. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.

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  1. I think this very well-performed study shows that in mice, an Aβ vaccination strategy using a DNA vaccine can generate strong anti-Aβ antibodies yet also a strong Th2 response, which should theoretically prevent a T cell response against Aβ. This is similar to what several drug companies are doing with non-DNA vaccine techniques. There may be some advantages to the DNA vaccine technique as pointed out in the manuscript. This type of approach should prevent a T cell response to Aβ, which may have caused the problems with encephalitis in the AN1792 study. However, a critical issue for humans studies in this area is whether all the toxicity issues encountered with AN1792 were due to an abnormal T cell response to Aβ. If so, this study, along with what is being done with non-DNA vaccines, is promising in that the T cell response to Aβ can probably be prevented. It is also possible that some of the encephalitis in AN1792 was not only caused by a T cell response but also by certain anti-Aβ antibodies to aggregated Aβ. This will need to be sorted out in the passive anti-Aβ antibody studies that are also moving along in clinical trials.

    View all comments by David Holtzman
  2. This study is an important advance showing that gene vaccines delivered by gene gun may hold promise for future use in the fight against Alzheimer disease. In 2003, Ghochikyan et al. (1) constructed a DNA minigene with Aβ fused to mouse interleukin-4 (pAβ42-IL-4) as a molecular adjuvant to generate anti-Aβ antibodies and enhance Th2-type immune responses. The DNA minigene-induced anti-Aβ antibodies bound to Aβ plaques in brain tissue from an AD patient.

    In 2004, we showed that Aβ42 gene vaccination with gene gun in AD double transgenic mice (APPswe/PSEN1(A246E) produced anti-Aβ42 antibodies that were predominantly IgG1, reflecting a Th2 immune response (2). In 2006 (3) and 2007 (4), we reported for the first time that the Aβ42 gene vaccine administered with a gene gun produced an IgG1 (Th2) immune response and significantly reduced brain levels of Aβ42 in treated APPswe/PS1ΔE9 double transgenic mice. In the 2007 report (4), brain Aβ42 levels were decreased by 41 percent and increased in plasma by 43 percent in vaccinated compared with control mice, as assessed by ELISA analysis. Aβ42 plaque deposits in cerebral cortex and hippocampus of vaccinated animals were reduced by 51 and 52 percent, respectively, compared with controls. Glial cell activation was also significantly attenuated in vaccinated compared with control mice. The 2007 study (4) also described a vaccinated rhesus monkey that developed anti-Aβ42 antibodies.

    Our publications (3,4) provide the first direct immunological evidence suggesting that Aβ42 gene immunization delivered by gene gun effectively induces a Th2 immune response and reduces brain Aβ42 levels in APPswe/PS1ΔE9 mice. Our Aβ42 gene vaccine is also preventive. We immunized the mice beginning at three months of age, and the Aβ42 deposition in this double transgenic line begins around five to six months. We examined the brains at 14-15 months and showed the 41 percent reduction in Aβ42 peptide levels. As the induced immune response was predominately Th2, which has a low probability of producing an inflammatory response, Aβ42 gene vaccination may be a safe and efficient option for Alzheimer disease immunotherapy.

    References:

    . Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur J Immunol. 2003 Dec;33(12):3232-41. PubMed.

    . Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch Neurol. 2004 Dec;61(12):1859-64. PubMed.

    . Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice. J Neurol Sci. 2006 May 15;244(1-2):151-8. PubMed.

    . Abeta42 gene vaccine prevents Abeta42 deposition in brain of double transgenic mice. J Neurol Sci. 2007 Sep 15;260(1-2):204-13. PubMed.

  3. I have a couple of quick points to make. First, Michael Agadjanyan is a brilliant immunologist. He and Dave Cribbs have been leaders in the development of safer and effective active immunization protocols against Aβ, both in this manuscript and others.

    Second, I reviewed the manuscript for PLoS (and signed the review), and the only concern I had was the absence of a control vaccine group. It is conceivable some of the effects were due to the fortnightly gene gun treatments and nonspecific immune activation rather than the specific effects against Aβ.

    Third, it is premature to consider prophylactic vaccination against Aß in the general population due to potential risks without any demonstrated benefit in man. However, carriers of dominant FAD mutations might consider the risk-benefit ratio to favor vaccination.

    Immunotherapy will likely be the first test of the amyloid hypothesis of AD pathogenesis, given its efficacy in clearing amyloid in animal models and the number of clinical trials underway. However, there are potential concerns associated with encephalitic reactions and development of micro-hemorrhage. A large number of studies have argued the absence of these reactions in their immunotherapy protocols means their approach is "safe". However, unless there are immunotherapy protocols tested in parallel which produce these toxic effects in the animal model used, it is uncertain that their protocol avoids the problem.

    We all anxiously await the results from the clinical trials using active and passive immunotherapy.

    View all comments by Dave Morgan
  4. The DNA epitope vaccine described by Movsesyan et al. has raised a discussion concerning preventative versus therapeutic strategies for the management of Alzheimer disease (AD). It goes without saying that before we can have this debate in earnest, the strategy at hand must be proven sufficiently safe in the therapeutic setting and even safer if it is to be applied in a preventative setting in people who are currently symptom-free. I do not believe that we are yet at that point with any anti-amyloid immunotherapy approach, so this discussion remains theoretical for the time being.

    Despite this, the discussion of when we need to intervene in AD remains relevant and important. The comments raised by Michael Agadjanyan on Alzforum echo the concerns previously voiced by many researchers and can be boiled down to this simple question: Can we achieve a meaningful impact of any therapy for AD if it is begun after the clinical symptoms become apparent? We do not yet know the answer to this question, but decades of therapeutic efforts with only modest success justify raising this concern.

    Every serious disease has a point of no return, and one has to at least entertain the possibility that this point may be prior to the onset of clinical symptoms in AD. Many postmortem studies have implied that the Aβ pathology characteristic of AD begins a decade or more prior to the clinical symptoms (Haroutunian et al., 1998; Price and Morris, 1999; Wolf et al., 1999). Today we have tools such as CSF determination of Aβ and tau markers and PET amyloid imaging that can indirectly (CSF) or directly (PET amyloid tracers) detect Aβ pathology in living patients.

    Several PET amyloid imaging studies have shown that about 25 percent of cognitively normal elderly show some evidence of early Aβ deposition (Mintun et al., 2006; Rowe et al., 2007; Aizenstein et al., 2008) and focal Aβ deposits are clearly present in some presenilin-1 mutation carriers at least a decade prior to their expected onset of clinical symptoms (Klunk et al., 2007). In time, we will learn if the presence of Aβ pathology in a cognitively normal person indicates preclinical AD or if it can be innocuous. We also will learn about the natural history of pathological changes in this pre-symptomatic period.

    While these imaging studies are ongoing, we will learn about the safety of several immunotherapy approaches, as well. We also will learn if these approaches are effective at: 1) removing Aβ from the human brain and 2) improving the clinical course of mild-moderate AD. It is entirely possible, and perhaps was foreshadowed by AN1792, that an immunotherapy (or any anti-amyloid therapy) can be relatively effective at removing Aβ, but show little or no clinical effects in mild to moderate AD. If such an anti-amyloid therapy also is safe, we, as a field, will face a very important decision. Do we abandon anti-amyloid therapy as clinically unproductive, or do we revise the trial design to focus on earlier stages of AD, including preclinical stages, i.e., embark on preventative anti-amyloid trials?

    The idea of preventative trial design presents considerable challenges to drug companies, and few, if any, are eager to pursue this approach at present. It will take a major paradigm shift and great patience and long-term thinking/commitment to contemplate a prevention trial that could last five to 10 years. At present, we have more questions than answers, but each should be given careful thought:

    • Could current economic forces that constrain trials to six to 24 months ensure failure in the search for an effective treatment for AD?
    • Could a focus on well-defined carriers of autosomal-dominant mutations for early onset familial AD make prevention trials with anti-amyloid therapy feasible?
    • Is the mere presence of Aβ deposition in the brain of an asymptomatic individual a disease in the same sense that the presence of various amyloids in the periphery are considered pathologic?
    • Could removal of brain Aβ be a primary outcome measure?

    It may be that our thinking must change before our success at treating AD can change.

    References:

    . Amyloid deposition is frequent and often is not associated with significant cognitive impairment in the elderly. Archives of Neurology (in press).

    . Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol. 1998 Sep;55(9):1185-91. PubMed.

    . Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.

    . [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. PubMed.

    . Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.

    . Imaging beta-amyloid burden in aging and dementia. Neurology. 2007 May 15;68(20):1718-25. PubMed.

    . Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study. Alzheimer Dis Assoc Disord. 1999 Oct-Dec;13(4):226-31. PubMed.

  5. This interesting paper by Movsesyan and coworkers describes a novel DNA-based Aβ vaccine that relies on amino acids 1-11 of the peptide in combination with the synthetic T cell peptide, PADRE, and the Th2-promoting chemokine CCL22. The authors have nicely shown that this vaccine reduces behavioral impairment and amyloid burden in brains of Frank LaFerla’s 3xTg-AD mice, but this was only appreciable when the vaccine was given in a prophylactic regimen to younger mice. This raises an important issue regarding timing of immunotherapy, which, if these results in mice translate to humans, suggests that treatment would need to begin early (likely in asymptomatic individuals) for it to be effective.

    I just wanted to raise one caveat for interpreting these results. Previous Aβ vaccination attempts by us and by other groups have failed to model the aseptic meningoencephalitis that occurred in about 5 percent of patients who received the Elan/Wyeth AN1792 vaccine. Further, we and others have not observed the auto-aggressive T cell response (presumed Th1 response that likely occurred in vaccinated patients) after vaccination of mice with the original Schenk et al. protocol or with other Aβ vaccines (unless pertussis toxin is co-administered, widely used to induce brain T cell penetration in experimental autoimmune encephalomyelitis). So it is not possible to conclude that a vaccine that does not induce auto-aggressive T cells in mice may be safe in humans unless detailed toxicology studies are performed in non-human primates.

  6. The current discussion appears to suggest that immunotherapy has the most potential as a preventative approach to managing Alzheimer disease (AD). The development of biomarkers will be critical for the design of these studies, and there are many exciting avenues being explored (e.g., comment by Dr. Klunk, plasma profiling by Tony Wyss-Coray’s group [Ray et al., 2007], CSF measures of Aβ and tau; also see discussion on ARF). Further, several groups of individuals have been identified as being at high risk for developing dementia. Thus, recruiting members of families with familial AD or possibly individuals with ApoE4/4 for clinical trials would be options. An additional group of adults who are at high risk for developing AD are individuals with Down syndrome. Indeed, the first signs of β amyloid (Aβ) pathology can occur in the early thirties (Hof et al., 1995; Leverenz, 1998), clearly at least a decade (and sometimes two) before dementia may be detected. These vulnerable individuals may benefit greatly from a preventative approach using immunotherapy if started in middle age. Given that virtually all adults with DS will develop full-blown AD pathology by the time they are in their forties (Wisniewski et al., 1985), this would be a fascinating cohort to study and a group of individuals that remains relatively underrepresented in AD clinical trials.

    On the other hand, I would like to remain somewhat optimistic about a possible therapeutic approach. But a simple Aβ-targeted treatment may be insufficient without repairing secondary pathologies associated with chronic Aβ exposure. In other words, what if we could remove Aβ and follow up or, in parallel, repair remaining neurons? Might we predict a significant improvement in cognition? As others have suggested, immunotherapy may not be as efficacious once the disease has progressed (to what point is unknown, but at least moderate to severe dementia). But given that our clinicians can detect very early signs of cognitive decline and identify subjects with mild dementia, there may be treatment opportunities here.

    Another idea might be to use immunotherapy as a short-term treatment to clear Aβ pathology and subsequently follow up with a regimen that prevents new Aβ deposition, such as BACE inhibitors or compounds that increase α-secretase activity (see, e.g., ARF Keystone BACE story; ARF SfN BACE story; Fahrenholz, 2007). In this way, immunotherapy does not need to be continued for an extensive period of time, minimizing possible development of adverse events. The “one bullet” hypothesis may be too simple for such a complex disease.

    References:

    . Alpha-secretase as a therapeutic target. Curr Alzheimer Res. 2007 Sep;4(4):412-7. PubMed.

    . Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down's syndrome. Quantitative regional analysis and comparison with Alzheimer's disease. Arch Neurol. 1995 Apr;52(4):379-91. PubMed.

    . Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol. 1998 Apr;150(2):296-304. PubMed.

    . Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007 Nov;13(11):1359-62. PubMed.

    . Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol. 1985 Mar;17(3):278-82. PubMed.

  7. Reply to comments above and on related Vaccine Page
    I agree completely with William Klunk that the discussion about preventive versus therapeutic vaccination is currently more theoretical than practical. This discussion will become more practical as scientists gain more knowledge on AD pathology and vaccination strategies. To draw a historic analogy, the approach of finding the right time when theory and knowledge intersect, has allowed the Manhattan Project to be successful. Thus, I agree with Klunk’s conclusion that “our thinking must change before our success at treating AD can change,” and this is why it is important to continue having these theoretical discussions.

    Let’s briefly consider the story of another historic example, the HIV vaccine. In 1997, President Clinton challenged the scientific community to create an HIV vaccine within a decade. As a result, NIH received extensive funds and announced a new vaccine lab, as well as formed an AIDS Vaccine Research Committee chaired by David Baltimore. During the first conference at NIH on the Innovation Grant for the HIV Vaccine Development Program in 1998, I mentioned that I found it hard to believe that a therapeutic HIV vaccine is realistic and that even the generation of a protective HIV vaccine will be unlikely because this virus is unbelievably variable and attacks/destroys the immune system. Baltimore, who headed this conference, asked me why I accepted this innovation grant if I do not believe in an HIV vaccine. My response was that this program should allow scientists from different disciplines to show that an HIV vaccine is not realistic, at least in the current state of our scientific knowledge. In 2006, Baltimore was quoted as saying: “We're going to live in a world without an HIV vaccine for at least another decade…and we've been saying it's going to be another decade for the last few decades” (see Discover story. Not surprisingly Merck’s latest HIV vaccine trial initiated in healthy volunteers failed, 25 years to the year when the first HIV-1 strain was isolated (see BBC news story).

    The situation with the AD vaccine is quite different from the one with the HIV-1 vaccine. I personally am very optimistic and think that a well-designed AD vaccine could safely induce the production of protective antibodies specific to β-amyloid. That’s because this protein is not changing (at least several N-terminal aa are available in any Aβ forms), is not destroying the immune system, and does not require generation of more complex cellular immune responses specific to this peptide. However, I also believe that this should be done before Aβ accumulation in the vasculature and parenchyma of brains induces an unalterable process.

    Specifically, the AN1792 vaccine is practically ineffective in AD patients (Patton et al., 2006), a peptide epitope vaccine in aged Tg 2576 mice as well as the Aβ42 vaccine in aged dogs are ineffective, but a DNA-based epitope vaccine works when applied as a preventive measure (Head et al., 2008; Mamikonyan et al., 2007; Movsesyan et al., 2008; Petrushina et al., 2007). As Liz Head notes above, it is possible that anti-Aβ42 antibodies could effectively remove toxic deposits of Aβ42 from parenchyma and vasculature, but this will not help to heal damaged neurons unless we could otherwise repair them or initiate neurogenesis. The removal of Aβ42 could be effective only when titers of antibodies are relatively high (Patton et al., 2006; Petrushina et al., 2007) and if they are present in the periphery for a rather long period of time.

    However, as David Holtzman notes, high titers of antibodies may also be detrimental because they may increase deposition of the toxic forms of Aβ and antibody-antigen complexes in the vasculature. Interestingly, we recently demonstrated that sub-stoichiometric concentrations of purified anti-Aβ antibody prevented Aβ42 aggregation and induced disaggregation of preformed Aβ42 fibrils down to a non-filamentous and non-toxic species. However, an anti-Aβ antibody could not disaggregate oligomers, although it did delay Aβ42 oligomer formation (Mamikonyan et al., 2007). These in-vitro observations suggest that therapeutic vaccination cannot disrupt toxic Aβ42 oligomers in vivo, and to the extent that AD is associated with accumulation of those oligomers in brain, I would expect therapeutic vaccination to be ineffective. Moreover, if these in vitro data mimic the situation in vivo, they suggest that even preventive vaccination could not protect elderly people from AD, although a therapeutic vaccine could delay its onset. Speaking with other scientists in the AD vaccine field, I know that many of them nine years after Dale Schenk and colleagues’ remarkable discovery believe that an AD vaccine can become a reality if it is used for protection of Aβ42 accumulation in the brains of healthy people. This raises other questions, including ones about the safety of a preventive vaccine, as noted by Holtzman and Terrence Town, and the cost of such a strategy, as noted by M. Paul Murphy.

    I’ll reply on safety first. The significant amount of data generated in AN1792 human trials as well as in many different mouse models of AD indicates that anti-Aβ antibodies can inhibit/clear Aβ deposits. Published data also suggest that although the Aβ42-based vaccine is safe in mice, it is not safe in AD patients (see Holtzman and Town comments), specifically when it is formulated into a strong Th1 adjuvant and may be in polysorbate B (Pride et al., 2008). As Holtzman notes, it is likely that activation of autoreactive Th cells (specific to Aβ42 peptide) and to a lesser extent proinflammatory cellular responses may induce adverse effects in AD patients. This is why we changed our first-generation DNA vaccine based on Aβ42 (Ghochikyan et al., 2003) to a DNA epitope vaccine (Ghochikyan et al., 2007; Movsesyan et al., 2008) that in theory should not induce autoreactive cellular responses in humans.

    Regarding Roger Rosenberg’s comment, a DNA vaccine expressing full-length Aβ42 could be potentially harmful to humans as was shown with AN1792 based on fibrillar Aβ42. Another difference between a DNA vaccine expressing Aβ42 and a DNA epitope vaccine as described by our groups is the potential of the latter for inducing strong cellular and humoral immunity not only in mice, but also in humans. We base this assumption on that fact that this DNA epitope vaccine is composed of a strong Th epitope that is proven not only in mice, rabbits, and monkeys but also in people expressing 14 different MHC (Alexander et al., 1994) and therefore has the potential to be highly immunogenic in all humans. We are almost certain that such a vaccine will not induce autoreactive T cells and proinflammatory cellular responses in humans (Monsonego et al., 2006; Pride et al., 2008), but its safety in rabbits, dogs, monkeys, maybe chimps, should be demonstrated first. We are planning immunological and toxicological studies in rabbits and monkeys immunized with a DNA epitope vaccine delivered by electroporation before we suggest clinical trials in people who have been identified as being high risk for developing dementia (see comments by Klunk, Head, and David Morgan).

    In these experiments we will use a control plasmid to demonstrate the specificity of vaccination. Of note, as was requested by the reviewer of Movsesyan et al., 2008, we have included data with control plasmid, encoding MDC fused with an irrelevant antigen, in the final version of the paper. Specifically, results with a control plasmid have been incorporated into Figures 2, 3, 4. These data demonstrate that the control vaccine does not induce anti-Aβ antibody in C57BL/6 (Figure 2) and 3xTg-AD (Figure 3) mice. Data in Figure 4 show that injections with an MDC-irrelevant control vaccine did not rescue aged 3xTg-AD mice from cognitive decline (see also reviewer comments and author responses in PLoS ONE.

    An economist could calculate the cost of a preventive vaccination strategy of healthy people better than biomed scientists. Into this calculation should go data as recently released by the Alzheimer’s Association: “…10 million baby boomers will get Alzheimer's disease in their lifetime. … today there are an estimated 5.2 million Americans living with Alzheimer's disease, which is the seventh-leading cause of death in the country and the fifth-leading cause of death for those over age 65” (2008 Alzheimer's Disease Facts and Figures. The calculation could compare the cost of treating all these people with, for example, the cost of treating AIDS patients in the U.S. ($13.1 billion in 2007). It would factor in that today there is no effective treatment for AD and so we often also have to treat the stressed and exhausted caregiver. In a Senate hearing earlier this month, former Speaker Newt Gingrich said: "Under current trends, federal spending on Alzheimer's will increase to more than $1 trillion per year by 2050 in today's dollars. That's more than one-tenth of America's current economy. With this amount of money at stake, the government simply will not be able to solve its looming fiscal problems if it fails to address the growing Alzheimer's crisis."

    Faced with such numbers, I think it is worth spending money and time (not only 10, but maybe 20 years) to study the efficacy of a preventive AD vaccine in humans who know they are at high risk for developing AD if we have enough data supporting such a strategy. That is why I call on the companies involved in passive and active AD vaccine clinical trials to provide detailed results on their clinical studies to the scientific community more quickly. This way, they will get rapid feedback from the community and, with their help, develop a safe and potent protective or therapeutic vaccine against this devastating disease (see comments).

    See also:

    Ghochikyan A, Movsesyan N, Mkrtichyan M, Petrushina I, Biragyn A, Cribbs DH, Agadjanyan MG (2007, March 14-18): DNA epitope vaccine induced strong anti-Aβ antibodies inhibiting AD like pathology in 3xTg-AD mice and protecting them from cognitive decline: 8th International Conference AD/PD, Salzburg, Austria.

    References:

    . Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity. 1994 Dec;1(9):751-61. PubMed.

    . Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur J Immunol. 2003 Dec;33(12):3232-41. PubMed.

    . A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta. J Neurosci. 2008 Apr 2;28(14):3555-66. PubMed.

    . Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. J Biol Chem. 2007 Aug 3;282(31):22376-86. PubMed.

    . Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5048-53. PubMed.

    . Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.

    . Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol. 2006 Sep;169(3):1048-63. PubMed.

    . Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J Neurosci. 2007 Nov 14;27(46):12721-31. PubMed.

    . Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis. 2008;5(3-4):194-6. PubMed.

  8. Comment by Mark A. Smith, Rudy J. Castellani, Paula I. Moreira, Akihiko Nunomura, Hyoung-gon Lee, Xiongwei Zhu, George Perry

    No Justification in Moving from Treatment to Prevention
    The use of immunotherapy as a preventative measure for Alzheimer disease has little merit. First, is abject (Smith et al., 2002) or presumed failure in use as a treatment a good start? If so, would this also be true for other failed treatments? Second, success in “preventing” the pathology/deficits in transgenic mice seems to be driving some of this move toward prevention (Movsesyan et al., 2008). With this logic, the list of potential preventatives would likewise expand to everything that works in mice. Since there is a laundry list of drugs that work in mice but fail in treating the disease, we are left with a laundry list of drugs that we could justify as a valid preventative strategy.

    The field has bet the bank on amyloid as a therapeutic and seems determined to bet another bundle on amyloid as a preventative. In our opinion, the failure thus far of treatment strategies is more an indication of a focus on incorrect targets than of not starting early enough (Smith et al., 2002; Castellani et al., 2006).

    References:

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

    . Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.

    . Predicting the failure of amyloid-beta vaccine. Lancet. 2002 May 25;359(9320):1864-5. 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.