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.

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.

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.

Active full-length DNA Aß42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology.

BACKGROUND: Alzheimer's disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-ß peptide 1-42 (Aß42) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. METHODS: Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA Aß42 immunotherapy were compared with brains from age- and gender-matched transgenic Aß42 peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. RESULTS: Quantitative ELISA showed a 40% reduction of Aß42 peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA Aß42 trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aß peptide reductions in the brain were due to the anti-Aß antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aß in the brain resulting in less tau kinase activation. CONCLUSIONS: The significance of these findings is that DNA Aß42 trimer immunotherapy targets two major pathologies in AD-amyloid plaques and neurofibrillary tangles-in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active Aß42 peptide immunization in patients with AD (AN1792).

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.

Downregulated apoptosis and autophagy after anti-Aß immunotherapy in Alzheimer's disease.

Aß immunization of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aß removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aß immunization, we have assessed the impact of previous Aß immunization on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunized with AN1792 (iAD) and from 27 nonimmunized AD (cAD) cases was immunolabeled for proapoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3ß on tyrosine 216 (GSK3ßtyr216 ), p53 and Cdk5/p35. Expression of these proteins was analyzed in relation to immunization status and other clinical data. The antigen load of all of these proapoptotic proteins was significantly lower in iAD than cAD (P < 0.0001). In cAD, significant correlations (P < 0.001) were observed between: Cdk5/p35 and GSK3ßtyr216 ; a-casp3 and Aß42 ; p53 and age at death. In iAD, significant correlations were found between GSK3ßtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aß42 ; and Cdk5/p35 and Aß-antibody level. Although neuronal loss was increased by immunization with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.

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.

Immunization of Tg-APPswe/PSEN1dE9 mice with Aß3-10-KLH vaccine prevents synaptic deficits of Alzheimer's disease.

The amyloid cascade hypothesis is widely accepted by researchers as the mechanism of Alzheimer's disease. Active immunization to eliminate Aß depositions has been used in preclinical and clinical studies. Aß3-10-KLH is a vaccine of the Aß3-10 peptide combined with keyhole limpet hemocyanin (KLH). We immunized 2.5-month-old Tg-APPswe/PSEN1dE9 mice with Aß3-10-KLH peptide and Aß1-42 peptide to eliminate Aß deposits in the brains of these transgenic mice. The results of immunohistochemical staining and transmission electron microscopy detection indicated that our new vaccine was more advantageous in protecting synaptic function and structure than the Aß1-42 peptide. Aß3-10-KLH peptide is an effective vaccine in the treatment of Alzheimer's disease.

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.

A novel recombinant 6Aß15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer's disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-ß (Aß) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aß15-THc-C immunogen was formulated with alum adjuvant as a novel Aß B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aß-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aß or oligomeric forms of Aß, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aß levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aß-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine.

A Novel Aß B-Cell Epitope Vaccine (rCV01) for Alzheimer's Disease Improved Synaptic and Cognitive Functions in 3 × Tg-AD Mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive amyloid-ß accumulation, loss of cognitive abilities, and synaptic alterations. Given the remarkable recovery of cognition in AD models of targeting-Aß immunotherapy, we sought to determine the molecular correlate(s) associated with improvement. We evaluated the efficacy of a recombinant chimeric 6Aß15-T antigen formulated with alum adjuvant as a novel Aß B-cell epitope vaccine (rCV01) in 3 × Tg-AD mice. rCV01 elicited robust Th2-polarized Aß-specific antibodies without autoimmune T cell responses in 3 × Tg-AD mice. The long-lasting anti-Aß42 antibodies were associated with markedly reduced AD-like pathology, enhanced synaptic function, and improved cognitive performance in aged 3 × Tg-AD mice. This is the first report to provide one hypothesis for the improved outcomes following vaccination is a reduction in the levels of active calpain in rCV01-immunized AD mice, which is likely attributable to preventing dynamin 1 and PSD-95 degradation allowing functional recovery of cognition. rCV01 is a highly immunogenic recombinant chimeric 6Aß15-T vaccine that shows clear neuroprotective properties in preclinical mouse models of AD and is a candidate for an effective AD vaccine.

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.

Alzheimer's Disease therapeutics: current and future therapies.

Pathologically, Alzheimer's Disease is characterized by amyloidal protein plaques that lead to dementia in the elderly population. While advances have been made in therapeutics over the course of the last 20 years, the drugs generally target the symptoms rather than the underlying pathology. Unfortunately, despite the advances, the mechanisms behind Alzheimer's Disease have still not been clearly identified. Some of these current treatments include acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonists. Recently, the pathophysiology behind this disease is becoming more clearly understood and this has led to some novel therapeutic targets that may be able to break the barrier and target the underlying disease. In this review, we will discuss Alzheimer's Disease pathology and the pharmacological therapy that has been in use for a long time as well as novel therapies.

Validating Immunotherapy in Alzheimer's Disease: The EB101 Vaccine.

Vaccination has become one of the most promising immunotherapeutic approaches in the prevention and treatment of Alzheimer's disease (AD) and related neuropathological hallmarks. Numerous immunotherapeutic interventions have attempted to achieve adaptive immunity against Aß with a range of different antigenic designs and immunomodulatory strategies, most of them with great success in AD mouse model studies. Most of these studies have shown that both active and passive immunization can drastically reduce amyloid deposition and prevent the decline in cognitive performance. New approved clinical trials are under investigation to test the effectiveness of those different vaccination approaches, although previous data showed modest clinical success with some adverse inflammatory events in immunized elderly patients. The search for new approaches to overcome these severe side effects has led to novel technical methods such as live vector or DNA vaccines, although the use of innovative adjuvants combined with selected amyloid peptides is among the most auspicious. In this review, we compare and discuss the past and contemporary vaccines and the future strategies that may lead to a viable improvement in AD prevention and treatment.

An anti-pyroglutamate-3 Aß vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice.

Pyroglutamate-3 amyloid-beta (pGlu-3 Aß) is an N-terminally truncated Aß isoform likely playing a decisive role in Alzheimer's disease pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aß immunoglobulin G1 (IgG1) monoclonal antibody, 07/1 (150 and 500 µg, intraperitoneal, weekly) and compare its efficacy with a general Aß IgG1 monoclonal antibody, 3A1 (200 µg, intraperitoneal, weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type levels in 2 hippocampal-dependent tests and partially spared compared with phosphate-buffered saline-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast with 3A1, treatment with 07/1 did not increase the concentration of Aß in plasma, suggesting different modes of Aß plaque clearance. In conclusion, early selective targeting of pGlu-3 Aß by immunotherapy may be effective in lowering cerebral Aß plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically modified form of Aß thereby is unlikely to interfere with potential physiologic function(s) of Aß that have been proposed.

Autophagy is involved in oral rAAV/Aß vaccine-induced Aß clearance in APP/PS1 transgenic mice.

The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targeting Aß clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.

4Aß1-15-Derived Monoclonal Antibody Reduces More Aß Burdens and Neuroinflammation than Homologous Vaccine in APP/PS1 Mice.

The common pathological hallmark of Alzheimer's disease (AD) is ß-amyloid plaque deposition. The ideal therapy would reduce the Aß burden with a low inflammatory immune response. Passive immunotherapy is an advanced treatment that dramatically reduces brain Aß pathologies in AD animal models. The objective of our study was to observe the effects of 5C8H5, a novel monoclonal antibody derived from 4Aß1-15, on brain Aß pathology in an APP/PS1 mouse model of AD. Six-month-old transgenic mice were administered 5C8H5, 4Aß1-15 or IgG, and same-aged wild-type untreated C57Bl/6J mice were employed as controls. Inflammatory factors and Aß40/42 levels were detected by ELISA, while Aß plaques, microglial cell activation, microhemorrhages and neurogenesis were evaluated by immunohistochemical staining. Compared with 4Aß1-15-treated mice, the mice in the 5C8H5 group induced more Aß clearance with less microglial cell activation in a niche of Th2-polarized immune response. The levels of proinflammatory factors, including IL-1ß, IL-6, TNF-α and IFN-γ, were significantly decreased in the CNS, while the level of antiinflammatory IL-4 was increased. Moreover, the mice in the 5C8H5 group induced more neurogenesis without microhemorrhage exacerbation and thereby performed better in behavioral assays than did the 4Aß1-15 group. In conclusion, the novel monoclonal antibody induces more Aß clearance and less microglial cell activation in the absence of inflammation, accompanied by an increased Th2-polarized immune response, which makes it a more promising therapeutic strategy. These data provide evidence that passive immunity could alleviate pathologic Aß alterations by modulating inflammation and should be pursued further for the treatment of AD.

Oral administration of a fusion protein between the cholera toxin B subunit and the 42-amino acid isoform of amyloid-ß peptide produced in silkworm pupae protects against Alzheimer's disease in mice.

A key molecule in the pathogenesis of Alzheimer's disease (AD) is a 42-amino acid isoform of the amyloid-ß peptide (Aß42), which is the most toxic element of senile plaques. In this study, to develop an edible, safe, low-cost vaccine for AD, a cholera toxin B subunit (CTB)-Aß42 fusion protein was successfully expressed in silkworm pupae. We tested the silkworm pupae-derived oral vaccination containing CTB-Aß42 in a transgenic mouse model of AD. Anti-Aß42 antibodies were induced in these mice, leading to a decreased Aß deposition in the brain. We also found that the oral administration of the silk worm pupae vaccine improved the memory and cognition of mice, as assessed using a water maze test. These results suggest that the new edible CTB-Aß42 silkworm pupae-derived vaccine has potential clinical application in the prevention of AD.

Alzheimer disease immunotherapeutics: then and now.

Dementia is a public health priority and one of the major contributors to morbidity and global non-communicable disease burden, thus necessitating the need for significant health-care interventions. Alzheimer disease (AD) is the most common cause of dementia and may contribute to 60-70% of cases. The cause and progression of AD are not well understood but have been thought to be due at least in part to protein misfolding (proteopathy) manifest as plaque accumulation of abnormally folded ß-amyloid and tau proteins in brain. There are about 8 million new cases per year. The total number of people with dementia is projected to almost double every 20 years, to 66 million in 2030 and 115 million in 2050. Immunotherapy in AD aimed at ß-amyloid covers 2 types of vaccination: active vaccination against Aß42 in which patients receive injections of the antigen itself, or passive vaccination in which patients receive injections of monoclonal antibodies (mAb) against Aß42. Three of the peptide vaccines for active immunizations, CAD106, ACC001, and Affitope, are in phase 2 clinical trials. Three of the mAbs solanezumab, gantenerumab, and crenezumab, are or were in phase 2 and 3 clinical studies. While the phase 3 trials failed, one of these may have shown a benefit at least in mild forms of AD. There is a need for a greater initiative in the development of immunotherapeutics. Several avenues have been explored and still to come.