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A tough trek in the development of an anti-amyloid therapy for Alzheimer's disease: Do we see hope in the distance?

      Highlights

      • Various hypotheses exist in exploration of the underlying etiology for the development of AD.
      • Aducanumab is a human IgG1 monoclonal antibody crossing reaction against N-terminal 3-7 amino-acids of both Aβ and sAPPα.
      • sAPPα plays neurotrophic and neuroprotective effects.
      • Aβ exerts both neurotoxic and neuroprotective actions.
      • May anti-amyloid therapy be a double-edged sword?

      Abstract

      The search for a clinically effective therapy for patients with Alzheimer's disease (AD) has been long and arduous. In some circles the recent US Food and Drug Administration (FDA) approval of the human monoclonal antibody, Aducanumab, was viewed as a welcome advance. However, the administrative decision, in the face of a negative review by the members of the FDA neurology advisory board raised many questions concerning its appropriateness. In response the FDA has modified the conditions under which the drug should be administered. Currently, the etiology of AD remains unknown. Thus, application of therapies based on the still controversial amyloid hypothesis deserves critical scrutiny. While successful animal studies based on the hypothesis have stimulated many clinical trials in humans, none of these have shown statistically clinical benefit, raising questions regarding the intrinsic validity of the hypothesis itself. However, each successive trial has benefited from the experiences of those which preceded it. Given these caveats, the relevance of an apparent beneficial response in a subset of Aducanumab treated study participants must be weighed carefully. There are competing hypotheses regarding the etiology and pathophysiology responsible for the development of AD, including tau protein aggregation, acetylcholine deficiency, neuroinflammation, among others, all of which remain controversial. Nonetheless, the newly approved agent, Aducanumab did show some subtle benefit in some mild AD patients. Understanding the current hypotheses and controversies may help better evaluate the limitations and challenges in anti-amyloid therapy and in exploration of more efficacious therapies in treating patients with AD in the future.

      Keywords

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      References

        • Alexander G.C.
        • Knopman D.S.
        • Emerson S.S.
        • et al.
        Revisiting FDA approval of Aducanumab.
        N. Engl. J. Med. 2021;
        • Rabinovici G.D.
        Controversy and Progress in Alzheimer’s disease - FDA approval of Aducanumab.
        N. Engl. J. Med. 2021; 385 (Epub 2021 Jul 28. PMID: 34320284): 771-774https://doi.org/10.1056/NEJMp2111320
        • Walker J.
        Cleveland Clinic, Mount Sinai and Providence Won’t Give Biogen’s New Alzheimer’s drug.
        Wall Street J. 2021; (Updated July 15, 2021 8:04 pm ET)
        • Baldwin J.W.
        • Dolan D.
        • Anderson K.
        • Hutter J.D.
        Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s DiseasePress.
        2022 (Accessed on January 22, 2022)
        • Dunn B.
        • Stein P.
        • Cavazzoni P.
        Approval of Aducanumab for Alzheimer Disease-The FDA’s perspective.
        JAMA Intern. Med. 2021; 181 (PMID: 34254984): 1276-1278https://doi.org/10.1001/jamainternmed.2021.4607
        • Petersen R.C.
        Aducanumab: what about the patient?.
        Ann. Neurol. 2021; 90 (Epub 2021 Aug 7. PMID: 34322904; PMCID: PMC8434994): 334-335https://doi.org/10.1002/ana.26181
        • Selkoe D.J.
        Treatments for Alzheimer’s disease emerge.
        Science. 2021; 373: 624-626
        • WHO
        Dementia Fact sheet.
        World Health Organization, 2020
        • Todd S.
        • Barr S.
        • Roberts M.
        • Passmore A.P.
        Survival in dementia and predictors of mortality: a review.
        Int J Geriatr Psychiatry. 2013; 28: 1109-1124
        • Meek P.D.
        • McKeithan K.
        • Schumock G.T.
        Economic considerations in Alzheimer’s disease.
        Pharmacotherapy. 1998; 18 (discussion 79-82): 68-73
        • Schumock G.T.
        Economic considerations in the treatment and management of Alzheimer’s disease.
        Am. J. Health Syst. Pharm. 1998; 55: S17-S21
      1. Alzheimer's disease facts and figures.
        Alzheimers Dement. 2021; 17: 327-406
        • Jack Jr., C.R.
        • Bennett D.A.
        • Blennow K.
        • et al.
        NIA-AA research framework: toward a biological definition of Alzheimer’s disease.
        Alzheimers Dement. 2018; 14: 535-562
        • Dubois B.
        • Villain N.
        • Frisoni G.B.
        • et al.
        Clinical diagnosis of Alzheimer’s disease: recommendations of the international working group.
        Lancet Neurol. 2021; 20: 484-496
        • Tackenberg C.
        • Kulic L.
        • Nitsch R.M.
        Familial Alzheimer’s disease mutations at position 22 of the amyloid beta-peptide sequence differentially affect synaptic loss, tau phosphorylation and neuronal cell death in an ex vivo system.
        PLoS One. 2020; 15e0239584
        • Vilchez D.
        • Saez I.
        • Dillin A.
        The role of protein clearance mechanisms in organismal ageing and age-related diseases.
        Nat. Commun. 2014; 5: 5659
        • Hardy J.
        • Allsop D.
        Amyloid deposition as the central event in the aetiology of Alzheimer’s disease.
        Trends Pharmacol. Sci. 1991; 12: 383-388
        • Mudher A.
        • Lovestone S.
        Alzheimer’s disease-do tauists and baptists finally shake hands?.
        Trends Neurosci. 2002; 25: 22-26
        • Wallace W.C.
        • Lieberburg I.
        • Schenk D.
        • Vigo-Pelfrey C.
        • Davis K.L.
        • Haroutunian V.
        Chronic elevation of secreted amyloid precursor protein in subcortically lesioned rats, and its exacerbation in aged rats.
        J. Neurosci. 1995; 15: 4896-4905
        • Wallace W.C.
        • Akar C.A.
        • Lyons W.E.
        Amyloid precursor protein potentiates the neurotrophic activity of NGF.
        Brain Res. Mol. Brain Res. 1997; 52: 201-212
        • Luo J.J.
        • Wallace M.S.
        • Hawver D.B.
        • Kusiak J.W.
        • Wallace W.C.
        Characterization of the neurotrophic interaction between nerve growth factor and secreted alpha-amyloid precursor protein.
        J. Neurosci. Res. 2001; 63: 410-420
        • Rohn T.T.
        • Ivins K.J.
        • Bahr B.A.
        • Cotman C.W.
        • Cribbs D.H.
        A monoclonal antibody to amyloid precursor protein induces neuronal apoptosis.
        J. Neurochem. 2000; 74: 2331-2342
        • Van Broeck B.
        • Van Broeckhoven C.
        • Kumar-Singh S.
        Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches.
        Neurodegener. Dis. 2007; 4: 349-365
        • Huang Y.
        • Mucke L.
        Alzheimer mechanisms and therapeutic strategies.
        Cell. 2012; 148: 1204-1222
        • Luo J.J.
        • Kusiak J.W.
        • Wallace M.
        • Wallace W.C.
        Dual roles of amyloid-beta and secreted forms of amyloid precursor protein in culture.
        2009
        • Wallace W.C.
        • Luo J.J.
        • Wallace M.
        • Hawyer D.
        • Kusiak J.W.
        A truncated form of secreted amyloid precursor protein induces apoptosis of neurons in culture.
        Neurobiol. Aging. 2000; 21: 260
        • Nistor M.
        • Don M.
        • Parekh M.
        • et al.
        Alpha- and beta-secretase activity as a function of age and beta-amyloid in down syndrome and normal brain.
        Neurobiol. Aging. 2007; 28: 1493-1506
        • Lott I.T.
        • Head E.
        Alzheimer disease and down syndrome: factors in pathogenesis.
        Neurobiol. Aging. 2005; 26: 383-389
        • Long J.M.
        • Holtzman D.M.
        Alzheimer disease: an update on pathobiology and treatment strategies.
        Cell. 2019; 179: 312-339
        • Polvikoski T.
        • Sulkava R.
        • Haltia M.
        • et al.
        Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein.
        N. Engl. J. Med. 1995; 333: 1242-1247
        • Weller R.O.
        • Preston S.D.
        • Subash M.
        • Carare R.O.
        Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease.
        Alzheimers Res. Ther. 2009; 1: 6
        • Rapoport M.
        • Ferreira A.
        PD98059 prevents neurite degeneration induced by fibrillar beta-amyloid in mature hippocampal neurons.
        J. Neurochem. 2000; 74: 125-133
        • Takeuchi A.
        • Irizarry M.C.
        • Duff K.
        • et al.
        Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss.
        Am. J. Pathol. 2000; 157: 331-339
        • Oddo S.
        • Billings L.
        • Kesslak J.P.
        • Cribbs D.H.
        • LaFerla F.M.
        Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome.
        Neuron. 2004; 43: 321-332
        • Behl C.
        • Davis J.B.
        • Lesley R.
        • Schubert D.
        Hydrogen peroxide mediates amyloid beta protein toxicity.
        Cell. 1994; 77: 817-827
        • Rottkamp C.A.
        • Raina A.K.
        • Zhu X.
        • et al.
        Redox-active iron mediates amyloid-beta toxicity.
        Free Radic. Biol. Med. 2001; 30: 447-450
        • Smith D.P.
        • Smith D.G.
        • Curtain C.C.
        • et al.
        Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge.
        J. Biol. Chem. 2006; 281: 15145-15154
        • Yankner B.A.
        • Duffy L.K.
        • Kirschner D.A.
        Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides.
        Science. 1990; 250: 279-282
        • Chen X.
        • Yan S.D.
        Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer’s disease.
        IUBMB Life. 2006; 58: 686-694
        • Christen Y.
        Oxidative stress and Alzheimer disease.
        Am. J. Clin. Nutr. 2000; 71: 621S-629S
        • Lu D.C.
        • Soriano S.
        • Bredesen D.E.
        • Koo E.H.
        Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity.
        J. Neurochem. 2003; 87: 733-741
        • Liu T.
        • Perry G.
        • Chan H.W.
        • et al.
        Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression.
        J. Neurochem. 2004; 88: 554-563
      2. Mucke L, Selkoe DJ. Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med;2:a006338.

      3. Freir DB, Fedriani R, Scully D, et al. Abeta oligomers inhibit synapse remodelling necessary for memory consolidation. Neurobiol Aging;32:2211–2218.

      4. Reed MN, Hofmeister JJ, Jungbauer L, et al. Cognitive effects of cell-derived and synthetically derived Abeta oligomers. Neurobiol Aging;32:1784–1794.

        • Bishop G.M.
        • Robinson S.R.
        Deposits of fibrillar A beta do not cause neuronal loss or ferritin expression in adult rat brain.
        J. Neural Transm. (Vienna). 2003; 110: 381-400
        • Rapoport M.
        • Dawson H.N.
        • Binder L.I.
        • Vitek M.P.
        • Ferreira A.
        Tau is essential to beta -amyloid-induced neurotoxicity.
        Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6364-6369
        • Gomez-Isla T.
        • Hollister R.
        • West H.
        • et al.
        Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease.
        Ann. Neurol. 1997; 41: 17-24
        • Holmes C.
        • Boche D.
        • Wilkinson D.
        • et al.
        Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial.
        Lancet. 2008; 372: 216-223
        • Lemere C.A.
        • Masliah E.
        Can Alzheimer disease be prevented by amyloid-beta immunotherapy?.
        Nat. Rev. Neurol. 2010; 6: 108-119
        • Vandenberghe R.
        • Riviere M.E.
        • Caputo A.
        • et al.
        Active Abeta immunotherapy CAD106 in Alzheimer’s disease: a phase 2b study.
        Alzheimers Dement (N Y). 2017; 3: 10-22
        • Turner R.S.
        • Thomas R.G.
        • Craft S.
        • et al.
        A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.
        Neurology. 2015; 85: 1383-1391
        • Schneeberger A.
        • Hendrix S.
        • Mandler M.
        • et al.
        Results from a phase II study to assess the clinical and immunological activity of AFFITOPE(R) AD02 in patients with early Alzheimer’s disease.
        J Prev Alzheimers Dis. 2015; 2: 103-114
        • Panza F.
        • Lozupone M.
        • Logroscino G.
        • Imbimbo B.P.
        A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease.
        Nat. Rev. Neurol. 2019; 15: 73-88
        • Ohno M.
        • Sametsky E.A.
        • Younkin L.H.
        • et al.
        BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease.
        Neuron. 2004; 41: 27-33
        • Egan M.F.
        • Kost J.
        • Voss T.
        • et al.
        Randomized trial of Verubecestat for prodromal Alzheimer’s disease.
        N. Engl. J. Med. 2019; 380: 1408-1420
        • Goedert M.
        • Spillantini M.G.
        • Crowther R.A.
        Tau proteins and neurofibrillary degeneration.
        Brain Pathol. 1991; 1: 279-286
        • Iqbal K.
        • Alonso Adel C.
        • Chen S.
        • et al.
        Tau pathology in Alzheimer disease and other tauopathies.
        Biochim. Biophys. Acta. 2005; 1739: 198-210
        • Chun W.
        • Johnson G.V.
        The role of tau phosphorylation and cleavage in neuronal cell death.
        Front. Biosci. 2007; 12: 733-756
        • Wang Y.
        • Mandelkow E.
        Tau in physiology and pathology.
        Nat. Rev. Neurosci. 2016; 17: 22-35
        • Strang K.H.
        • Golde T.E.
        • Giasson B.I.
        MAPT mutations, tauopathy, and mechanisms of neurodegeneration.
        Lab. Investig. 2019; 99: 912-928
        • Hutton M.
        • Lendon C.L.
        • Rizzu P.
        • et al.
        Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.
        Nature. 1998; 393: 702-705
        • Poorkaj P.
        • Bird T.D.
        • Wijsman E.
        • et al.
        Tau is a candidate gene for chromosome 17 frontotemporal dementia.
        Ann. Neurol. 1998; 43: 815-825
        • Bugiani O.
        • Murrell J.R.
        • Giaccone G.
        • et al.
        Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.
        J. Neuropathol. Exp. Neurol. 1999; 58: 667-677
        • Spillantini M.G.
        • Murrell J.R.
        • Goedert M.
        • Farlow M.R.
        • Klug A.
        • Ghetti B.
        Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.
        Proc. Natl. Acad. Sci. 1998; 95: 7737-7741
        • Kurosinski P.
        • Guggisberg M.
        • Götz J.
        Alzheimer’s and Parkinson’s disease–overlapping or synergistic pathologies?.
        Trends Mol. Med. 2002; 8: 3-5
        • Goedert M.
        • Spillantini M.
        • Crowther R.
        • et al.
        Tau gene mutation in familial progressive subcortical gliosis.
        Nat. Med. 1999; 5: 454-457
        • Yasuda M.
        • Kawamata T.
        • Komure O.
        • Kuno S.
        • D’Souza I.
        • Poorkaj P.
        • Kawai J.
        • Tanimukai S.
        • Yamamoto Y.
        • Hasegawa H.
        • Sasahara M.
        • Hazama F.
        • Schellenberg G.D.
        • Tanaka C.
        A mutation in the microtubule-associated protein tau in pallido-nigro-luysian degeneration.
        Neurology. 1999; 53 (PMID: 10489057): 864-868https://doi.org/10.1212/wnl.53.4.864
        • Ishihara T.
        • Zhang B.
        • Higuchi M.
        • Yoshiyama Y.
        • Trojanowski J.Q.
        • Lee V.M.-Y.
        Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice.
        Am. J. Pathol. 2001; 158: 555-562
        • Probst A.
        • Götz J.
        • Wiederhold K.
        • et al.
        Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein.
        Acta Neuropathol. 2000; 99: 469-481
        • Spittaels K.
        • Van den Haute C.
        • Van Dorpe J.
        • et al.
        Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein.
        Am. J. Pathol. 1999; 155: 2153-2165
        • Hirano A.
        • Nakano I.
        • Kurland L.T.
        • Mulder D.W.
        • Holley P.W.
        • Saccomanno G.
        Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis.
        J. Neuropathol. Exp. Neurol. 1984; 43: 471-480
        • Rouleau G.A.
        • Clark A.W.
        • Rooke K.
        • et al.
        SOD1 mutation is assosiated with accumulation of neurofilaments in amyotrophic lateral scelaries.
        Ann. Neurol. 1996; 39: 128-131
        • Munoz D.
        • Greene C.
        • Perl D.
        • Selkoe D.
        Accumulation of phosphorylated neurofilaments in anterior horn motoneurons of amyotrophic lateral sclerosis patients.
        J. Neuropathol. Exp. Neurol. 1988; 47: 9-18
        • Zhou L.
        • Miller B.
        • McDaniel C.
        • Kelly L.
        • Kim O.
        • Miller C.
        Frontotemporal dementia: neuropil spheroids and presynaptic terminal degeneration.
        Annals of Neurology. 1998; 44: 99-109
        • Lee V.M.-Y.
        • Kenyon T.K.
        • Trojanowski J.Q.
        Transgenic animal models of tauopathies.
        Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2005; 1739: 251-259
        • AJF DAaM
        Davies AP and Moloney AJF.
        Lancet. 1976; ii: 1403
        • Bowen D.M.
        • Smith C.B.
        • White P.
        • Davison A.N.
        Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies.
        Brain. 1976; 99: 459-496
        • Perry E.K.
        • Gibson P.H.
        • Blessed G.
        • Perry R.H.
        • Tomlinson B.E.
        Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue.
        J. Neurol. Sci. 1977; 34: 247-265
        • Francis P.T.
        • Palmer A.M.
        • Snape M.
        • Wilcock G.K.
        The cholinergic hypothesis of Alzheimer’s disease: a review of progress.
        J. Neurol. Neurosurg. Psychiatry. 1999; 66: 137-147
        • Martorana A.
        • Esposito Z.
        • Koch G.
        Beyond the cholinergic hypothesis: do current drugs work in Alzheimer’s disease?.
        CNS Neurosci Ther. 2010; 16: 235-245
        • Greenfield S.
        Brain drugs of the future.
        BMJ. 1998; 317: 1698-1701
        • Sinyor B.
        • Mineo J.
        • Ochner C.
        Alzheimer’s disease, inflammation, and the role of antioxidants.
        J Alzheimers Dis Rep. 2020; 4: 175-183
        • Kinney J.W.
        • Bemiller S.M.
        • Murtishaw A.S.
        • Leisgang A.M.
        • Salazar A.M.
        • Lamb B.T.
        Inflammation as a central mechanism in Alzheimer’s disease.
        Alzheimers Dement (N Y). 2018; 4: 575-590
        • Eikelenboom P.
        • van Exel E.
        • Hoozemans J.J.
        • Veerhuis R.
        • Rozemuller A.J.
        • van Gool W.A.
        Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer’s disease.
        Neurodegener. Dis. 2010; 7: 38-41
        • Greig N.H.
        • Mattson M.P.
        • Perry T.
        • et al.
        New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists.
        Ann. N. Y. Acad. Sci. 2004; 1035: 290-315
        • Hickman S.
        • Izzy S.
        • Sen P.
        • Morsett L.
        • El Khoury J.
        Microglia in neurodegeneration.
        Nat. Neurosci. 2018; 21: 1359-1369
        • Kempuraj D.
        • Thangavel R.
        • Natteru P.
        • et al.
        Neuroinflammation induces neurodegeneration.
        Journal of Neurology, Neurosurgery and Spine. 2016; 1
        • Glass C.K.
        • Saijo K.
        • Winner B.
        • Marchetto M.C.
        • Gage F.H.
        Mechanisms underlying inflammation in neurodegeneration.
        Cell. 2010; 140: 918-934
        • Streit W.J.
        Microglia as neuroprotective, immunocompetent cells of the CNS.
        Glia. 2002; 40: 133-139
        • Akiyama H.
        • Barger S.
        • Barnum S.
        • et al.
        Inflammation and Alzheimer’s disease.
        Neurobiol. Aging. 2000; 21: 383-421
        • Wyss-Coray T.
        • Loike J.D.
        • Brionne T.C.
        • et al.
        Adult mouse astrocytes degrade amyloid-β in vitro and in situ.
        Nat. Med. 2003; 9: 453-457
        • Cartier L.
        • Hartley O.
        • Dubois-Dauphin M.
        • Krause K.-H.
        Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases.
        Brain Res. Rev. 2005; 48: 16-42
        • Ballatore C.
        • Lee V.M.-Y.
        • Trojanowski J.Q.
        Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders.
        Nat. Rev. Neurosci. 2007; 8: 663-672
        • Kwon H.S.
        • Koh S.-H.
        Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes.
        Translational Neurodegeneration. 2020; 9: 1-12
        • Guzman-Martinez L.
        • Maccioni R.B.
        • Andrade V.
        • Navarrete L.P.
        • Pastor M.G.
        • Ramos-Escobar N.
        Neuroinflammation as a common feature of neurodegenerative disorders.
        Front. Pharmacol. 2019; 10: 1008
        • Cortés N.
        • Andrade V.
        • Guzmán-Martínez L.
        • Estrella M.
        • Maccioni R.B.
        Neuroimmune tau mechanisms: their role in the progression of neuronal degeneration.
        Int. J. Mol. Sci. 2018; 19: 956
        • Maccioni R.B.
        • Rojo L.E.
        • Fernandez J.A.
        • Kuljis R.O.
        The role of neuroimmunomodulation in Alzheimer’s disease.
        Ann. N. Y. Acad. Sci. 2009; 1153: 240-246
        • Abbott N.J.
        • Patabendige A.A.
        • Dolman D.E.
        • Yusof S.R.
        • Begley D.J.
        Structure and function of the blood–brain barrier.
        Neurobiol. Dis. 2010; 37: 13-25
        • Baufeld C.
        • O’Loughlin E.
        • Calcagno N.
        • Madore C.
        • Butovsky O.
        Differential contribution of microglia and monocytes in neurodegenerative diseases.
        J. Neural Transm. 2018; 125: 809-826
        • Liddelow S.A.
        • Barres B.A.
        Reactive astrocytes: production, function, and therapeutic potential.
        Immunity. 2017; 46: 957-967
        • Oksanen M.
        • Lehtonen S.
        • Jaronen M.
        • Goldsteins G.
        • Hämäläinen R.H.
        • Koistinaho J.
        Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms.
        Cell. Mol. Life Sci. 2019; 76: 2739-2760
        • Andreadou E.
        • Pantazaki A.A.
        • Daniilidou M.
        • Tsolaki M.
        Rhamnolipids, microbial virulence factors, in Alzheimer’s disease.
        J. Alzheimers Dis. 2017; 59: 209-222
        • Goldman S.M.
        • Kamel F.
        • Ross G.W.
        • et al.
        Peptidoglycan recognition protein genes and risk of Parkinson’s disease.
        Mov. Disord. 2014; 29: 1171-1180
        • Berer K.
        • Gerdes L.A.
        • Cekanaviciute E.
        • et al.
        Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice.
        Proc. Natl. Acad. Sci. 2017; 114: 10719-10724
        • Franceschi C.
        • Bonafe M.
        • Valensin S.
        • et al.
        Inflamm-aging: an evolutionary perspective on immunosenescence.
        Ann. N. Y. Acad. Sci. 2000; 908: 244-254
        • Yankner B.A.
        • Lu T.
        • Loerch P.
        The aging brain.
        Annu Rev Pathol Mech Dis. 2008; 3: 41-66
        • Aisen P.S.
        • Davis K.L.
        • Berg J.D.
        • Schafer K.
        • Campbell K.
        • Thomas R.G.
        • Weiner M.F.
        • Farlow M.R.
        • Sano M.
        • Grundman M.
        • Thal L.J.
        A randomized controlled trial of prednisone in Alzheimer’s disease. Alzheimer’s Disease Cooperative Study.
        Neurology. 2000; 54 (PMID: 10680787): 588-593https://doi.org/10.1212/wnl.54.3.588
        • Aisen P.S.
        • Schafer K.A.
        • Grundman M.
        • et al.
        Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.
        Jama. 2003; 289: 2819-2826
        • Group AC
        Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial.
        The Lancet Neurology. 2008; 7: 41-49
        • Scharf S.
        • Mander A.
        • Ugoni A.
        • Vajda F.
        • Christophidis N.
        A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease.
        Neurology. 1999; 53 (PMID: 10408559): 197-201https://doi.org/10.1212/wnl.53.1.197
        • Thal L.J.
        • Ferris S.H.
        • Kirby L.
        • et al.
        A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.
        Neuropsychopharmacology. 2005; 30: 1204-1215
        • Group AR
        Cognitive function over time in the Alzheimer’s disease anti-inflammatory prevention trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib.
        Arch. Neurol. 2008; 65: 896
        • Pasqualetti P.
        • Bonomini C.
        • Dal Forno G.
        • et al.
        A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease.
        Aging Clin. Exp. Res. 2009; 21: 102-110
        • Rogers J.
        • Kirby L.C.
        • Hempelman S.R.
        • Berry D.L.
        • McGeer P.L.
        • Kaszniak A.W.
        • Zalinski J.
        • Cofield M.
        • Mansukhani L.
        • Willson P.
        • et al.
        Clinical trial of indomethacin in Alzheimer’s disease.
        Neurology. 1993; 43 (PMID: 8351023): 1609-1611https://doi.org/10.1212/wnl.43.8.1609
        • Familian A.
        • Boshuizen R.S.
        • Eikelenboom P.
        • Veerhuis R.
        Inhibitory effect of minocycline on amyloid β fibril formation and human microglial activation.
        Glia. 2006; 53: 233-240
        • Garcez M.L.
        • Mina F.
        • Bellettini-Santos T.
        • et al.
        Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice.
        Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2017; 77: 23-31
        • Howard R.
        • Zubko O.
        • Bradley R.
        • et al.
        Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial.
        JAMA neurology. 2020; 77: 164-174
        • Kriz J.
        • Nguyen M.D.
        • Julien J.-P.
        Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis.
        Neurobiol. Dis. 2002; 10: 268-278
        • Gordon P.H.
        • Moore D.H.
        • Miller R.G.
        • et al.
        Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.
        The Lancet Neurology. 2007; 6: 1045-1053
        • Choi S.-H.
        • Aid S.
        • Bosetti F.
        The distinct roles of cyclooxygenase-1 and-2 in neuroinflammation: implications for translational research.
        Trends Pharmacol. Sci. 2009; 30: 174-181
        • Reines S.
        • Block G.
        • Morris J.
        • et al.
        Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study.
        Neurology. 2004; 62: 66-71
        • Heneka M.T.
        • Carson M.J.
        • El Khoury J.
        • et al.
        Neuroinflammation in Alzheimer’s disease.
        Lancet Neurol. 2015; 14: 388-405
        • Irwin M.R.
        • Vitiello M.V.
        Implications of sleep disturbance and inflammation for Alzheimer’s disease dementia.
        Lancet Neurol. 2019; 18: 296-306
        • Cataldo J.K.
        • Prochaska J.J.
        • Glantz S.A.
        Cigarette smoking is a risk factor for Alzheimer’s disease: an analysis controlling for tobacco industry affiliation.
        J. Alzheimers Dis. 2010; 19: 465-480
        • Moulton P.V.
        • Yang W.
        Air pollution, oxidative stress, and Alzheimer’s disease.
        J. Environ. Public Health. 2012; 2012472751
        • Paul K.C.
        • Haan M.
        • Mayeda E.R.
        • Ritz B.R.
        Ambient air pollution, noise, and late-life cognitive decline and dementia risk.
        Annu. Rev. Public Health. 2019; 40: 203-220
        • Deane R.
        • Zlokovic B.V.
        Role of the blood-brain barrier in the pathogenesis of Alzheimer’s disease.
        Curr. Alzheimer Res. 2007; 4: 191-197
        • Xu H.
        • Finkelstein D.I.
        • Adlard P.A.
        Interactions of metals and apolipoprotein E in Alzheimer’s disease.
        Front. Aging Neurosci. 2014; 6: 121
        • Huang Y.
        Apolipoprotein E and Alzheimer disease.
        Neurology. 2006; 66: S79-S85
        • Mahley R.W.
        • Weisgraber K.H.
        • Huang Y.
        Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease.
        Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 5644-5651
        • Tapia-Arancibia L.
        • Aliaga E.
        • Silhol M.
        • Arancibia S.
        New insights into brain BDNF function in normal aging and Alzheimer disease.
        Brain Res. Rev. 2008; 59: 201-220
        • Schindowski K.
        • Belarbi K.
        • Buee L.
        Neurotrophic factors in Alzheimer’s disease: role of axonal transport.
        Genes Brain Behav. 2008; 7: 43-56
        • Bartzokis G.
        Alzheimer’s disease as homeostatic responses to age-related myelin breakdown.
        Neurobiol. Aging. 2011; 32: 1341-1371
        • Cai Z.
        • Xiao M.
        Oligodendrocytes and Alzheimer’s disease.
        Int J Neurosci. 2016; 126: 97-104
        • Reisberg B.
        • Franssen E.H.
        • Hasan S.M.
        • et al.
        Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer’s and other dementing processes.
        Eur. Arch. Psychiatry Clin. Neurosci. 1999; 249: 28-36
        • Miklossy J.
        Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria.
        J Neuroinflammation. 2011; 8: 90
        • Allen H.B.
        Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid-beta with regard to potential treatment and prevention.
        J. Alzheimers Dis. 2016; 53: 1271-1276
        • Kamer A.R.
        • Craig R.G.
        • Dasanayake A.P.
        • Brys M.
        • Glodzik-Sobanska L.
        • de Leon M.J.
        Inflammation and Alzheimer’s disease: possible role of periodontal diseases.
        Alzheimers Dement. 2008; 4: 242-250
        • Kamer A.R.
        • Dasanayake A.P.
        • Craig R.G.
        • Glodzik-Sobanska L.
        • Bry M.
        • de Leon M.J.
        Alzheimer’s disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis.
        J. Alzheimers Dis. 2008; 13: 437-449
        • Collins S.M.
        • Surette M.
        • Bercik P.
        The interplay between the intestinal microbiota and the brain.
        Nat Rev Microbiol. 2012; 10: 735-742
        • Yegambaram M.
        • Manivannan B.
        • Beach T.G.
        • Halden R.U.
        Role of environmental contaminants in the etiology of Alzheimer’s disease: a review.
        Curr. Alzheimer Res. 2015; 12: 116-146
        • Ismail N.A.
        • Leong Abdullah M.F.I.
        • Hami R.
        • Ahmad Yusof H.
        A narrative review of brain-derived neurotrophic factor (BDNF) on cognitive performance in Alzheimer’s disease.
        Growth Factors. 2020; 38: 210-225
        • Yiannopoulou K.G.
        • Papageorgiou S.G.
        Current and future treatments in Alzheimer disease: an update.
        Journal of central nervous system disease. 2020; 12 (1179573520907397)
        • Cummingsa J.
        • Leeb G.
        • Ritterb A.
        • Sabbaghb M.
        • Zhong K.
        Alzheimer’s disease drug development pipeline: 2019.
        Alzheimer Dement. 2019; 5: 272-293
        • Yang H.Q.
        • Sun Z.K.
        • Ba M.W.
        • Xu J.
        • Xing Y.
        Involvement of protein trafficking in deprenyl-induced alpha-secretase activity regulation in PC12 cells.
        Eur. J. Pharmacol. 2009; 610: 37-41
        • Filip V.
        • Kolibas E.
        Selegiline in the treatment of Alzheimer’s disease: a long-term randomized placebo-controlled trial. Czech and Slovak senile dementia of Alzheimer type study group.
        J. Psychiatry Neurosci. 1999; 24: 234-243
        • Zamrini E.
        • McGwin G.
        • Roseman J.M.
        Association between statin use and Alzheimer’s disease.
        Neuroepidemiology. 2004; 23: 94-98
        • Parvathy S.
        • Ehrlich M.
        • Pedrini S.
        • et al.
        Atorvastatin-induced activation of Alzheimer’s alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding.
        J. Neurochem. 2004; 90: 1005-1010
        • Vellas B.
        • Sol O.
        • Snyder P.J.
        • et al.
        EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study.
        Curr. Alzheimer Res. 2011; 8: 203-212
        • Marcade M.
        • Bourdin J.
        • Loiseau N.
        • et al.
        Etazolate, a neuroprotective drug linking GABA(a) receptor pharmacology to amyloid precursor protein processing.
        J. Neurochem. 2008; 106: 392-404
        • Rezai-Zadeh K.
        • Shytle D.
        • Sun N.
        • et al.
        Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.
        J. Neurosci. 2005; 25: 8807-8814
        • Obregon D.F.
        • Rezai-Zadeh K.
        • Bai Y.
        • et al.
        ADAM10 activation is required for green tea (−)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein.
        J. Biol. Chem. 2006; 281: 16419-16427
        • Feldman H.H.
        • Doody R.S.
        • Kivipelto M.
        • et al.
        Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe.
        Neurology. 2010; 74: 956-964
        • Farlow M.R.
        • Thompson R.E.
        • Wei L.J.
        • et al.
        A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of Bryostatin in the treatment of moderately severe to severe Alzheimer’s disease.
        J. Alzheimers Dis. 2019; 67: 555-570
        • Luo Y.
        • Bolon B.
        • Kahn S.
        • et al.
        Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation.
        Nat. Neurosci. 2001; 4: 231-232
        • Roberds S.L.
        • Anderson J.
        • Basi G.
        • et al.
        BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics.
        Hum. Mol. Genet. 2001; 10: 1317-1324
        • Ohno M.
        • Chang L.
        • Tseng W.
        • et al.
        Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1.
        Eur. J. Neurosci. 2006; 23: 251-260
        • Vingtdeux V.
        • Giliberto L.
        • Zhao H.
        • et al.
        AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.
        J. Biol. Chem. 2010; 285: 9100-9113
        • Uddin M.S.
        • Al Mamun A.
        • Kabir M.T.
        • et al.
        Neuroprotective role of polyphenols against oxidative stress-mediated neurodegeneration.
        Eur. J. Pharmacol. 2020; 886173412
        • Marambaud P.
        • Zhao H.
        • Davies P.
        Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides.
        J. Biol. Chem. 2005; 280: 37377-37382
        • Huang T.C.
        • Lu K.T.
        • Wo Y.Y.
        • Wu Y.J.
        • Yang Y.L.
        Resveratrol protects rats from Abeta-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation.
        PLoS One. 2011; 6e29102
        • Abushakra S.
        • Porsteinsson A.
        • Vellas B.
        • et al.
        Clinical benefits of Tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 alleles: the “APOE4 gene-dose effect”.
        J Prev Alzheimers Dis. 2016; 3: 219-228
        • Zhu C.W.
        • Grossman H.
        • Neugroschl J.
        • et al.
        A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: a pilot study.
        Alzheimers Dement (N Y). 2018; 4: 609-616
        • Ringman J.M.
        • Frautschy S.A.
        • Teng E.
        • et al.
        Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.
        Alzheimers Res. Ther. 2012; 4: 43
        • Panza F.
        • Lozupone M.
        • Logroscino G.
        • Imbimbo B.P.
        A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease.
        Nat. Rev. Neurol. 2019; 15: 73-88
        • Schenk D.
        • Barbour R.
        • Dunn W.
        • et al.
        Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
        Nature. 1999; 400: 173-177
        • Janus C.
        • Pearson J.
        • McLaurin J.
        • et al.
        A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease.
        Nature. 2000; 408: 979-982
        • Morgan D.
        • Diamond D.M.
        • Gottschall P.E.
        • et al.
        A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease.
        Nature. 2000; 408: 982-985
        • Bayer A.J.
        • Bullock R.
        • Jones R.W.
        • et al.
        Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD.
        Neurology. 2005; 64: 94-101
        • Lambracht-Washington D.
        • Rosenberg R.N.
        Advances in the development of vaccines for Alzheimer’s disease.
        Discov. Med. 2013; 15: 319-326
        • Wiessner C.
        • Wiederhold K.H.
        • Tissot A.C.
        • et al.
        The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects.
        J. Neurosci. 2011; 31: 9323-9331
        • Winblad B.
        • Andreasen N.
        • Minthon L.
        • et al.
        Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study.
        Lancet Neurol. 2012; 11: 597-604
        • Winblad B.M.
        • Floesser A.
        • Imbert G.
        • Dumortier T.
        • He Y.
        • Maguire R.P.
        • Karlsson M.
        • Östlund H.
        • Lundmark J.
        • Orgogozo J.-M.
        • Graf A.
        Results of the first-in-man study with the active Aβ Immunotherapy CAD106 in Alzheimer patients.
        Alzheimers Dement. 2009; : 5
        • Lambracht-Washington D.
        • Qu B.X.
        • Fu M.
        • Eagar T.N.
        • Stuve O.
        • Rosenberg R.N.
        DNA beta-amyloid(1-42) trimer immunization for Alzheimer disease in a wild-type mouse model.
        JAMA. 2009; 302: 1796-1802
        • Qu B.X.
        • Lambracht-Washington D.
        • Fu M.
        • Eagar T.N.
        • Stuve O.
        • Rosenberg R.N.
        Analysis of three plasmid systems for use in DNA a beta 42 immunization as therapy for Alzheimer’s disease.
        Vaccine. 2010; 28: 5280-5287
        • Rosenberg R.N.
        • Fu M.
        • Lambracht-Washington D.
        Active full-length DNA Abeta42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology.
        Alzheimers Res. Ther. 2018; 10: 115
        • Arndt J.W.
        • Qian F.
        • Smith B.A.
        • et al.
        Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-beta.
        Sci. Rep. 2018; 8: 6412
        • Food, Administration D
        FDA grants accelerated approval for Alzheimer’s drug.
        2021
        • Knopman D.S.
        • Jones D.T.
        • Greicius M.D.
        Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019.
        Alzheimers Dement. 2021; 17: 696-701
        • Kuller L.H.
        • Lopez O.L.
        ENGAGE and EMERGE: truth and consequences?.
        Alzheimers Dement. 2021; 17: 692-695
        • Budd-Haeberlein S.
        • Von Hein C.
        • Tian Y.
        • Chalkias S.
        • Muralidharan K.
        EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease.
        Clinical Trials on Alzheimer’s Disease Conference. 2019; : 4-7
        • Lin G.
        • Whittington M.
        • Synnott P.
        • et al.
        Aducanumab for Alzheimer’s disease: effectiveness and value; draft evidence report.
        Institute for Clinical and Economic Review. 2021; 5
        • Alexander G.C.
        • Emerson S.
        • Kesselheim A.S.
        Evaluation of Aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility.
        JAMA. 2021; 325: 1717-1718
        • Alexander G.C.
        • Karlawish J.
        The problem of Aducanumab for the treatment of Alzheimer disease.
        Ann. Intern. Med. 2021; 174 (Epub 2021 Jun 17. PMID: 34138642): 1303-1304https://doi.org/10.7326/M21-2603
        • Wallace W.C.
        • Akar C.A.
        • Lyons W.E.
        • Kole H.K.
        • Egan J.M.
        • Wolozin B.
        Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity.
        Brain Res. Mol. Brain Res. 1997; 52: 213-227
        • Smith-Swintosky V.L.
        • Pettigrew L.C.
        • Craddock S.D.
        • Culwell A.R.
        • Rydel R.E.
        • Mattson M.P.
        Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury.
        J. Neurochem. 1994; 63: 781-784
        • Luo J.J.
        • Wallace W.
        • Riccioni T.
        • Ingram D.K.
        • Roth G.S.
        • Kusiak J.W.
        Death of PC12 cells and hippocampal neurons induced by adenoviral-mediated FAD human amyloid precursor protein gene expression.
        J. Neurosci. Res. 1999; 55: 629-642
        • Whitson J.S.
        • Selkoe D.J.
        • Cotman C.W.
        Amyloid beta protein enhances the survival of hippocampal neurons in vitro.
        Science. 1989; 243: 1488-1490
        • Plant L.D.
        • Boyle J.P.
        • Smith I.F.
        • Peers C.
        • Pearson H.A.
        The production of amyloid beta peptide is a critical requirement for the viability of central neurons.
        J. Neurosci. 2003; 23: 5531-5535
        • Giuffrida M.L.
        • Caraci F.
        • Pignataro B.
        • et al.
        Beta-amyloid monomers are neuroprotective.
        J. Neurosci. 2009; 29: 10582-10587
        • Lopez-Toledano M.A.
        • Shelanski M.L.
        Neurogenic effect of beta-amyloid peptide in the development of neural stem cells.
        J. Neurosci. 2004; 24: 5439-5444
        • Rao K.S.
        • Hegde M.L.
        • Anitha S.
        • et al.
        Amyloid beta and neuromelanin--toxic or protective molecules? The cellular context makes the difference.
        Prog. Neurobiol. 2006; 78: 364-373
        • Sinha M.
        • Bhowmick P.
        • Banerjee A.
        • Chakrabarti S.
        Antioxidant role of amyloid beta protein in cell-free and biological systems: implication for the pathogenesis of Alzheimer disease.
        Free Radic. Biol. Med. 2012; 56: 184-192
        • Bishop G.M.
        • Robinson S.R.
        Human Abeta1-42 reduces iron-induced toxicity in rat cerebral cortex.
        J. Neurosci. Res. 2003; 73: 316-323
        • Robinson S.R.
        • Bishop G.M.
        Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer’s disease.
        Neurobiol. Aging. 2002; 23: 1051-1072
        • Whitehouse P.J.G.
        • Saini V.
        • Alexander G.C.
        • Avorn J.
        • Brownlee S.
        • Camp C.
        • Carome M.A.
        • Chertkow M.
        • Fugh-Berman A.
        • George D.R.
        • Howard R.J.
        • Richard E.
        • Kesselheim A.S.
        • Langa K.M.
        • Larson E.B.
        • Perry G.
        • Schneider L.S.
        Call for the Accelerated Withdrawal of Aducanumab.
        (Accessed on January 8, 2022)