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Cited by 53Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

The DOI matches its Crossref record; 244 of the 249 references it cites were found in a registry or an index.

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach

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Morató, Xavier, Pytel, Vanesa, Jofresa, Sara, Ruiz, Agustín, Boada, Mercè·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23169305PMC PMC9409252
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Abstract

Since 1906, when Dr. Alois Alzheimer first described in a patient “a peculiar severe disease process of the cerebral cortex”, people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60–70% of cases. Pathologically, AD is characterized by the deposition of amyloid β-peptide (Aβ) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer’s disease is needed.

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Figure 1 Anti-Aβ protein strategies for the development of DMT. Both active and passive immunotherapy are currently under evaluation for reducing amyloid deposition and related progression of cognitive impairment in AD (polyclonal vs. monoclonal approach). In parallel, other small molecules under study target Aβ upstream preventing Aβ misfolding and the generation of toxic peptides.
Figure 1 Anti-Aβ protein strategies for the development of DMT. Both active and passive immunotherapy are currently under evaluation for reducing amyloid deposition and related progression of cognitive impairment in AD (polyclonal vs. monoclonal approach). In parallel, other small molecules under study target Aβ upstream preventing Aβ misfolding and the generation of toxic peptides.CC BY · PubMed Central
Figure 2 Anti-Tau strategies for the development of DMT. Passive immunotherapy is the main strategy under evaluation for reducing the cell-to-cell spread of extracellular Tau. At this moment specific phosphor-Tau mAbs are under clinical development. Other strategies such as active vaccination and antisense oligonucleotides to reduce Tau levels are also under evaluation in clinical trials.
Figure 2 Anti-Tau strategies for the development of DMT. Passive immunotherapy is the main strategy under evaluation for reducing the cell-to-cell spread of extracellular Tau. At this moment specific phosphor-Tau mAbs are under clinical development. Other strategies such as active vaccination and antisense oligonucleotides to reduce Tau levels are also under evaluation in clinical trials.CC BY · PubMed Central
Figure 3 Anti-inflammatory strategies for the development of DMT. Inflammation plays a central role in AD and at this moment is the main therapeutical strategy in clinical development for AD. Some molecules target specific players of inflammation or microglial activation (such as TNFα, TREM2, or CD33) while others have a broader anti-inflammatory effect (GLP1 agonist, Plasma exchange).
Figure 3 Anti-inflammatory strategies for the development of DMT. Inflammation plays a central role in AD and at this moment is the main therapeutical strategy in clinical development for AD. Some molecules target specific players of inflammation or microglial activation (such as TNFα, TREM2, or CD33) while others have a broader anti-inflammatory effect (GLP1 agonist, Plasma exchange).CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Renee, 2015, CSF1 receptor signaling is necessary for microglia viability, which unmasks a cell that rapidly repopulates the microglia-depleted adult brain, Neuron, 82, 380
  2. Xiao, 2021, Group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate, Alzheimer‘s Dement., 7, 1

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Metadata

Authors
Morató, X., Pytel, V., Jofresa, S., Ruiz, A., & Boada, M.
Affiliations
  • Universitat Internacional de Catalunya (ES)
  • Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
Corresponding author
Morató, Xavier
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-08-18
Volume
23
Issue
16
Pages
9305
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23169305
PMC
PMC9409252
OpenAlex
W4292247066
Cited by
53
References
249
Citations by year
2026: 10 · 2025: 16 · 2024: 15 · 2023: 10 · 2022: 2
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords
Alzheimer's disease, disease-modifying therapy, symptomatic treatment, drug development pipeline, polypharmacology, personalized medicine, amyloid-beta, tau hyperphosphorylation, cholinesterase inhibitors, memantine, aducanumab, anti-amyloid monoclonal antibodies, neuroinflammation
MeSH terms
Donepezil, Alzheimer Disease, Animals, Humans, Memantine, Amyloid beta-Peptides, Patient-Centered Care, Polypharmacology

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