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Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

Alvaro Barrera-Ocampo, Universidad Icesi , Cali, Colombia.

Departamento de Ciencias Farmacéuticas , Grupo de Investigación Natura, Facultad de Ciencias Naturales , Universidad Icesi , Cali, Colombia.

Francisco Lopera, Universidad de Antioquia, Medellin, Colombia.

Grupo de Neurociencias de Antioquia , Escuela de Medicina, Universidad de Antioquia, Medellin, Colombia.
Barrera-Ocampo, A., & Lopera, F. (2016). Amyloid-beta immunotherapy: the hope for Alzheimer disease?. Colombia Medica, 47(4), 203–212.

Ali G-C, Guerchet M, Wu Y-T, Prince M, Prina M. Chapter 2: The global prevalence of dementia Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. World Alzheimer Report 2015. The Global Impact of Dementia. An analysis of prevalence, incidence, cost and trends. Alzheimer's Disease International (ADI):; London: 2015. p. 10–29

Alzheimer's Association. Special Report: The personal financial impact of Alzheimer's on families Alzheimer's Association. 2016 Alzheimer's Disease Facts and Figures. Chicago: Alzheimer's Association; 2016. p. 58–67.

WHO. The Epidemiology and Impact of Dementia: Current state and future trends. 2015. WHO/MSD/MER/15.3. p. 4.

McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH. The diagnosis of dementia due to Alzheimer's disease recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263–269

van der Flier WM.Pijnenburg YA.Fox NC.Scheltens P. Early-onset versus late-onset Alzheimer's disease the case of the missing APOE ?4 allele. Lancet Neurol. 2011;10(3):280–288

Lautenschlager NT, Cupples LA, Rao VS, Auerbach SA, Becker R, Burke J. Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study What is in store for the oldest old? Neurology. 1996;46(3):641–650

Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry. 2007;68(4):613–618

Scarabino D, Broggio E, Gambina G, Maida C, Gaudio MR, Corbo RM. Apolipoprotein E genotypes and plasma levels in mild cognitive impairment conversion to Alzheimer's disease A follow-up study. Am J Med Genet B Neuropsychiatr Genet. 2016;171(8):1131–1138

Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005;62(10):1556–1560

Li W, Risacher SL, McAllister TW, Saykin AJ. Traumatic brain injury and age at onset of cognitive impairment in older adults. J Neurol. 2016;263(7):1280–1285

Killin LO, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia a systematic review. BMC Geriatr. 2016;16(1):175

Villemagne VL, Pike KE, Chételat G, Ellis KA, Mulligan RS, Bourgeat P. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann Neurol. 2011;69(1):181–192

Saint-Aubert L, Almkvist O, Chiotis K, Almeida R, Wall A, Nordberg A. Regional tau deposition measured by [(18)F]THK5317 positron emission tomography is associated to cognition via glucose metabolism in Alzheimer's disease. Alzheimers Res Ther. 2016;8(1):38

James OG, Doraiswamy PM, Borges-Neto S. PET Imaging of Tau Pathology in Alzheimer's Disease and Tauopathies. Front Neurol. 2015;6:38

Perl DP. Neuropathology of Alzheimer's disease. Mt Sinai J Med. 2010;77(1):32–42

Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8(6):595–608

Wilcock GK, Esiri MM. Plaques, tangles and dementia A quantitative study. J Neurol Sci. 1982;56(2-3):343–356

Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259

Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998;95(11):6448–6453

Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101–112

Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007;101(5):1172–1184

Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791–1800

Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF. Molecular, structural, and functional characterization of Alzheimer's disease evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005;25(34):7709–7717

Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011;121(2):171–181

Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 2000;924:17–25

Zhang H, Ma Q, Zhang YW, Xu H. Proteolytic processing of Alzheimer's β-amyloid precursor protein. J Neurochem. 2012;120 1:9–21

Lee J, Retamal C, Cuitiño L, Caruano-Yzermans A, Shin JE, van Kerkhof P. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes. J Biol Chem. 2008;283(17):11501–11508

Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A. 1990;87(4):1561–1565

Ehehalt R, Keller P, Haass C, Thiele C, Simons K. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol. 2003;160(1):113–123

Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008;283(44):29615–29619

Fahrenholz F, Gilbert S, Kojro E, Lammich S, Postina R. Alpha-secretase activity of the disintegrin metalloprotease ADAM 10 Influences of domain structure. Ann N Y Acad Sci. 2000;920:215–222

Asai M, Hattori C, Szabó B, Sasagawa N, Maruyama K, Tanuma S. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem Biophys Res Commun. 2003;301(1):231–235

Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990;248(4959):1122–1124

Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer's disease. Mol Brain. 2011;4:3

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286(5440):735–741

Selkoe DJ, Wolfe MS. Presenilin running with scissors in the membrane. Cell. 2007;131(2):215–221

St George-Hyslop P, Fraser PE. Assembly of the presenilin -/ε-secretase complex. J Neurochem. 2012;120 1:84–88

Mori H, Takio K, Ogawara M, Selkoe DJ. Mass spectrometry of purified amyloid beta protein in Alzheimer's disease. J Biol Chem. 1992;267(24):17082–17086

Serra-Batiste M, Ninot-Pedrosa M, Bayoumi M, Gairí M, Maglia G, Carulla N. Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proc Natl Acad Sci U S A. 2016;113(39):10866–10871

Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A. Amyloid beta-protein fibrillogenesis Structure and biological activity of protofibrillar intermediates. J Biol Chem. 1999;274(36):25945–25952

Harper JD, Wong SS, Lieber CM, Lansbury PT. Assembly of A beta amyloid protofibrils an in vitro model for a possible early event in Alzheimer's disease. Biochemistry. 1999;38(28):8972–8980

Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M. Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J. 2010;29(19):3408–3420

Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci. 2011;31(18):6627–6638

Yang TT, Hsu CT, Kuo YM. Cell-derived soluble oligomers of human amyloid-beta peptides disturb cellular homeostasis and induce apoptosis in primary hippocampal neurons. J Neural Transm (Vienna). 2009;116(12):1561–1569

Bertram L, Tanzi RE. Alzheimer's disease: one disorder, too many genes? Hum Mol Genet. 2004;13 Spec No 1:R135–R141

Goate A, Hardy J. Twenty years of Alzheimer's disease-causing mutations. J Neurochem. 2012;120 1:3–8

Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039

Larner AJ, Doran M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J Neurol. 2006;253(2):139–158

Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997;3(1):67–72

Lopera F, Ardilla A, Martínez A, Madrigal L, Arango-Viana JC, Lemere CA. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997;277(10):793–799

Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease a retrospective cohort study. Lancet Neurol. 2011;10(3):213–220

Sherrington R, Froelich S, Sorbi S, Campion D, Chi H, Rogaeva EA. Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet. 1996;5(7):985–988

Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010;133(4):1143–1154

Lindquist SG, Hasholt L, Bahl JM, Heegaard NH, Andersen BB, Nørremølle A. A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment. Eur J Neurol. 2008;15(10):1135–1139

Vélez JI, Lopera F, Patel HR, Johar AS, Cai Y, Rivera D. Mutations modifying sporadic Alzheimer's disease age of onset. Am J Med Genet B Neuropsychiatr Genet. 2016;171(8):1116–1130

Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014;20(4):415–418

Lachén-Montes M, González-Morales A, de Morentin XM, Pérez-Valderrama E, Ausín K, Zelaya MV. An early dysregulation of FAK and MEK/ERK signaling pathways precedes the β-amyloid deposition in the olfactory bulb of APP/PS1 mouse model of Alzheimer's disease. J Proteomics. 2016;148:149–158

Sorbi S, Hort J, Erkinjuntti T, Fladby T, Gainotti G, Gurvit H. EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia. Eur J Neurol. 2012;19(9):1159–1179

Ihl R, Bunevicius R, Frölich L, Winblad B, Schneider LS, Dubois B. World Federation of Societies of Biological Psychiatry guidelines for the pharmacological treatment of dementias in primary care. Int J Psychiatry Clin Pract. 2015;19(1):2–7

Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M. Effectiveness of cholinesterase inhibitors and memantine for treating dementia evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379–397

Cummings JL, Isaacson RS, Schmitt FA, Velting DM. A practical algorithm for managing Alzheimer's disease what, when, and why? Ann Clin Transl Neurol. 2015;2(3):307–323

Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD005593

McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;(2):CD003154

Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M. Effect of vitamin E and memantine on functional decline in Alzheimer disease the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33–44

Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61(1):46–54

Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005;64(1):94–101

Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64(9):1553–1562

Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2012;11(7):597–604

Farlow MR, Andreasen N, Riviere ME, Vostiar I, Vitaliti A, Sovago J. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):23

Muhs A, Hickman DT, Pihlgren M, Chuard N, Giriens V, Meerschman C. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A. 2007;104(23):9810–9815

Morrone CD, Liu M, Black SE, McLaurin J. Interaction between therapeutic interventions for Alzheimer's disease and physiological Aβ clearance mechanisms. Front Aging Neurosci. 2015;7:64

Lichtlen P, Mohajeri MH. Antibody-based approaches in Alzheimer's research safety, pharmacokinetics, metabolism, and analytical tools. J Neurochem. 2008;104(4):859–874

Booth CM, Tannock IF. Randomised controlled trials and population-based observational research partners in the evolution of medical evidence. Br J Cancer. 2014;110(3):551–555

Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R. Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease. Proc Natl Acad Sci U S A. 1997;94(4):1550–1555

Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061–2070

Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9(4):363–372

La Porte SL, Bollini SS, Lanz TA, Abdiche YN, Rusnak AS, Ho WH. Structural basis of C-terminal β-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease. J Mol Biol. 2012;421(4-5):525–536

Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol. 2013;36(1):14–23

Miyoshi I, Fujimoto Y, Yamada M, Abe S, Zhao Q, Cronenberger C. Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study. Int J Clin Pharmacol Ther. 2013;51(12):911–923

DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001;98(15):8850–8855

Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):311–321

Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H. Phase 3 solanezumab trials Secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016;12(2):110–120

Carlson C, Siemers E, Hake A, Case M, Hayduk R, Suhy J. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease. Alzheimers Dement (Amst). 2016;2:75–85

Abbott A, Dolgin E. Failed Alzheimer's trial does not kill leading theory of disease. Nature. 2016;540(7631):15–16

Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F. Gantenerumab a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers. Dis. 2012;28(1):49–69

Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69(2):198–207

Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016;537(7618):50–56

Kastanenka KV, Bussiere T, Shakerdge N, Qian F, Weinreb PH, Rhodes K, et al.. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. J Neurosci. 2016;36(50):12549–12558

Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K. An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ J. Neurosci. 2012;32(28):9677–9689

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M. The Alzheimer's prevention initiative composite cognitive test score sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry. 2014;75(6):652–660

Tucker S, Möller C, Tegerstedt K, Lord A, Laudon H, Sjödahl J. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43(2):575–588

Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswald G. Safety and tolerability of BAN2401--a clinical study in Alzheimer's disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016;8(1):14

Qu J, Yu S, Zheng Y, Yang H, Zhang J. Aptamer and its applications in neurodegenerative diseases. Cell Mol Life Sci. 2016;


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Received 2016-11-10
Accepted 2017-01-02
Published 2016-12-28