Maternal antibodies facilitate Amyloid-ß clearance by activating Fc-receptor-Syk-mediated phagocytosis.

Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-ß (Aß) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aß overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-Aß MAbs might promote the removal of early Aß accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing Aß1-11 was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aß plaque formation. MAbs reduce the offspring's cortical Aß levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits. MAbs elicit a long-term shift in microglial phenotype in a mechanism involving activation of the FcγR1/Syk/Cofilin pathway. These data suggest that maternal immunization can alleviate cognitive decline mediated by early Aß deposition, as occurs in EOAD and DS.

Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys.

ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aß) protein oligomer. Development of ABT-736 for Alzheimer's disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein. Follow-up investigations indicated polyspecificity of ABT-736, including unintended high-affinity binding to monkey and human plasma protein platelet factor 4 (PF-4), known to be involved in heparin-induced thrombocytopenia (HIT) in humans. The chronic AEs observed at the lower doses after repeat administration in monkeys were consistent with HIT pathology. Screening for a backup antibody revealed that ABT-736 possessed additional unintended binding characteristics to other, unknown factors. A subsequently implemented screening funnel focused on nonspecific binding led to the identification of h4D10, a high-affinity Aß oligomer binding antibody that did not bind PF-4 or other unintended targets and had no AEs in vivo. This strengthened the hypothesis that ABT-736 toxicity was not Aß target-related, but instead was the consequence of polyspecificity including PF-4 binding, which likely mediated the acute and chronic AEs and the HIT-like pathology. In conclusion, thorough screening of antibody candidates for nonspecific interactions with unrelated molecules at early stages of discovery can eliminate candidates with polyspecificity and reduce potential for toxicity caused by off-target binding.

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation.

Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies.The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.

Emerging Promise of Immunotherapy for Alzheimer's Disease: A New Hope for the Development of Alzheimer's Vaccine.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language. OBJECTIVE: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine. SUMMARY: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aß) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aß conformers. The induction of an effective vaccine's immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aß oligomers (AßOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation. CONCLUSION: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials.

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aß peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aß pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aß, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.

How plausible is an Alzheimer's disease vaccine?

Introduction: Alzheimer's disease (AD) vaccination is one of the last therapeutic options after two decades of stagnation in terms of drug development. About 140 (85%) immunization procedures against Aß deposition and 25 (15%) against Tau have been reported, but no Food and Drug Administration approval of any AD vaccine has been achieved. This might be attributed to deficient pathogenic targets, inappropriate models, defective immunotherapeutic procedures, and inadequate clinical trial design.Areas covered: The issues covered include the following: AD pathogenic mechanisms, rationale for active and passive immunization, vaccine targets, anti-Aß/Tau vaccines, vaccine technologies, animal models, and clinical trials.Expert opinion: A vaccine against AD is technically feasible; however, important methodological aspects should be changed for a tentative clinical success, including (i) the development of multitarget AD immunotherapies; (ii) the optimization of antibody titers and epitopes; (iii) the pharmacogenetic/pharmacoepigenetic validation of the immunization procedure; (iv) the prophylactic treatment of genetically stratified patients at a pre-symptomatic stage; and (v) the definition of primary endpoints in prevention, based on objective/multifactorial biomarkers. Even with exquisite protocols, a successful vaccine would be potentially useful in at most 20-30% of defined cases, according to the genetic, epigenetic, and pharmacogenetic background of AD patients.

Multiple Antigenic Peptide System Coupled with Amyloid Beta Protein Epitopes As An Immunization Approach to Treat Alzheimer's Disease.

Latest studies suggest that Alzheimer's disease (AD) is one of the "four big killers" that threaten the health of the elderly. AD affects about 46 million people across the world, and there is a critical need for research on new therapies for treating AD. The purpose of the present study was to develop and evaluate immunogens to elicit antibodies against the formation of amyloid beta protein (Aß), a pathological hallmark of AD, as a therapeutic strategy in AD. In this study, serial potential immunogenic epitopes were screened according to the Aß sequence. The screened linear epitopes on the Aß C-terminal fragment were coupled with either the carrier protein keyhole limpet hemocyanin (KLH) or the synthesized 4-branch peptide (MAP4). MAP4 immunogens could effectively elicit immunogenicity against Aß1-42 monomer and fiber in Balb/C mice. Furthermore, MAP4 sera could also effectively inhibit the formation of the Aß1-42 fiber. Interestingly, one of the MAP4 sera was able to depolymerize the Aß1-42 fibers that had aggregated. The monoclonal antibody, 1H7, was shown to inhibit the formation of Aß1-42 fiber. MAP4 carrier may provide benefits over current immunization strategies, as it does not induce inflammation. In conclusion, the MAP4-Aß conjugates offer a promising approach for the development of a safe and effective AD vaccine.

Active immunization with norovirus P particle-based amyloid-ß chimeric protein vaccine induces high titers of anti-Aß antibodies in mice.

BACKGROUND: Active immunotherapy targeting amyloid-ß (Aß) is a promising treatment for Alzheimer's disease (AD). Numerous preclinical studies and clinical trials demonstrated that a safe and effective AD vaccine should induce high titers of anti-Aß antibodies while avoiding the activation of T cells specific to Aß. RESULTS: An untagged Aß1-6 chimeric protein vaccine against AD based on norovirus (NoV) P particle was expressed in Escherichia coli and obtained by sequential chromatography. Analysis of protein characteristics showed that the untagged Aß1-6 chimeric protein expressed in soluble form exhibited the highest particle homogeneity, with highest purity and minimal host cell protein (HCP) and residual DNA content. Importantly, the untagged Aß1-6 chimeric soluble protein could induce the strongest Aß-specific humoral immune responses without activation of harmful Aß-specific T cells in mice. CONCLUSIONS: The untagged Aß1-6 chimeric protein vaccine is safe and highly immunogenic. Further research will determine the efficacy in cognitive improvement and disease progression delay.

AADvac1, an Active Immunotherapy for Alzheimer's Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development.

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer's disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer's. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients' brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer's disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

Recent advancements toward therapeutic vaccines against Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by protein aggregates of amyloid ß (Aß) and tau. These proteins have normal physiological functions, but in AD, they undergo a conformational change and aggregate as toxic oligomeric and fibrillar species with a high ß-sheet content. AREAS COVERED: Active and passive immunotherapeutic approaches are among the most attractive methods for targeting misfolded Aß and tau. Promising preclinical testing of various immunotherapeutic approaches has yet to translate to cognitive benefits in human clinical trials. Knowledge gained from these past failures has led to the development of second-generation Aß-active immunotherapies, anti-Aß monoclonal antibodies targeting a wide array of Aß conformations, and to a number of immunotherapies targeting pathological tau. This review covers the more recent advances in vaccine development for AD from 2016 to present. EXPERT COMMENTARY: Due to the complex pathophysiology of AD, greatest clinical efficacy will most likely be achieved by concurrently targeting the most toxic forms of both Aß and tau.

Improved synaptic and cognitive function in aged 3 × Tg-AD mice with reduced amyloid-ß after immunotherapy with a novel recombinant 6Aß15-TF chimeric vaccine.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder impairing memory and cognition. In this study, we describe the immunogenicity and protective efficacy of the novel recombinant 6Aß15-TF chimeric antigen as a subunit protein vaccine for AD. Recombinant 6Aß15-TF chimeric vaccine induced strong Aß-specific humoral immune responses without Aß-specific T cell immunity in C57/BL6 and 3 × Tg-AD mice at different ages. As an early immunotherapy model for AD, this vaccine induced high titers of long-lasting anti-Aß42 antibodies in aged 3 × Tg-AD mice, which led to improve behavioral performance and markedly reduced the levels of insoluble and soluble Aß and Aß oligomers. In agreement with these findings, immunotherapy with 6Aß15-TF prevented the Aß-induced decrease of presynaptic and postsynaptic proteins in aged 3 × Tg-AD mice. Our results suggest that this novel and highly immunogenic recombinant 6Aß15-TF chimeric vaccine provides neuroprotection in AD mice and can be considered an effective AD candidate vaccine.

An Aß3-10-KLH vaccine reduced Alzheimer's disease-like pathology and had a sustained effect in Tg-APPswe/PSEN1dE9 mice.

Alzheimer's disease is a neurodegenerative disease that affects many patients worldwide. The amyloid cascade hypothesis has been adopted by most researchers as the mechanism underlying Alzheimer's disease. Aß plaques have been considered the core factor in the neurotoxic effect in Alzheimer's disease, though some controversy remains. Further effort is necessary to elucidate the mechanism and to develop effective treatments. Previous studies have indicated that eliminating Aß plaques could improve synaptic plasticity and cognitive function. Researchers have developed various forms of vaccines to prevent Aß deposition or eliminate Aß plaques and have made some progress. We developed a new vaccine, Aß3-10-KLH, to increase the level of the anti-Aß immune response, and we show that this vaccine resulted in a sustained prevention of Aß deposition at 4 months after cessation of the vaccine treatment. At the same time point, the expression of synaptophysin and NMDAR2B in APP/PS1 transgenic mice was increased by immunization.

Prophylactic Vaccine Based on Pyroglutamate-3 Amyloid ß Generates Strong Antibody Response and Rescues Cognitive Decline in Alzheimer's Disease Model Mice.

Clearance of amyloid ß (Aß) by immunotherapy is one of the fancy methods to treat Alzheimer's disease (AD). However, the failure of some clinical trials suggested that there may be something ignored in the past development of immunotherapy. Pyroglutamate-3 Aß (AßpE3-X), which was found to be abundant in the patients' brain, has attracted much attention after the report that AßpE3-42 could serve as a template to exacerbate the aggregation of Aß. In addition, AßpE3-X could not be recognized by the antibodies targeting the N-terminus of Aß, suggesting that AßpE3-X maybe the ignored one. Indeed, passive immunization targeting AßpE3-X has shown some beneficial results, while active immunotherapy has not been extensively studied. In the present study, we designed and synthesized a novel peptide vaccine targeting AßpE3-X, which contains AßpE3-15 as B cell epitope and P2 as T cell epitope. We showed that this vaccine could induce strong antibody response to AßpE3-X. We also showed that prophylactic immunization of AD model mice with our vaccine could reduce Aß plaques and rescue cognitive decline. This new kind of Aß vaccine will open up new directions for AD immunotherapy.

Norovirus P particle-based active Aß immunotherapy elicits sufficient immunogenicity and improves cognitive capacity in a mouse model of Alzheimer's disease.

Disease-modifying immunotherapies focusing on reducing amyloid-beta (Aß) deposition are the main treatment for Alzheimer's disease (AD). However, none of the Aß immunotherapies has produced clinically meaningful results to date. The main reason for this lack of efficacy is that the vaccine induces insufficiently high antibody titers, as it contains small B-cell epitope of Aß to avoid Aß42-specific T-cell activation. With the aim of generating a potent AD vaccine, we designed the protein PP-3copy-Aß1-6-loop123, comprising three copies of Aß1-6 inserted into three loops of a novel vaccine platform, the norovirus P particle, which could present Aß at its surface and remarkably enhance the immunogenicity of the vaccine. We demonstrated that PP-3copy-Aß1-6-loop123 was able to elicit high antibody titers against Aß42, without causing T-cell activation, in AD mice regardless of their age. Importantly, PP-3copy-Aß1-6-loop123 treatment successfully reduced amyloid deposition, rescued memory loss, and repaired hippocampus damage in AD mice. The Aß antibodies induced by this active immunotherapy reacted with and disrupted aggregated Aß, reducing its cellular toxicity. In addition, our results suggested PP-3copy-Aß1-6-loop123 immunization could restore Aß42 homeostasis in both the serum and brain. Thus, the P particle-based Aß epitope vaccine is a sufficiently immunogenic and safe immunotherapeutic intervention for Alzheimer's disease.

Rejecting the Alzheimer's disease vaccine development for the wrong reasons.

The development of amyloid ß (Aß) vaccines for Alzheimer's disease (AD) has consistently failed clinically, an outcome that is assumed to result from flaws in the proposed role of Aß as the crucial causative agent of this disease. This opinion resulted in this research approach being disregarded, yet, review of the development of these vaccines indicates that they are more suited to transgenic mice, which is unsurprising given that these animal models were used to determine the efficacy of these vaccines, and that the approach overlooked research findings relevant to AD vaccines. Hence, new strategies using new immunogens and anti-inflammatory adjuvants mimicking the natural protective immunity against AD should be implemented to develop effective preventive vaccines.

Active immunization with the peptide epitope vaccine Aß3-10-KLH induces a Th2-polarized anti-Aß antibody response and decreases amyloid plaques in APP/PS1 transgenic mice.

Active amyloid-ß (Aß) immunotherapy is effective in preventing Aß deposition, facilitating plaque clearance, and improving cognitive functions in mouse models of Alzheimer's disease (AD). Developing a safe and effective AD vaccine requires a delicate balance between inducing adequate humoral immune responses and avoiding T cell-mediated autoimmune responses. In this study, we designed 2 peptide epitope vaccines, Aß3-10-KLH and 5Aß3-10, prepared respectively by coupling Aß3-10 to the immunogenic carrier protein keyhole limpet hemocyanin (KLH) or by joining 5 Aß3-10 epitopes linearly in tandem. Young APP/PS1 mice were immunized subcutaneously with Aß3-10-KLH or 5Aß3-10 mixed with Freund's adjuvant, and the immunopotencies of these Aß3-10 peptide vaccines were tested. Aß3-10-KLH elicited a robust Th2-polarized anti-Aß antibody response and inhibited Aß deposition in APP/PS1 mice. However, 5Aß3-10 did not induce an effective humoral immune response. These results indicated that Aß3-10-KLH may be a safe and efficient vaccine for AD and that conjugating the antigen to a carrier protein may be more effective than linking multiple peptide antigens in tandem in applications for antibody production and vaccine preparation.

Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-ß B-cell epitope chimeric protein as subunit vaccine.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. The neuropathological features of the disease include senile plaques (SPs), neurofibrillary tangles (NFTs) and neuronal loss in affected brain regions. The amyloid cascade hypothesis suggests that production and accumulation of excessive amyloid-ß (Aß) may be the main cause in the onset and progression of Alzheimer's disease. Active and passive immunotherapy targeting Aß may be the most promising strategy to prevent or treat AD. This commentary focuses on the prophylactic immunotherapy of Alzheimer's disease using recombinant Aß B-cell epitope chimeric protein as subunit vaccine targeting amyloid-ß. We discuss the efficiency and perspective of this type of recombinant subunit protein vaccine and suggest a novel direction on the path to a successful AD immunotherapy. This novel chimeric protein immunogen as subunit vaccine of AD may be designed to mimic the assembly states of Aß42 or oligomers using multivalent foldable Aß1-15 (B cell epitopes of Aß42) and foreign T helper (Th) epitopes (as the T cell epitopes of Aß42) constructs.

Immunotherapy targeting pyroglutamate-3 Aß: prospects and challenges.

Immunization against amyloid-ß (Aß) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer's patients is challenging. In recent years, a number of promising Aß immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aß peptides enabling the study of the toxic potential of each of the major forms. One such form, amino-terminally truncated and modified pyroglutamate (pGlu)-3 Aß peptide appears to play a seminal role for disease initiation, qualifying it as novel target for immunotherapy approaches.

Alzheimer's disease Advax(CpG)- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aß pathological molecules.

Although ß-amyloid (Aß) may be the primary driver of Alzheimer's disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aß and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aß (AV-1959R), Tau (AV-1980R) or Aß/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax(CpG), delta inulin, Alhydrogel(®), Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in Advax(CpG) induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with Advax(CpG) induced robust antibody responses against various forms of both, Aß and tau pathological molecules. While anti-Aß antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with Advax(CpG) adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials.

A retrospective analysis of the Alzheimer's disease vaccine progress - The critical need for new development strategies.

The promising results obtained with aducanumab and solanezumab against Alzheimer's disease (AD) strengthen the vaccine approach to prevent AD, despite of the many clinical setbacks. It has been problematic to use conjugated peptides with Th1/Th2 adjuvants to induce immune responses against conformational epitopes formed by Aß oligomers, which is critical to induce protective antibodies. Hence, vaccination should mimic natural immunity by using whole or if possible conjugated antigens, but biasing the response to Th2 with anti-inflammatory adjuvants. Also, selection of the carrier and cross-linking agents is important to prevent suppression of the immune response against the antigen. That certain compounds having phosphorylcholine or fucose induce a sole Th2 immunity would allow antigens with T-cell epitopes without inflammatory autoimmune reactions to be used. Another immunization method is DNA vaccines combined with antigenic ones, which favors the clonal selection and expansion of high affinity antibodies needed for immune protection, but this also requires Th2 immunity. Since AD transgenic mouse models have limited value for immunogen selection as shown by the clinical studies, screening may require the use of validated antibodies and biophysical methods to identify the antigens that would be most likely recognized by the human immune system and thus capable to stimulate a protective antibody response. To induce an anti-Alzheimer's disease protective immunity and prevent possible damage triggered by antigens having B-cell epitopes-only, whole antigens might be used; while inducing Th2 immunity with sole anti-inflammatory fucose-based adjuvants. This approach would avert a damaging systemic inflammatory immunity and the suppression of immunoresponse against the antigen because of carrier and cross-linkers; immune requirements that extend to DNA vaccines.