actual clearance.


    . Alzheimer disease therapy: can the amyloid cascade be halted?. J Clin Invest. 2003 Jan;111(1):11-8. PubMed.

    . Disease modifying therapy for AD?. J Neurochem. 2006 Nov;99(3):689-707. PubMed.

    . Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.

  5. This report is an interesting follow-on from a case report that showed evidence of Aβ plaque removal following immunization with the Elan/Wyeth AN1792 Aβ vaccine (Nicoll et al., 2003). Holmes and coworkers (2008) now extend the findings of the original case report to eight additional cases, which demonstrated varying degrees of histological evidence of Aβ plaque clearance. What I found most interesting about this report is that, even within this relatively small sample, the cases that had the most prominent (so-called “very extensive”) evidence of Aβ plaque removal also had the highest Aβ antibody titers. This further cements the relationship between Aβ-directed immunity and plaque clearance, which has now been observed by us and by many others in AD mice.

    There are a few issues that I’d like to comment on. I find it noteworthy that seven out of eight cases had MMSE scores of zero when last screened. The authors point out that these were “end stage” AD cases—and judging from the MMSE scores, that’s an understatement. I agree with Todd Golde that AD immunotherapy in this small, severely affected cohort is not a robust test of the amyloid cascade hypothesis in humans. But, I don’t believe that this detracts at all from the provocative nature of the findings, and from the message to keep an open mind and to critically consider the etiological contribution of Aβ to AD. More than likely, what these data are telling us is that there is a cutoff beyond which severe neuronal damage/loss has already occurred, and removing Aβ from the equation will have little if any effect clinically. This has prompted a number of researchers to conclude that prevention by immunotherapy is a more viable strategy. That may be true, but when should vaccination be initiated—five, 10, 20, or more years before symptoms manifest? Also, what biomarkers should be used to determine those at risk: APOE genotype, CSF Aβ, CSF tau, plasma Aβ? At this stage, a preventative Aβ vaccine seems much more viable for the It is unfortunate that an adjuvant-alone (placebo) treatment group could not be evaluated side-by-side with the AN1792-treated cases, and that historical non-vaccinated AD cases had to be used as controls. It is possible that the inflammatory side effects of the Th1-biasing vaccine adjuvant (QS-21) negatively impacted cognitive function and/or survival independently of the synthetic Aβ42 peptide. Along those lines, the authors comment that “only one patient had clinical features of meningoencephalitis….” Did the authors evaluate CD4+ T cells in these vaccinated cases, and if so, were they present in greater quantity than in the historical non-vaccinated AD cases?

    In summary, this paper represents a timely, thought-provoking examination of the clinical and pathological correlates of Aβ vaccination. As we move forward in this exciting time of AD therapeutics, it will be important to view the results of such clinical trials with open eyes and without bias toward whichever AD pathogenic hypothesis we hold close to our hearts.


    . Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.

    . Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.

  6. Once more we see that plaques are a poor correlate of cognitive status in AD. This does not, however, preclude a role for other manifestations (or "flavors") of APP in the pathophysiology of AD.

    View all comments by Paul Coleman
  7. It is worth reading the comments on this paper that have already been posted on Alzforum. This thorough analysis of the long-term effects of the (foreshortened) Elan Aβ-immunization trial (AN1792) in the U.K. is both sobering and, to the BAPtists among us, a bracing challenge. Why, if Aβ plaques are being removed, does cognition continue to deteriorate in immunized AD patients? Both Holmes et al. and the accompanying commentary by St. George-Hyslop and Morris nicely summarize the potential reasons for this disappointment, from the technical (too few subjects to draw firm conclusions) to the mechanistic (e.g., if dementia has already set in, the treatment is too late, or it is necessary to target Aβ oligomers).

    These comments should be taken seriously, as they encapsulate key issues that must be addressed if the Aβ cascade hypothesis (or at least the future of immunization therapy) is to survive this trial. To the opponents of the Aβ cascade hypothesis, it might seem that we Aβ stalwarts run the risk of straining a hand-waving muscle right now, but the evidence supporting a primary role of Aβ in disease pathogenesis remains considerable and compelling. Perhaps, as St. George-Hyslop and Morris say, a pluralistic approach will be necessary to address the complex degenerative process, but I believe that a monotherapy eventually will emerge from a deeper understanding of the disease process, particularly in the early stages of AD.

    The future of the immunization approach to AD (or of any disease-modifying approach, for that matter) may well lie in prevention. But who will run the lengthy and expensive trials that are needed to determine whether it will work? And will the resolve to test preventive measures be weakened by the failure of therapeutic trials conducted long after the disease has begun to take its toll on the subjects?

    View all comments by Lary Walker
  8. This paper is a jarring wake-up call to all Alzheimer disease investigators that placed all their research marbles in the amyloid hypothesis basket, as the clinical pathological findings suggest serious rethinking of the Aβ42 vaccination approach. Based on this report and the mounting evidence from Aβ vaccination trials spoken about at the ICAD meeting, it is becoming clear that an amyloid vaccination mono-therapeutic approach to AD treatment is simply not the sole answer. It can be argued that adding more subjects to the Holmes et al. study is appropriate for further clarification, but both clinical trial and neuropathologic studies of the brain of folks who have come to autopsy with mild cognitive impairment (MCI) provide extensive evidence that amyloid is not a strong correlative of cognitive decline (Mufson et al., 1999; Forman et al., 2005).

    Data derived from our ongoing clinical molecular pathologic investigations of MCI using the cholinotrophic basal forebrain system as a model for neuronal selective vulnerability has shown that these neurons display a myriad of biochemical and molecular alterations, which appear to be unrelated to amyloid deposition (Counts and Mufson, 2004). For example, cholinergic neurons are simultaneously undergoing re-expression of cell cycle markers, alterations in neurotrophic support and the ratio of tau epitopes but not changes in APP or presenilin expression. The molecular signature of these neurons is commensurate with a hypothesis related to multiple cellular and connectivity-based dysregulation, which probably begins several decades before the onset of clinical symptoms. What initiates neuronal dysfunction remains unknown, and merits serious research in relevant animal models as well as in well-characterized postmortem human brain tissues. In this regard, it would be of interest to examine the molecular pathology of the cholinergic basal forebrain (CBF) neurons in the same vaccine treated brains examined by Holmes et al. to determine whether amyloid removal from cortical and hippocampal parenchymal projection sites of the CBF neurons rejuvenates these cell bodies.

    To anyone who has ever examined the brain of a patient with AD, it is evident that the disease is not simply an amyloidosis. AD is a multi-neuronal system disconnection syndrome of unknown etiology, with pronounced selective cell loss, synaptic dysfunction, atrophy, vascular pathology, tau pathology, in addition to intracellular Aβ disturbances and extracellular amyloid deposition, among other problems that may yet be discovered. It is not our intention to advocate any singular hypothesis of AD, rather to suggest that other treatment approaches and modalities should be pursued with a solid federal and private funding base in addition to amyloid-based clinical trials. An effective treatment will ultimately be a poly-pharmaceutical approach that targets both mechanisms underlying neurodegeneration as well as symptoms of cognitive decline until the etiology of AD is revealed.


    . Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis. Neurology. 2007 Mar 6;68(10):757-63. PubMed.

    . Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. Exp Neurol. 1999 Aug;158(2):469-90. PubMed.

    . The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease. J Neuropathol Exp Neurol. 2005 Apr;64(4):263-72. PubMed.

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Therapeutics Citations

  1. AN-1792
  2. Dimebon

News Citations

  1. Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
  2. Madrid: News from the Vaccine Front—Phase 2 Postmortem, Part 1
  3. Washington: Functional Improvement From Stopped Vaccine
  4. AD Immunotherapy: Toward Prevention, DNA-based Vaccines?
  5. Boston: Clinical Trial Results for Dimebon Unveiled
  6. Washington: Alzhemed Non-story Yields Spotlight to Phase 2 Treatments
  7. Trial Troika—Immunotherapy Interrupted, Lipitor Lags, Dimebon Delivers

Paper Citations

  1. . The role of the immune system in clearance of Abeta from the brain. Brain Pathol. 2008 Apr;18(2):267-78. PubMed.
  2. . Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54. PubMed.
  3. . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. PubMed.
  4. . Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008 Jul 2;28(27):6787-93. PubMed.
  5. . Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.
  6. . Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. 2001 Jun;939:425-35. PubMed.
  7. . Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci. 2003 May;993:334-44; discussion 345-9. PubMed.

Other Citations

  1. ARF live discussion

External Citations

  1. Medivation, Inc.
  2. global trial

Further Reading


  1. . Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol Aging. 2000 Nov-Dec;21(6):797-806. PubMed.
  2. . Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neurosci. 1998 Apr 15;18(8):2801-7. PubMed.
  3. . The role of the immune system in clearance of Abeta from the brain. Brain Pathol. 2008 Apr;18(2):267-78. PubMed.
  4. . Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008 Jul 2;28(27):6787-93. PubMed.

Primary Papers

  1. . Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
  2. . Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008 Jul 19;372(9634):207-15. PubMed.