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      Efficacy and safety of anti‐amyloid‐ β immunotherapy for Alzheimer's disease: a systematic review and network meta‐analysis

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          Abstract

          To review the optimality and safety of different anti‐Amyloid‐ β(Aβ) immunotherapies for Alzheimer's disease ( AD). Published randomized controlled trials were comprehensively reviewed from electronic databases (Cochrane library, Embase, Pubmed, and Google scholar). Pooled outcomes as mean difference or odds ratio values with 95% confidence interval were reported. The network estimates with confidence and predictive intervals for all pairwise relative effects was evaluated. Optimal intervention was ranked by benefit‐risk ratio based on the surface under the cumulative ranking curve. Eleven eligible RCTs from 9 literatures, including 5141 patients and 5 interventions were included. The quality of evidence was rated low in comparisons. For efficacy, in terms of Mini‐Mental State Examination, aducanumab and solanezumab are significantly effective than placebo. For safety, in terms of Amyloid‐Related Imaging Abnormalities ( ARIA), bapineuzumab and aducanumab are significantly worse than placebo. There were no significant differences in outcomes of Alzheimer's disease Assessment Scale‐Cognitive subscale, Disability Assessment for Dementia, Adverse Events, and mortality. Given the clinical therapeutic effects of anti‐A β immunotherapies for AD, aducanumab and solanezumab improve the cognitive function, while aducanumab and bapineuzumab may increase the risks of ARIA.

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          2015 Alzheimer's disease facts and figures.

          (2015)
          This report discusses the public health impact of Alzheimer’s disease (AD), including incidence and prevalence, mortality rates, costs of care and the overall effect on caregivers and society. It also examines the challenges encountered by health care providers when disclosing an AD diagnosis to patients and caregivers. An estimated 5.3 million Americans have AD; 5.1 million are age 65 years, and approximately 200,000 are age <65 years and have younger onset AD. By mid-century, the number of people living with AD in the United States is projected to grow by nearly 10 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops AD every 67 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year, and the estimated prevalence is expected to range from 11 million to 16 million. In 2013, official death certificates recorded 84,767 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age 65 years. Between 2000 and 2013, deaths resulting from heart disease, stroke and prostate cancer decreased 14%, 23% and 11%, respectively, whereas deaths from AD increased 71%. The actual number of deaths to which AD contributes (or deaths with AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 2015, an estimated 700,000 Americans age 65 years will die with AD, and many of them will die from complications caused by AD. In 2014, more than 15 million family members and other unpaid caregivers provided an estimated 17.9 billion hours of care to people with AD and other dementias, a contribution valued at more than $217 billion. Average per-person Medicare payments for services to beneficiaries age 65 years with AD and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2015 for health care, long-term care and hospice services for people age 65 years with dementia are expected to be $226 billion. Among people with a diagnosis of AD or another dementia, fewer than half report having been told of the diagnosis by their health care provider. Though the benefits of a prompt, clear and accurate disclosure of an AD diagnosis are recognized by the medical profession, improvements to the disclosure process are needed. These improvements may require stronger support systems for health care providers and their patients.
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            Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.

            J.-M. Orgogozo, S. Gilman, J-F Dartigues … (2003)
            AD is characterized by cerebral deposition of beta-amyloid plaques with amyloid beta-peptide (Abeta) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Abeta42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (AN1792) with QS-21 as adjuvant. Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo (p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Abeta42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. Postvaccination meningoencephalitis occurred without clear relation to serum anti-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.
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              Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease.

              Mercé Boada, Isidre Ferrer, Mariana A F Costa … (2003)
              Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.
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                Author and article information

                Contributors
                Jin‐Shan Feng: jinshanfeng@foxmail.com
                Journal
                Journal ID (nlm-ta): Ann Clin Transl Neurol
                Journal ID (iso-abbrev): Ann Clin Transl Neurol
                Journal ID (doi): 10.1002/(ISSN)2328-9503
                Journal ID (publisher-id): ACN3
                Title: Annals of Clinical and Translational Neurology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2328-9503
                Publication date (Electronic): 30 October 2017
                Publication date Collection: December 2017
                Volume: 4
                Issue: 12 ( doiID: 10.1002/acn3.2017.4.issue-12 )
                Pages: 931-942
                Affiliations
                [ 1 ] Department of Functional Neurosurgery Beijing Tiantan Hospital Capital Medical University Beijing 100061 China
                [ 2 ] Department of General Surgery the Second Xiangya Hospital Central South University Changsha 410011 China
                [ 3 ] Department of Psychology Guangdong Medical University Zhanjiang 524023 China
                [ 4 ] Department of Neurology Affiliated Hospital of Guangdong Medical University Zhanjiang 524023 China
                [ 5 ] Scientific Research Center (Campus Zhanjiang) Guangdong Medical University Zhanjiang 524023 China
                Author notes
                [*] [* ] Correspondence

                Jin‐Shan Feng, Scientific Research Center (Campus Zhanjiang), Guangdong Medical University, Zhanjiang 524023, China. Tel: +867592388010; Fax: +867592388009; E‐mail: jinshanfeng@ 123456foxmail.com

                Author information
                http://orcid.org/0000-0002-9721-1378
                Article
                Publisher ID: ACN3469
                DOI: 10.1002/acn3.469
                PMC ID: 5740249
                PubMed ID: 29296624
                SO-VID: 9bc38aa4-14a3-4028-af80-1bce044640ee
                Copyright © © 2017 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 19 June 2017
                Date revision received : 18 August 2017
                Date accepted : 22 August 2017
                Page count
                Figures: 4, Tables: 1, Pages: 12, Words: 7046
                Funding
                Funded by: Medical Research Fund of Guangdong Province
                Award ID: A2015481
                Funded by: Traditional Chinese Medicine Research Projects of Guangdong Province
                Award ID: 20171152
                Funded by: Doctoral Research Fund of Guangdong Medical University
                Award ID: B2014004
                This work was funded by Medical Research Fund of Guangdong Province grant A2015481; Traditional Chinese Medicine Research Projects of Guangdong Province grant 20171152; Doctoral Research Fund of Guangdong Medical University grant B2014004.
                Categories
                Subject: Review Article
                Subject: Review Article
                Custom metadata
                source-schema-version-number 2.0
                component-id acn3469
                cover-date December 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:22.12.2017

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