Abeta42 immunization in Alzheimer's disease generates Abeta N-terminal antibodies

Serum samples from Alzheimer's disease (AD) patients immunized with Abeta42 (AN1792) were analyzed to determine the induced antibody properties including precise amyloid-beta peptide (Abeta) epitopes and amyloid plaque-binding characteristics. The predominant response in these patients is independent of whether or not meningoencephalitis developed and is against the free amino terminus of Abeta. The immunostaining of amyloid plaques in brain tissue by patient sera is adsorbable by a linear Abeta1-8 peptide, demonstrating that the antibodies are directed predominantly to this epitope and not dependent on Abeta conformations or aggregates specific to plaques. Furthermore, the antibodies are not capable of binding amyloid precursor protein and would be predicted to be competent in facilitating clearance of amyloid plaques in AD brains.     

Immunotherapy of Alzheimer's disease. Results of experimental investigations and treatment of perspectives

This review discusses the molecular basis and current status of immunotherapeutic strategies for prevention and treatment of Alzheimer's disease (AD). From the molecular view-point AD belongs to the group of conformational diseases. In-vitro studies demonstrated that monoclonal antibodies could modulate the conformation of Abeta peptides with subsequent inhibition of amyloid fibrils formation and aggregation. The efficacy of this approach was then successfully proved in the murine models of AD using predominantly Abeta (42) peptide as immunogen. Immunisation of the young animals essentially prevented the development of beta-amyloid plaques formation and of concomittant neuropathology. Treatment of the older animals markedly reduced the pre-existing AD-like neuropathology. Immunisation was capable of preventing cognitive deficits in the young transgenic animals and improve the memory and behavioural disturbances in the older animals. Measurement of specific murine immunoglobulines in Abeta-vaccinated mice demonstrated a predominant IgG1 and IgG2b isotypes, suggesting a type 2 (T (H)2) T-helper cell immune response, which drives humoral immunity. The intensity of the immune response depended on transgenic animals genotype, dose, frequency and route of immunogen administration. The mechanism of antibodies action in transgenic animals consists of inducing conformational and solubility changes in Abeta peptides as well as their peripheral sink. Lymphocyte proliferation assays using Abeta peptides and splenocytes from vaccinated mice demonstrated that vaccine specifically stimulated T-cell epitopes present within the Abeta-peptide. Extensive quantitative morphological, histochemical and molecular analysis of brain tissue from several species of Abeta-immunised transgenic and non-transgenic animals showed no evidence of autoimmune reaction, complement activation or cross-reaction. No pathological changes were found in all other organs, including the kidney. Neuropathologic examination in a patient treated with vaccine revealed similar vaccination effects as in experimental animals. An aseptic meningo-encephalitis was reported in 5 % of patients included in a clinical trial in which a vaccine containing Abeta (42) peptide (AN1792) was administered intramuscularly. The causal relationship to the vaccine administration cannot be excluded since in transgenic mice a transient microglia activation was seen. However, this relatively infrequent although severe adverse effect points to a possible participation of some actually unknown risk factors in the treated patients. With regard to the rapid progress in biotechnology, especially in the vaccines technology, the development of efficacious and safe immunogens as well as of new vaccination techniques for immuntherapy of AD can be expected in the next future.     

Immunotherapy as treatment for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the deposition of beta-amyloid (A beta)-containing extracellular neuritic plaques, intracellular neurofibrillary tangles and neuronal loss. Much evidence supports the hypothesis that A beta peptide aggregation contributes to AD pathogenesis, however, currently approved therapeutic treatments do nothing to stop or reverse A beta deposition. The success of active and passive anti-A beta immunotherapies in both preventing and clearing parenchymal amyloid in transgenic mouse models led to the initiation of an active anti-A beta vaccination (AN1792) trial in human patients with mild-to-moderate AD, but was prematurely halted when 6% of inoculated patients developed aseptic meningoencephalitis. Autopsy results from the brains of four individuals treated with AN1792 revealed decreased plaque burden in select brain areas, as well as T-cell lymphocytes in three of the patients. Furthermore, antibody responders showed some improvement in memory task measures. These findings indicated that anti-A beta therapy might still be a viable option for the treatment of AD, if potentially harmful proinflammatory processes can be avoided. Over the past 6 years, this target has led to the development of novel experimental immunization strategies, including selective A beta epitope targeting, antibody and adjuvant modifications, as well as alternative routes and mechanisms of vaccine delivery, to generate anti-A beta antibodies that selectively target and remove specific A beta species without evoking autoimmunity. Results from the passive vaccination AD clinical trials that are currently underway will provide invaluable information about both the effectiveness of newly improved anti-A beta vaccines in clinical treatment, as well as the role of the A beta peptide in the pathogenesis of the disease.     

Immunotherapy for Alzheimer's disease

Recent studies in murine models of Alzheimer's disease (AD) have found that active immunisation with amyloid-beta peptide (Abeta) or passive immunisation with Abeta antibodies can lessen the severity of Abeta-induced neuritic plaque pathology through the activation of microglia. These antibodies can be detected in the serum and CSF. Whether they slow down or speed up the development and progression of AD has not been determined. Furthermore, the conditions that induce formation of such antibodies are unknown, or how specific they are to AD. However, the evidence suggests at least a potential beneficial role for some features of neuroinflammation in AD. A clinical phase II study of an active immunisation approach with AN1792 was started in 2001, but was recently suspended after some patients developed serious adverse events. These were most likely caused by the activation of the proinflammatory cascade. Immunotherapy approaches represent fascinating ways to test the amyloid hypothesis and may offer genuine opportunities to modify disease progression. This review focuses on immunisation strategies and details of the pathways involved in antibody clearance of Abeta.     

A novel recombinant adeno-associated virus vaccine reduces behavioral impairment and beta-amyloid plaques in a mouse model of Alzheimer's disease

Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). Deposition of the amyloid-beta peptide (Abeta) in brain, particularly its 42-amino acid isoform (Abeta42), has been shown to play a primary and crucial role in the pathogenesis of AD. In this study we have developed a recombinant adeno-associated virus (AAV) vaccine against AD. This vaccine could express CB-Abeta42 (cholera toxin B subunit and Abeta42 fusion protein) in vivo. A single administration of the AAV-CB-Abeta42 vaccine induced a prolonged, strong production of Abeta-specific serum IgG in transgenic mice that overexpressed the London mutant of amyloid precursor protein (APP/V717I), and resulted in improved ability of memory and cognition, decreased Abeta deposition in the brain, and a resultant decrease in plaque-associated astrocytosis. Our results extended the immunological approaches for the treatment and prevention of AD to an oral, intranasal, or intramuscular route that might be better tolerated in human patients than repetitive parental immunizations in the presence of adjuvant. AAV has attracted tremendous interest as a promising vector for gene delivery. Our results raised the possibility that AAV-CB-Abeta42 vector immunization may provide the basis of a novel and promising Alzheimer's disease vaccination program.     

Vaccination of Alzheimer's model mice with adenovirus vector containing quadrivalent foldable Abeta(1-15) reduces Abeta burden and behavioral impairment without Abeta-specific T cell response

Active amyloid beta (Abeta) vaccination has been shown to be effective in clearing cerebral Abeta and improving cognitive function in mouse models of Alzheimer's disease (AD). The meningoencephalitis observed in AD vaccination trial was likely related to excessive T cell-mediated immunity caused by the immunogen Abeta(1-42). To avoid this toxicity, previous researchers have been using synthetic truncated Abeta derivatives that promote humoral immunity. In this study, we develop a novel adenovirus vaccine, which can express quadrivalent foldable Abeta(1-15) (4xAbeta(15)) and gene adjuvant GM-CSF in vivo. Importantly, the 4xAbeta(15) sequence includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. The 4xAbeta(15) adenovirus vaccine induces an Abeta-specific IgG1 predominant humoral immune response, and reduces brain Abeta deposition and cognition deficits in Tg2576 mice. Detection of IL-4 and IFN-gamma in restimulated splenocytes shows a significant Th2-polarized immune response. Stimulation of splenocytes with 4xAbeta(15) peptides results in robust proliferative responses, whereas proliferation is absent after stimulation with full-length Abeta, which indicates that the 4xAbeta(15) adenovirus vaccine does not induce Abeta-specific T cellular immune response. Thus, our results raise the possibility that adenovirus vector encoding 4xAbeta(15) would be a promising candidate for future AD vaccination program.     

Deglycosylated anti-amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration

Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.     

What is the dominant aβ species in human brain tissue? A review

Interest in the beta amyloid (Abeta) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer's disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Abeta peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer's disease impact on Abeta production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Abeta in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Abeta production and clearance that may assist with better treatment design and delivery. Abeta40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Abeta under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Abeta40 are low with Abeta42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Abeta40 compared with Abeta42, findings which may have been predicted by their physiochemical differences. In Alzheimer's disease this equilibrium is disrupted significantly increasing Abeta peptide levels in brain tissue. The disease-specific increase in Abeta40 brain tissue levels in Alzheimer's disease appears to be an important though overlooked pathological change compared with the well-documented Abeta42 change observed both in the aged and in Alzheimer's disease. These findings are discussed in association with Abeta peptide function and a model of toxicity developed.     

Amyloid beta peptide as a vaccine for Alzheimer's disease involves receptor-mediated transport at the blood-brain barrier.

Much research is now focused on a potential vaccine for Alzheimer's disease (AD). Current studies involve administering the amyloid beta peptide (Abeta) in Freund's complete adjuvant, which cannot be used in humans. Our studies show that the immune complex of Abeta is taken up by a receptor-mediated process at the blood-brain barrier (BBB). The success of immunization for AD, therefore, may be critically dependent on circulating Abeta levels which are lower in AD patients compared to AD transgenic mice. Moreover, we have found that modifying the antibody with polyamine increases its BBB permeability and may provide a better approach to passive immunization for Alzheimer's disease.     

Development of a safe oral Abeta vaccine using recombinant adeno-associated virus vector for Alzheimer's disease

A new oral vaccine for Alzheimer's disease was developed using recombinant adeno-associated virus vector carrying Abeta cDNA (AAV/Abeta). Oral administration of the vaccine without adjuvant induced the expression and secretion of Abeta1-43 or Abeta1-21 in the epithelial cell layer of the intestine in amyloid precursor protein transgenic mice. Serum antibody levels were elevated for more than six months, while T cell proliferative responses to Abeta was not detected. Brain Abeta burden was significantly decreased compared to the control without inflammatory changes. This oral AAV/Abeta vaccine seems to be promising for prevention and treatment of Alzheimer's disease.     

Perspective of dementia therapy]

As growing population of the elderly over 65 years of age, dementia will be one of the most important diseases in Japan. To defeat the dementia, the following strategies would be needed; 1) acceleration of basic research for dementia, 2) acceleration of clinical research for dementia, 3) development of care system for patients with dementia, and 4) provision of social basis for the elderly. On the basis of an understanding of the pathophysiology, treatments of Alzheimer's disease includes the following components: antiamyloid therapies including secretase inhibitors, metal binding agents and Abeta vaccine, neuroprotective strategies, cholinesterase inhibitors, memantine, immunotherapy including Abeta vaccine, anti-inflammatory therapy, hormone-replacement therapy, psychopharmacologic agents, nonpharmacologic interventions and health maintenance activities, and an alliance between clinicians and family members and other caregivers responsible for the patient. The combination therapies with pharmacologic and nonpharmacologic components are probably useful for patients with Alzheimer disease or other dementia. In addition, development of accurate diagnostic methods of dementia and the early detection system of amyloid in the brain are expected. Responsibility of neurologist for dementia is getting important next 10 years in Japan.     

BACE inhibitors as potential therapeutics for Alzheimer's disease

Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Abeta production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.     

The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease

beta-Amyloid (Abeta) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing Abeta deposition is a goal of drug therapy for AD, because excessive amounts of Abeta may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited Abeta secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective M1 agonist AF102B to 19 AD patients and measured total Abeta (Abeta(total)) levels in cerebrospinal fluid (CSF) before and during treatment. Abeta(total) levels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in Abeta(total) levels in CSF during treatments in separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti-inflammatory drug hydroxychloroquine. CSF Abeta(total) levels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces Abeta levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long-term therapeutic benefits by lowering amyloid in AD.     

CD40L disruption enhances Abeta vaccine-mediated reduction of cerebral amyloidosis while minimizing cerebral amyloid angiopathy and inflammation

Amyloid-beta (Abeta) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active Abeta immunization has also yielded favorable results in a subset of AD patients. However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells. We have shown that blocking the CD40-CD40 ligand (L) interaction mitigates Abeta-induced inflammatory responses and enhances Abeta clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40-CD40L blockade could enhance the efficacy of Abeta(1-42) immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40-CD40L interaction enhanced Abeta(1-42) immunization efficacy to reduce cerebral amyloidosis in the PSAPP and Tg2576 mouse models of AD. Potentially deleterious pro-inflammatory immune responses, cerebral amyloid angiopathy (CAA) and cerebral microhemorrhage were reduced or absent in these combined approaches. Pharmacologic blockade of CD40L decreased T-cell neurotoxicity to Abeta-producing neurons. Further reduction of cerebral amyloidosis in Abeta-immunized PSAPP mice completely deficient for CD40 occurred in the absence of Abeta immunoglobulin G (IgG) antibodies or efflux of Abeta from brain to blood, but was rather correlated with anti-inflammatory cytokine profiles and reduced plasma soluble CD40L. These results suggest CD40-CD40L blockade promotes anti-inflammatory cellular immune responses, likely resulting in promotion of microglial phagocytic activity and Abeta clearance without generation of neurotoxic Abeta-reactive T-cells. Thus, combined approaches of Abeta immunotherapy and CD40-CD40L blockade may provide for a safer and more effective Abeta vaccine.     

Assessment of the bioactivity of antibodies against beta-amyloid peptide in vitro and in vivo

The accumulation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). Abeta removal from the brain by immune therapy shows promising potential for the treatment of patients with AD, although the mechanisms of the antibody action are incompletely understood. In this study we compared the biological activities of antibodies raised against various Abeta fragments for Abeta reduction in vitro and in vivo. Antibodies against Abeta enhanced the uptake of Abeta42 aggregates up to 6-fold by primary microglial cells in vitro. The kinetics of Abeta42 uptake varied considerably among antibodies. Based on the activity to mediate Abeta42 uptake by microglial cells, we identified a bioactive antibody that significantly reduced Abeta42 levels in the brains of transgenic mice with neuronal expression of an AD-related mutated amyloid precursor protein. This effect depended on the epitopes recognized by the antibody. Our data suggest that the ability to facilitate Abeta42 uptake by primary microglia cells in vitro can be used to predict the biological activity of the antibody by passive immunization in vivo. This protocol may prove useful for the rapid validation of the activity of antibodies designed to be used in immune therapy of AD.     

Down-regulation of insulin-degrading enzyme by presenilin 1 V97L mutant potentially underlies increased levels of amyloid beta 42

Amyloid beta (Abeta)42 plays a pivotal role in Alzheimer's disease. We previously reported a novel presenilin (PS)1 mutant (V97L) that was expressed in related patients with early onset Alzheimer's disease. We found that patients with the V97L mutation had increased levels of extracellular and intracellular Abeta42. Here we found that the increased extracellular level of Abeta42 was always accompanied by a reduction of insulin-degrading enzyme (IDE) activity on the plasma membranes. However, increase of intracellular Abeta42 was associated with decreased expression and activity of IDE in the cytosol and endoplasmic reticulum in the PS1 V97L mutant-transfected human SH-SY5Y cell line. These studies indicate that pathological levels of Abeta42 may be caused by the negative effects of PS1 (V97L) on IDE expression and activity. Our findings provide evidence for the molecular basis of familial Alzheimer's disease pathogenesis.     

缺陷腺病毒载体表达重复10次的Aβ3-10基因疫苗鼻黏膜免疫APPswe, PSEN1dE9转基因小鼠可诱导出Th2型免疫反应

Immunotherapy for Alzheimer’s disease (AD) is effective in improving cognitive function in transgenic mouse models of AD. Because the AN1792 [beta-amyloid (Aβ) 1-42] vaccine was halted because of T cell mediated meningoencephalitis, many scientists are searching for a novel vaccine to avoid the T cell mediated immune response caused by the Aβ1-42. Importantly, the time when the immunization is begun can influence the immune effect. In this study, an adenovirus vaccine was constructed containing 10 × Aβ3-10 repeats and gene adjuvant CpG DNA. Transgenic AD mice were immunized intranasally for 3 months. After 10 × Aβ3-10 vaccine immunization, high titers of anti-Aβ42 IgG1 predominant antibodies were induced. In spatial learning ability and probe tests, the 10 × Aβ3-10 immunized mice showed significantly improved memories compared to control mice. The 10 × Aβ3-10 vaccine resulted in a robust Th2 dominant humoral immune response and reduced learning deficits in AD mice. In addition, the 10 × Aβ3-10 vaccine might be more efficient if administered before Aβ aggregation at an early stage in the AD mouse brain. Thus, the adenovirus vector encoding 10 × Aβ3-10 is a promising vaccine for AD.     

Interaction of amyloid binding alcohol dehydrogenase/Abeta mediates up-regulation of peroxiredoxin II in the brains of Alzheimer's disease patients and a transgenic Alzheimer's disease mouse model

Alzheimer's patients have increased levels of both the 42 beta amyloid-beta-peptide (Abeta) and amyloid binding alcohol dehydrogenase (ABAD) which is an intracellular binding site for Abeta. The over-expression of Abeta and ABAD in transgenic mice has shown that the binding of Abeta to ABAD results in exaggerating neuronal stress and impairment of learning and memory. From a proteomic analysis of the brains from these animals we identified that peroxiredoxin II levels increase in Alzheimer's diseased brain. This increase in peroxiredoxin II levels protects neurons against Abeta induced toxicity. We also demonstrate, for the first time in living animals, that the expression level of peroxiredoxin II is an indicator for the interaction of ABAD and Abeta as its expression levels return to normal if this interaction is perturbed. Therefore this indicates the possibility of reversing changes observed in Alzheimer's disease and that the Abeta-ABAD interaction is a suitable drug target.     

Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity

Niemann-Pick type C disease is a neurovisceral storage disorder. Neurofibrillary tangles similar to those in Alzheimer's disease have been reported in most juvenile/adult patients without amyloid beta protein (Abeta) deposits. Recently, we found deposits of Abeta in the form of diffuse plaques in three (31- and 32-year-old sisters and a 37-year-old man) of nine Niemann-Pick type C disease patients, who presented with most severe tauopathy and with numerous neurofibrillary tangles. Abeta deposits were not detected in any of the control brains of patients younger than age 42 years. These three patients with Abeta deposit all were homozygotes of apolipoprotein E epsilon 4. Our study suggested that NPC1 gene mutations combined with homozygosity of apolipoprotein E epsilon 4 alleles could manifest neuropathology similar to that of Alzheimer's disease. Investigation of these patients may provide an important clue for understanding the pathogenesis of Alzheimer's disease.     

Anti-β-amyloid immunotherapy for Alzheimer's disease: focus on bapineuzumab

Recent advances in our understanding of the neurobiology of Alzheimer's disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain β-amyloid (Aβ) via anti-Aβ antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-Aβ immunotherapies of clearing Aβ deposits from the brain of the AD patients. An active anti-Aβ vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on bapineuzumab will tell us if passive anti-Aβ immunization is able to alter the course if this devastating disease.