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Curated Papers > Recent high-impact research on "Alzheimer's Disease" (IF≥30, last 5 years)

Alzheimer's disease: From immunotherapy to immunoprevention. ​

Literature Information ​

DOI10.1016/j.cell.2023.08.021
PMID37729908
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2023
Times Cited108
KeywordsARIA, Tau, aducanumab, aduhelm, cerebral amyloid antipathy
Literature TypeJournal Article, Review, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0092-8674
Pages4260-4270
Issue186(20)
AuthorsMathias Jucker, Lary C Walker

TL;DR ​

Recent trials of Aβ-immunotherapy have demonstrated that clearing aggregated Aβ from the brains of symptomatic Alzheimer's patients can modestly slow disease progression, underscoring the need for improved understanding of disease mechanisms and early intervention. The study advocates for an immunoprevention strategy that combines clinical trial insights with preclinical models to enhance antibody selection, optimize intervention timing, identify early biomarkers, and reduce side effects.

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ARIA · Tau · aducanumab · aduhelm · cerebral amyloid antipathy

Abstract ​

Recent Aβ-immunotherapy trials have yielded the first clear evidence that removing aggregated Aβ from the brains of symptomatic patients can slow the progression of Alzheimer's disease. The clinical benefit achieved in these trials has been modest, however, highlighting the need for both a deeper understanding of disease mechanisms and the importance of intervening early in the pathogenic cascade. An immunoprevention strategy for Alzheimer's disease is required that will integrate the findings from clinical trials with mechanistic insights from preclinical disease models to select promising antibodies, optimize the timing of intervention, identify early biomarkers, and mitigate potential side effects.

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Primary Questions Addressed ​

  1. What are the specific mechanisms by which Aβ-immunotherapy affects the progression of Alzheimer's disease?
  2. How can early biomarkers be identified to enhance the effectiveness of immunoprevention strategies?
  3. What role do preclinical disease models play in the development of new immunotherapeutic approaches for Alzheimer's?
  4. How can the timing of intervention be optimized to maximize the benefits of immunoprevention in Alzheimer's patients?
  5. What potential side effects should be considered when developing immunotherapy and immunoprevention strategies for Alzheimer's disease?

Key Findings ​

Research Background and Objectives ​

Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid-beta (Aβ) plaques in the brain, which is associated with cognitive decline. Recent trials of Aβ-immunotherapy have demonstrated that removing these aggregates in symptomatic patients can slow disease progression. However, the observed clinical benefits have been modest, indicating a critical need for a more profound understanding of the disease mechanisms and the necessity of early intervention.

Main Methods/Materials/Experimental Design ​

The study emphasizes the development of an immunoprevention strategy for Alzheimer's disease. This approach involves:

  1. Integration of Clinical and Preclinical Findings: Combining insights from clinical trials with mechanistic data from preclinical models.
  2. Selection of Promising Antibodies: Identifying antibodies that effectively target Aβ aggregates.
  3. Optimization of Intervention Timing: Determining the most effective time points for intervention in the disease progression.
  4. Identification of Early Biomarkers: Discovering biomarkers that can indicate the early stages of Alzheimer's disease.
  5. Mitigation of Side Effects: Addressing potential adverse effects associated with immunotherapy.

The following flowchart summarizes the technical route of the proposed immunoprevention strategy:

Mermaid diagram

Key Results and Findings ​

  • Efficacy of Aβ-Immunotherapy: Recent trials provide evidence that Aβ removal can slow Alzheimer's progression, albeit with modest clinical benefits.
  • Need for Early Intervention: The results underscore the importance of addressing the disease at earlier stages for more effective treatment outcomes.

Main Conclusions/Significance/Innovation ​

The study highlights the urgent need for an integrated immunoprevention strategy for Alzheimer's disease. By synthesizing findings from both clinical and preclinical studies, researchers can better select therapeutic antibodies, optimize intervention timing, and identify biomarkers that facilitate early diagnosis. This approach is innovative as it combines various research domains to enhance the effectiveness of Alzheimer's treatment.

Research Limitations and Future Directions ​

  • Limitations: The modest clinical benefits observed in trials suggest that current therapies may not be sufficient alone, and further exploration into the underlying mechanisms of Alzheimer's disease is needed.
  • Future Directions: Future research should focus on:
    • Enhancing the understanding of the pathogenic cascade of Alzheimer's.
    • Developing more effective immunotherapies that can be administered earlier in the disease process.
    • Identifying and validating new biomarkers for early detection of Alzheimer's disease.

This structured approach will facilitate the development of more effective strategies to combat Alzheimer's disease, potentially leading to better patient outcomes.

References ​

  1. Donanemab in Early Alzheimer's Disease. - Mark A Mintun;Albert C Lo;Cynthia Duggan Evans;Alette M Wessels;Paul A Ardayfio;Scott W Andersen;Sergey Shcherbinin;JonDavid Sparks;John R Sims;Miroslaw Brys;Liana G Apostolova;Stephen P Salloway;Daniel M Skovronsky - The New England journal of medicine (2021)
  2. Brain borders at the central stage of neuroimmunology. - Justin Rustenhoven;Jonathan Kipnis - Nature (2022)
  3. Passive immunotherapies targeting Aβ and tau in Alzheimer's disease. - Steven S Plotkin;Neil R Cashman - Neurobiology of disease (2020)
  4. Immunotherapeutic approaches for Alzheimer's disease. - Thomas Wisniewski;Fernando Goñi - Neuron (2015)
  5. Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease. - Tze How Mok;Akin Nihat;Nour Majbour;Danielle Sequeira;Leah Holm-Mercer;Thomas Coysh;Lee Darwent;Mark Batchelor;Bradley R Groveman;Christina D Orr;Andrew G Hughson;Amanda Heslegrave;Rhiannon Laban;Elena Veleva;Ross W Paterson;Ashvini Keshavan;Jonathan M Schott;Imogen J Swift;Carolin Heller;Jonathan D Rohrer;Alexander Gerhard;Christopher Butler;James B Rowe;Mario Masellis;Miles Chapman;Michael P Lunn;Jan Bieschke;Graham S Jackson;Henrik Zetterberg;Byron Caughey;Peter Rudge;John Collinge;Simon Mead - Brain : a journal of neurology (2023)
  6. Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the AppNL-F/NL-F knock-in mouse model of Alzheimer's disease. - Emelie Andersson;Nina Schultz;Takashi Saito;Takaomi C Saido;Kaj Blennow;Gunnar K Gouras;Henrik Zetterberg;Oskar Hansson - Alzheimer's research & therapy (2023)
  7. Biomarkers for neurodegenerative diseases. - Oskar Hansson - Nature medicine (2021)
  8. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. - Mathias Jucker;Lary C Walker - Nature neuroscience (2018)
  9. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. - Oliver Preische;Stephanie A Schultz;Anja Apel;Jens Kuhle;Stephan A Kaeser;Christian Barro;Susanne Gräber;Elke Kuder-Buletta;Christian LaFougere;Christoph Laske;Jonathan Vöglein;Johannes Levin;Colin L Masters;Ralph Martins;Peter R Schofield;Martin N Rossor;Neill R Graff-Radford;Stephen Salloway;Bernardino Ghetti;John M Ringman;James M Noble;Jasmeer Chhatwal;Alison M Goate;Tammie L S Benzinger;John C Morris;Randall J Bateman;Guoqiao Wang;Anne M Fagan;Eric M McDade;Brian A Gordon;Mathias Jucker; - Nature medicine (2019)
  10. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. - Clifford R Jack;David A Bennett;Kaj Blennow;Maria C Carrillo;Billy Dunn;Samantha Budd Haeberlein;David M Holtzman;William Jagust;Frank Jessen;Jason Karlawish;Enchi Liu;Jose Luis Molinuevo;Thomas Montine;Creighton Phelps;Katherine P Rankin;Christopher C Rowe;Philip Scheltens;Eric Siemers;Heather M Snyder;Reisa Sperling; - Alzheimer's & dementia : the journal of the Alzheimer's Association (2018)

Literatures Citing This Work ​

  1. Targeting autophagy in Alzheimer's disease: Animal models and mechanisms. - Xiao-Wen Zhang;Xiang-Xing Zhu;Dong-Sheng Tang;Jia-Hong Lu - Zoological research (2023)
  2. Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. - Yang Yang;Alexey G Murzin;Sew Peak-Chew;Catarina Franco;Holly J Garringer;Kathy L Newell;Bernardino Ghetti;Michel Goedert;Sjors H W Scheres - Acta neuropathologica communications (2023)
  3. Advances in the study of the effects of gut microflora on microglia in Alzheimer's disease. - Jin-Jing Wu;Zhe Wei - Frontiers in molecular neuroscience (2023)
  4. Therapeutic potential of curcumin on the cognitive decline in animal models of Alzheimer's disease: a systematic review and meta-analysis. - Longmin Fan;Zheyu Zhang - Naunyn-Schmiedeberg's archives of pharmacology (2024)
  5. Causal relationships between peripheral immune cells and Alzheimer's disease: a two-sample Mendelian randomization study. - Jing Liao;Yongquan Zhang;Zhanhong Tang;Pinjing Liu;Luoyi He - Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology (2024)
  6. Olfactory deficit: a potential functional marker across the Alzheimer's disease continuum. - Dongming Liu;Jiaming Lu;Liangpeng Wei;Mei Yao;Huiquan Yang;Pin Lv;Haoyao Wang;Yajing Zhu;Zhengyang Zhu;Xin Zhang;Jiu Chen;Qing X Yang;Bing Zhang - Frontiers in neuroscience (2024)
  7. Protective roles of peroxiporins AQP0 and AQP11 in human astrocyte and neuronal cell lines in response to oxidative and inflammatory stressors. - Zein Amro;Lyndsey E Collins-Praino;Andrea J Yool - Bioscience reports (2024)
  8. Border-associated macrophages in the central nervous system. - Rui Sun;Haowu Jiang - Journal of neuroinflammation (2024)
  9. Investigating the causal relationship between immune cell and Alzheimer's disease: a mendelian randomization analysis. - Min Shen;Linlin Zhang;Chen Chen;Xiaocen Wei;Yuning Ma;Yuxia Ma - BMC neurology (2024)
  10. Isolation, Bioactivity, and Molecular Docking of a Rare Gastrodin Isocitrate and Diverse Parishin Derivatives from Gastrodia elata Blume. - Jie Zhou;Jia-Qian Chen;Shilin Gong;Yu-Juan Ban;Li Zhang;Ying Liu;Jian-Lin Wu;Na Li - ACS omega (2024)

... (98 more literatures)

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