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...  Read more

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:
1. Ghochikyan A, Vasilevko V, Petrushina I, Movsesyan N, Babikyan D, Tian W, Sadzikava N, Ross TM, Head E, Cribbs DH, Agadjanyan MG. 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. Abstract

2. Qu B, Rosenberg RN, Li L, Boyer PJ, Johnston SA. Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch Neurol. 2004 Dec;61(12):1859-64. Abstract

3. Qu B, Boyer PJ, Johnston SA, Hynan LS, Rosenberg RN. Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice. J Neurol Sci. 2006 May 15;244(1-2):151-8. Epub 2006 Mar 6. Abstract

4. Qu BX, Xiang Q, Li L, Johnston SA, Hynan LS, Rosenberg RN. Abeta42 gene vaccine prevents Abeta42 deposition in brain of double transgenic mice. J Neurol Sci. 2007 Sep 15;260(1-2):204-13. Abstract

View all comments by Roger N. Rosenberg

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...  Read more

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:
Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE (2008) Amyloid deposition is frequent and often is not associated with significant cognitive impairment in the elderly. Archives of Neurology (in press).

Haroutunian V, Perl DP, Purohit DP, Marin D, Khan K, Lantz M, Davis KL, Mohs RC. Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol. 1998 Sep;55(9):1185-91. Abstract

Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. Abstract

Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, Dekosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. Abstract

Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. Abstract

Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O'Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007 May 15;68(20):1718-25. Abstract

Wolf DS, Gearing M, Snowdon DA, Mori H, Markesbery WR, Mirra SS. 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. Abstract

View all comments by William Klunk

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...  Read more

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.

View all comments by Terrence Town

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...  Read more

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

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

Hof PR, Bouras C, Perl DP, Sparks DL, Mehta N, Morrison JH. 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. Abstract

Leverenz JB, Raskind MA. 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. Abstract

Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007 Nov;13(11):1359-62. Abstract

Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol. 1985 Mar;17(3):278-82. Abstract

View all comments by Elizabeth Head

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...  Read more

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).

References:
Alexander J, Sidney J, Southwood S, Ruppert J, Oseroff C, Maewal A, Snoke K, Serra HM, Kubo RT, Sette A, et al. (1994): Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1:751-61. Abstract

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.

Ghochikyan A, Vasilevko V, Petrushina I, Tran M, Sadzikava N, Babikyan D, Movsesyan N, Tian W, Ross TM, Cribbs DH, Agadjanyan MG (2003): Generation and characterization of the humoral immune response to DNA immunization with a chimeric b-amyloid-interleukin-4 minigene. Eur. J. Immunol. 33:3232-41. Abstract

Head E, Pop V, Vasilevko V, Hill M, Saing T, Sarsoza F, Nistor M, Christie LA, Milton S, Glabe C, Barrett E, Cribbs D (2008): A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta. J Neurosci 28:3555-66. Abstract

Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, Petrushina I, Movsesyan N, Mina E, Kiyatkin A, Glabe C, Cribbs DH, Agadjanyan MG (2007): Anti-Abeta 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 282:22376-86. Abstract

Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, Fisher Y, Owens T, Weiner HL (2006): 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 103:5048-53. Abstract

Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG (2008): Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine- a novel immunotherapeutic strategy. PLoS ONE 3:e21-24. Abstract

Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle GD, Luehrs DC, Kuo YM, Lopez J, Brune D, Ferrer I, Masliah E, Newel AJ, Beach TG, Castano EM, Roher AE (2006): Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol 169:1048-63. Abstract

Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH, Agadjanyan MG (2007): Alzheimer's Disease Peptide Epitope Vaccine Reduces Insoluble But Not Soluble/Oligomeric A{beta} Species in Amyloid Precursor Protein Transgenic Mice. J Neurosci 27:12721-12731. Abstract

Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS (2008): Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 5:194-6. Abstract

View all comments by Michael G. Agadjanyan

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...  Read more

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:
Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006) Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl) 111(6): 503-9. Abstract

Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG (2008) Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS ONE 3(5): e2124. Abstract

Smith MA, Atwood CS, Joseph JA, Perry G (2002) Predicting the failure of amyloid-beta vaccine. Lancet 359(9320): 1864-5. Abstract

Smith MA, Casadesus G, Joseph JA, Perry G (2002) Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med 33(9): 1194-9. Abstract

View all comments by Rudy Castellani
View all comments by Hyoung-gon Lee
View all comments by Paula Moreira
View all comments by Akihiko Nunomura
View all comments by George Perry
View all comments by Mark A. Smith
View all comments by Xiongwei Zhu

Results are also expected imminently for the CLASP study, which investigated the effects of simvastatin on progression of AD using a prospective format similar to the LEADe study. The results of the CLASP study will be particularly informative. Simvastatin has shown the most consistent positive effect over a number of different study paradigms, but there could be a difference between results obtained when examining...  Read more

Results are also expected imminently for the CLASP study, which investigated the effects of simvastatin on progression of AD using a prospective format similar to the LEADe study. The results of the CLASP study will be particularly informative. Simvastatin has shown the most consistent positive effect over a number of different study paradigms, but there could be a difference between results obtained when examining the effects of simvastatin in patients with cardiovascular risk factors (such as occurs in an epidemiological study) compared to results obtained when studying the effects of simvastatin in a patient population that exhibited normal cholesterol levels at the outset of the study. So, stay tuned.

References:
1. Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. Abstract

2. Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. Abstract

View all comments by Benjamin Wolozin

The presence of Aβ in artery walls could reflect failure of perivascular transport of soluble proteins along the walls of cutaneous arteries. Experimental studies (1) have shown that soluble proteins drain from the extracellular spaces of the brain along the basement membranes of capillaries and arteries and that this effectively represents the lymphatic drainage pathway for the brain. Aβ is deposited in these pathways in cerebral amyloid angiopathy in humans (2) and in mice (3).

Perivascular drainage of soluble Aβ from the brain is probably driven by the contrary waves that result from the pulse waves traveling along...  Read more

The presence of Aβ in artery walls could reflect failure of perivascular transport of soluble proteins along the walls of cutaneous arteries. Experimental studies (1) have shown that soluble proteins drain from the extracellular spaces of the brain along the basement membranes of capillaries and arteries and that this effectively represents the lymphatic drainage pathway for the brain. Aβ is deposited in these pathways in cerebral amyloid angiopathy in humans (2) and in mice (3).

Perivascular drainage of soluble Aβ from the brain is probably driven by the contrary waves that result from the pulse waves traveling along arteries (4). As arteries stiffen with age, the amplitude of the pulse wave is reduced and the consequent reduction in motive force for perivascular drainage may contribute to the development of cerebral amyloid angiopathy in the elderly (4).

There is evidence that perivascular drainage of amyloidogenic peptides is not confined to the brain. Transthyretin amyloid is deposited in artery walls in peripheral nerves (5), and cystatin C amyloid angiopathy involves not only cerebral arteries but also arteries in other organs (6), reflecting a general phenomenon of “protein elimination failure arteriopathy (PEFA)” (2). The report nearly 20 years ago by Joachim, Mori, and Selkoe (7) of Aβ deposited in the walls of arteries in the skin and intestines supports the concept that Aβ drains along perivascular pathways in organs other than the brain.

Deposition of Aβ in arteries in the skin may be analogous to the failure of elimination of granular osmiophilic material (GOM) from the walls of arteries in the skin in CADASIL, a condition in which the cerebral arteries are the most severely affected (8). In transgenic mice with CADASIL, arteries in the brain and other organs including the tail are severely affected (9). These observations lead to the conclusion that the highly developed perivascular drainage in the brain also occurs in other organs of the body, albeit to a lesser extent.

Two possibilities emerge to account for vasculitis in the skin in the patient treated with Aβ immunotherapy: (a) drainage of Aβ from skin along perivascular pathways and its deposition as amyloid in artery walls followed by immune complex formation in the vessel walls themselves and inflammation, and (b) drainage of Aβ immune complexes from the skin interstitial fluid along perivascular drainage pathways and a vasculitic reaction in the artery walls.

One major question that remains is whether Aβ or immune complexes will enter artery walls in a similar way in organs other than the skin and induce vasculitis.

References:
1. Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JAR, Perry VH, Weller RO. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries. Significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 2008;34:131-44. Abstract

2. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. Perivascular Drainage of Amyloid-beta Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer's Disease. Brain Pathol 2008;18:253-66. Abstract

3. Herzig MC, Van Nostrand WE, Jucker M. Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol 2006;16:40-54. Abstract

4. Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 2006;238:962-74. Abstract

5. Reilly MM, Staunton H. Peripheral nerve amyloidosis. Brain Pathol 1996;6:163-77. Abstract

6. Palsdottir A, Snorradottir AO, Thorsteinsson L. Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects. Brain Pathol 2006;16:55-9. Abstract

7. Joachim CL, Mori H, Selkoe DJ. Amyloid beta-protein deposition in tissues other than brain in Alzheimer's disease. Nature 1989;341:226-30. Abstract

8. Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 1997;56:947-64. Abstract

9. Ruchoux MM, Domenga V, Brulin P, Maciazek J, Limol S, Tournier-Lasserve E, Joutel A. Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol 2003;162:329-42. Abstract

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