A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease

Panza, Francesco; Lozupone, Madia; Logroscino, Giancarlo; Imbimbo, Bruno P.

doi:10.1038/s41582-018-0116-6

Cited by 965Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease

Panza, Francesco, Lozupone, Madia, Logroscino, Giancarlo, Imbimbo, Bruno P.·2019·Nature Reviews Neurology

DOI 10.1038/s41582-018-0116-6

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Abstract

Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15-20 years before clinical symptoms occur, mainly owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease.

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Aβ buildup can start 15-20 years before clinical symptoms appear, indicating therapy effectiveness may depend on early intervention.
“Studies have shown that Aβ buildup can start 15–20 years before clinical symptoms appear, indicating that therapy effectiveness may depend on early intervention [88,89].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [88]

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Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice
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The Essential Role of Soluble Aβ Oligomers in Alzheimer’s Disease
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Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6
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Two Phase 2 Multiple Ascending–Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease
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Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs
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Anesthesia with Isoflurane Increases Amyloid Pathology in Mice Models of Alzheimer'S Disease
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Combined Treatment with a BACE Inhibitor and Anti-Aβ Antibody Gantenerumab Enhances Amyloid Reduction in APP London Mice
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Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review
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Physiological Roles of Amyloid-?? and Implications for its Removal in Alzheimer???s Disease
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Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis
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Effect of the inhaled anesthetics isoflurane, sevoflurane and desflurane on the neuropathogenesis of Alzheimer’s disease (Review)
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AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer’s Disease
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Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease.
Haeberlein, S. B., O'Gorman, J. T., Chiao, P.-C., Bussière, T., von Rosenstiel, P., Tian, Y., Zhu, Y., von Hehn, C., Gheuens, S., Skordos, L., et al. (2017) · PubMed · doi:10.14283/jpad.2017.39 · Cited by 88 · see citing works
Coronary Artery Bypass Surgery Provokes Alzheimer's Disease-Like Changes in the Cerebrospinal Fluid
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Simvastatin therapy prevents brain trauma‐induced increases in β‐amyloid peptide levels
Abrahamson, E. E., Ikonomović, M. D., Dixon, C. E., & DeKosky, S. T. (2009) · Annals of Neurology · doi:10.1002/ana.21731 · Cited by 87 · see citing works
Is Brain Amyloid Production a Cause or a Result of Dementia of The Alzheimer's Type?
Struble, R. G., Ala, T., Patrylo, P. R., Brewer, G. J., & Yan, X. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100846 · Cited by 84 · see citing works
Normal cognition in transgenic BRI2-Aβ mice
Kim, J., Chakrabarty, P., Hanna, A., March, A., Dickson, D. W., Borchelt, D. R., Golde, T., & Janus, C. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-15 · Cited by 83 · see citing works
Lessons from a BACE1 inhibitor trial: Off‐site but not off base
Lahiri, D. K., Maloney, B., Long, J. M., & Greig, N. H. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.11.004 · Cited by 82 · see citing works
Amyloid-β Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory
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Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models
Bouter, Y., López‐Noguerola, J. S., Tucholla, P., Crespi, G. A. N., Parker, M. W., Wiltfang, J., Miles, L. A., & Bayer, T. A. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1489-x · Cited by 74 · see citing works
Amyloid precursor protein (APP) contributes to pathology in the SOD1G93A mouse model of amyotrophic lateral sclerosis
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Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation
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A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8‐OH quinoline in Alzheimer's disease: The PBT2‐204 IMAGINE study
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Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies
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Cognitive impairment in nondiabetic middle-aged and older adults is associated with insulin resistance
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Multiple‐dose ponezumab for mild‐to‐moderate Alzheimer's disease: Safety and efficacy
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Coaccumulation of Calcium and β-Amyloid in the Thalamus after Transient Middle Cerebral Artery Occlusion in Rats
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Presence of Sodium Dodecyl Sulfate-Stable Amyloid β-Protein Dimers in the Hippocampus CA1 Not Exhibiting Neurofibrillary Tangle Formation
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BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides
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Monitoring of β-Amyloid Dynamics after Human Traumatic Brain Injury
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Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ‐54861911, a potent oral BACE inhibitor
Timmers, M., Broeck, B. V., Ramael, S., Slemmon, J., Waepenaert, K. D., Russu, A., Bogert, J., Stieltjes, H., Shaw, L. M. J., Engelborghs, S., et al. (2016) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.08.001 · Cited by 61 · see citing works
Open‐heart surgery increases cerebrospinal fluid levels of A lzheimer‐associated amyloid β
Reinsfelt, B., Westerlind, A., Blennow, K., Zetterberg, H., & RICKSTEN, S. ‐. (2012) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.2012.02769.x · Cited by 60 · see citing works
Regulation of Presynaptic Ca2+, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal β-Amyloid Fragment
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Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses
Yu, Y., Jans, D. C., Winblad, B. G., Tjernberg, L. O., & Schedin‐Weiss, S. (2018) · Life Science Alliance · doi:10.26508/lsa.201800028 · Cited by 58 · see citing works
Living with the enemy: a physiological role for the β-amyloid peptide
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O1‐06‐05: First‐in‐human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta‐amyloid levels after single dosing
Lai, R. Y. K., Albala, B., Kaplow, J. M., Aluri, J., Yen, M., & Satlin, A. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.05.237 · Cited by 57 · see citing works
Insulin, Synaptic Function, and Opportunities for Neuroprotection
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Chronic Sleep Restriction Induces Cognitive Deficits and Cortical Beta‐Amyloid Deposition in Mice via BACE 1‐Antisense Activation
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Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice
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An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies
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Detection of β-amyloid oligomers as a predictor of neurological outcome after brain injury: Laboratory investigation
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Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels
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Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies
Fuller, J. P., Stavenhagen, J. B., Christensen, S., Kartberg, F., Glennie, M. J., & Teeling, J. L. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1484-2 · Cited by 44 · see citing works
Rational heterodoxy: Cholesterol reformation of the amyloid doctrine
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The biochemical aftermath of anti-amyloid immunotherapy
Maarouf, C. L., Daugs, I. D., Kokjohn, T. A., Kalback, W. M., Patton, R., Luehrs, D. C., Masliah, E., Nicoll, J. A. R., Sabbagh, M. N., Beach, T. G., et al. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-39 · Cited by 43 · see citing works
Is ‘friendly fire’ in the brain provoking Alzheimer’s disease?
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Helicobacter pylori and the risk of dementia: A population‐based study
Fani, L., Wolters, F. J., Ikram, M. K., Bruno, M. J., Albert Hofman, D., Koudstaal, P. J., Murad, S. D., & Ikram, M. A. (2018) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2018.05.005 · Cited by 43 · see citing works
RESULTS FROM A PHASE II STUDY TO ASSESS THE CLINICAL AND IMMUNOLOGICAL ACTIVITY OF AFFITOPE® AD02 IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE
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Comparison of Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of the Amyloid &bgr; Monoclonal Antibody Solanezumab in Japanese and White Patients With Mild to Moderate Alzheimer Disease
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THE ALZHEIMER’S PREVENTION INITIATIVE GENERATION PROGRAM: EVALUATING CNP520 EFFICACY IN THE PREVENTION OF ALZHEIMER’S DISEASE
López, C. L., Caputo, A., Liu, F., Riviere, M., Rouzade‐Dominguez, M., Thomas, R. G., Langbaum, J. B. S., Lenz, R., Reiman, E. M., Graf, A., et al. (2017) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2017.37 · Cited by 36 · see citing works
Is Alzheimer's disease amyloidosis the result of a repair mechanism gone astray?
Kokjohn, T. A., Maarouf, C. L., & Roher, A. E. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.05.2429 · Cited by 30 · see citing works
Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage
Villarreal, S. A., Zhao, F., Hyde, L. A., Holder, D., Forest, T. W., Sondey, M., Chen, X., Sur, C., Parker, E. M., & Kennedy, M. E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170056 · Cited by 29 · see citing works
An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers
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ESTABLISHING COMPOSITE COGNITIVE ENDPOINTS FOR USE IN PRECLINICAL ALZHEIMER’S DISEASE TRIALS
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REVERSIBLE AND SPECIES-SPECIFIC DEPIGMENTATION EFFECTS OF AZD3293, A BACE INHIBITOR FOR THE TREATMENT OF ALZHEIMER’S DISEASE, ARE RELATED TO BACE2 INHIBITION AND CONFINED TO EPIDERMIS AND HAIR
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Alzheimer disease
Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606 · see citing works
Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689 · see citing works
Amyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019
Knopman, D. S., Jones, D. T., & Greicius, M. D. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12213 · Cited by 524 · see citing works
Gut microbiota and dysbiosis in Alzheimer's disease: Implications for pathogenesis and treatment
Liu, S., Gao, J., Zhu, M., Liu, K., & Zhang, H.-L. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02073-3 · Cited by 516 · see citing works
Microglia use TAM receptors to detect and engulf amyloid β plaques
Huang, Y., Happonen, K. E., Burrola, P. G., O’Connor, C., Hah, N., Huang, L., Nimmerjahn, A., & Lemke, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00913-5 · Cited by 483 · see citing works
Tau-targeting therapies for Alzheimer disease: Current status and future directions
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371 · see citing works
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00456 · Cited by 360 · see citing works
“There is an urgent need for developing pharmacological treatments with a diseasemodifying effect to halt the disease at its earliest preclinical stage where brain and cognitive functions can still be preserved (2, 3).”
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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review
Jeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101496 · Cited by 306 · see citing works
The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis
Tolar, M., Abushakra, S., & Sabbagh, M. (2020) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.09.075 · Cited by 275 · see citing works
Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab
Shi, M., Chu, F., Zhu, F., & Zhu, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.870517 · Cited by 275 · see citing works
Role of tau protein in Alzheimer’s disease: The prime pathological player
Muralidar, S., Ambi, S. V., Sekaran, S., Thirumalai, D., & Palaniappan, B. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.07.327 · Cited by 278 · see citing works
A Perspective on Multi-target Drugs for Alzheimer’s Disease
Benek, O., Korabecny, J., & Soukup, O. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.04.008 · Cited by 260 · see citing works
Prevention of dementia in an ageing world: Evidence and biological rationale
Grande, G., Qiu, C., & Fratiglioni, L. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101045 · Cited by 229 · see citing works
Sodium Oligomannate: First Approval
Syed, Y. Y. (2020) · Drugs · doi:10.1007/s40265-020-01268-1 · Cited by 187 · see citing works
Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology
Da Mesquita, S., Herz, J., Wall, M., Dykstra, T., de Lima, K. A., Norris, G. T., Dabhi, N., Kennedy, T., Baker, W., & Kipnis, J. (2021) · Science Advances · doi:10.1126/sciadv.abe4601 · Cited by 172 · see citing works
Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?
Panza, F., Lozupone, M., Seripa, D., & Imbimbo, B. P. (2019) · Annals of Neurology · doi:10.1002/ana.25410 · Cited by 178 · see citing works
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Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease
Harris, S. S., Wolf, F., De Strooper, B., & Busche, M. A. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.005 · Cited by 161 · see citing works
Time to test antibacterial therapy in Alzheimer’s disease
Panza, F., Lozupone, M., Solfrizzi, V., Watling, M., & Imbimbo, B. P. (2019) · Brain · doi:10.1093/brain/awz244 · Cited by 161 · see citing works
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Investigational BACE inhibitors for the treatment of Alzheimer’s disease
Imbimbo, B. P., & Watling, M. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1683160 · Cited by 132 · see citing works
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The Future of Precision Medicine in the Cure of Alzheimer’s Disease
Arafah, A., Khatoon, S., Rasool, I., Khan, A., Rather, M. A., Abujabal, K. A., Faqih, Y. A. H., Rashid, H., Rashid, S. M., Bilal Ahmad, S., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11020335 · Cited by 133 · see citing works
Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model
Zhang, Y., Fung, I. T. H., Sankar, P., Chen, X., Robison, L. S., Ye, L., D’Souza, S. S., Salinero, A. E., Kuentzel, M. L., Chittur, S. V., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000037 · Cited by 113 · see citing works
Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease
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Authors: Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P.
Affiliations: Casa Sollievo della Sofferenza (IT)
University of Bari Aldo Moro (IT)
Chiesi (Italy) (IT)
Corresponding author: Panza, Francesco
ORCID: Panza, Francesco
Lozupone, Madia
Logroscino, Giancarlo
Imbimbo, Bruno P.
Venue: Nature Reviews Neurology
Publisher: Springer Science and Business Media LLC
Published: 2019-01-04
Volume: 15
Issue: 2
Pages: 73-88
ISSN: 1759-4758 (ISSN-L)
1759-4766
DOI: 10.1038/s41582-018-0116-6
OpenAlex: W2907547898
Cited by: 965
References: 221
Citations by year: 2026: 58 · 2025: 103 · 2024: 117 · 2023: 151 · 2022: 141 · 2021: 154 · 2020: 176 · 2019: 64 · 2018: 1
FWCI: 15.87
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Neurology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, amyloid-beta, amyloid-beta oligomers, amyloid-beta clearance, amyloid plaques, monoclonal antibodies, disease-modifying therapy, clinical trial failure, sporadic Alzheimer's disease, risk factor control
MeSH terms: Alzheimer Disease, Animals, Humans, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Drug Delivery Systems, Amyloid Precursor Protein Secretases, Antibodies, Monoclonal, Humanized

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A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease

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