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NEWS & VIEWSALZHEIMER DISEASE

Lessons from immunotherapy for Alzheimer diseaseYan-Jiang Wang

Amyloid-β (Aβ) is suggested to have a pivotal role in the pathogenesis of Alzheimer disease (AD) and is a major therapeutic target. Recent phase III trials of the anti-Aβ monoclonal antibodies bapineuzumab and solanezumab, which failed to improve cognitive function in patients, provide valuable insights for the future development of immunotherapies.Wang, Y.‑J. Nat. Rev. Neurol. advance online publication 18 March 2014; doi:10.1038/nrneurol.2014.44

Alzheimer disease (AD) is the most common age-related dementia and affects 35.6 million people worldwide; however, no disease-modifying treatments are currently available. Amyloid-β (Aβ) is generated from the cleavage of amyloid precursor protein (APP) and is thought to have a vital role in the pathogenesis of AD. Over the past two decades, therapies have been developed to remove Aβ plaques, inhibit Aβ aggregation and deposition, or reduce the production of Aβ in the brain via inhibition of γ-secretase and β-secretase. All of these strategies, however, have failed in clinical trials. Recently, phase III trials of two monoclonal antibodies against Aβ, bapineuzumab and solanezumab, failed to significantly improve clinical outcomes in patients with mild to moderate AD.1,2

These failures raise important questions regarding the validity of Aβ as a therapeu-tic target. Neither antibody slowed cogni-tive or functional decline as assessed with the AD Assessment Scale and the Disability Assessment for Dementia scores. Treatment with bapineuzumab decreased the rate of Aβ deposition, as visualized on PET, and reduced the concentration of phosphory-lated tau in cerebrospinal fluid in APOE*ε4 carriers.1 Patients with mild AD treated with solanezumab had marginal but nonsignifi-cant improvements in clinical outcomes;

however, serum Aβ concentrations in these patients were significantly increased, sug-gesting a shift in soluble Aβ from the brain to the periphery.2 Overall, the total Aβ burden was unchanged in patients treated with solanezumab and bapineuzumab, and the antibodies failed to significantly deplete Aβ plaques. Furthermore, in both trials, one-quarter of the patients classified with mild AD had negative amyloid findings on PET, suggesting that they did not have AD. Thus, the benefits of anti-amyloid therapy might not have been adequately tested in these two trials.

Another concern raised by the results of these trials is whether or not the most appropriate antibodies to remove brain Aβ plaques have ever been used. Bapin-euzumab and solanezumab treatment, as shown in these trials, did not result in robust Aβ clearance. Bapineuzumab is a humanized analogue of the murine anti-body 3D6, which targets N-terminal Aβ and recognizes both soluble and insoluble Aβ. In animal experiments, this agent was not effective in removing Aβ plaques owing to saturation of the antibody with soluble Aβ.3 Solanezumab is a humanized analogue of the murine antibody 266, which targets the central domain of Aβ and only recog-nizes soluble Aβ. The 266 antibody slowed Aβ accumulation in the brain but failed to deplete Aβ plaques in animal studies. Moreover, solanezumab is likely to have impeded the efflux of soluble Aβ from the brain in patients owing to the formation of Aβ–antibody complexes in the brain inter-stitial fluid and cerebrospinal fluid, as sug-gested from animal studies.4 In this regard,

only antibodies with robust evidence of removing Aβ plaques should be used for future immunotherapy trials.

The epitope specificity of antibodies against Aβ is crucial to their efficacy, and might be an explanation for the lack of Aβ plaque clearance or cognitive improve-ment when using middle-region-targeting antibodies such as solanezumab, or anti-bodies that target the C-terminus of Aβ. The N-terminal region of Aβ is exposed on the surface of Aβ fibrils, whereas the middle and C-terminal regions of Aβ are ‘masked’ in the fibrils.5 N-terminal anti-bodies, such as bapineuzumab, can recog-nize both soluble and insoluble Aβ, whereas other anti bodies can only target soluble Aβ. N-terminal targeting antibodies may be more appropriate for the removal of Aβ plaques, and might be used for both preven-tion and treatment of AD. Conversely, anti-bodies against the middle and C-terminal regions of Aβ, such as solanezumab, are less effective in plaque clearance and might be more effective in preventing plaque formation.

Any potential immunotherapies for AD raise safety issues and concerns. Amyloid-related imaging abnormalities (ARIA-E) thought to represent vasogenic oedema and sulcal effusions were seen in a dose-dependent manner in patients who received bapineuzumab, but were less frequent in those who received solanezumab. The high incidence of oedema in patients treated with bapineuzumab probably relates to engagement of the antibodies with amyloid plaques in cerebral arterioles.6 ARIA-E might be prevented by prophylactic anti-body therapy against Aβ plaque formation, and/or by more-gradual increases in the antibody dose.

Previous clinical trials have suggested that immunotherapy can lead to other adverse effects such as microhaemor-rhage and neuro inflammation. In addi-tion, there are safety concerns related to

‘‘…therapeutic management might be achieved by targeting AD pathogenesis at different disease stages’’

‘‘…the failures of the phase III trials ... provide valuable lessons for the development of Aβ immunotherapies’’

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NEWS & VIEWS

enhanced neuro toxicity secondary to plaque mobilization- associated Aβ oligomerization, antibody- mediated neuroskeletal damage, and autoimmunity due to cross-reactivity of Aβ antibodies with APP at the neuronal membrane.7 In general, these adverse effects are associated with the entry of antibod-ies against Aβ into the brain. A means to block antibody entry while promoting Aβ efflux by sequestering Aβ in the periphery (peripheral Aβ clearance) might be a safe approach to clear amyloid plaques. A study in mice indicated that increasing the periph-eral sink of Aβ, combined with enhance-ment of Aβ degradation via upregulation of low- density lipoprotein receptor-related protein and neprilysin (also known as membrane metallo endopeptidase) in the liver, was associated with reduced levels of brain Aβ.8 Repeated injections of the enzyme neprilysin, however, have failed to attenuate the burden of brain Aβ in animal models.9 A greater understanding of the underlying mechanisms of peripheral Aβ clearance, which remain largely unknown, might provide important insights for the development of anti-amyloid therapies.

The failures of current and previous trials of immunotherapy suggest that targeting of Aβ alone might not be enough to prevent or slow AD progression, as multiple mecha-nisms are involved in AD patho genesis and their relative contributions might vary at different stages of the disease.10 The current consensus is that anti-amyloid therapies should be given in the early stage of the

disease as a preventative measure. The need exists, however, to develop treatments for patients in late stages of the disease. Successful therapeutic management might be achieved by targeting AD pathogenesis at different disease stages. This approach could entail preventing the production of Aβ, pro-tection of synaptic function and inhibition of tau hyperphosphorylation at the preclini-cal stage; removal of Aβ plaques, protec-tion of synaptic function and neurons, and attenuation of tau hyperphosphorylation at the mild cognitive impairment stage; and, finally, targeting Aβ accumulation, synap-tic dysfunction, tau hyperphosphorylation, neuroinflammation and oxidative stress, as well as providing neuronal protection and cognitive training, at the dementia stage.

In conclusion, the failures of the phase III trials of bapineuzumab and solanezumab provide valuable lessons for the devel-opment of Aβ immunotherapies. Use of appropriate antibodies and specific thera-peutic targets at different stages of the disease might be a promising way to cure or prevent AD in the future.

Department of Neurology, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yu-Zhong District, Chongqing 400042, China. yanjiang_wang@tmmu.edu.cn

AcknowledgementsY.‑J.W. is supported by the National Natural Science Foundation of China (grant numbers 81270423 and 30973144) and the Natural Science Foundation Project of Chongqing Science and Technology

Committee (grant number CSTC2010BA5004). Y.‑J.W. thanks Professors Jun Tan and Brian Giunta at the University of South Florida, USA for critical reading of the paper.

Competing interestsThe author declares no competing interests.

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