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Cited by 71Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Lost in translation: Inconvenient truths on the utility of mouse models in Alzheimer’s disease research

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Granzotto, Alberto, Vissel, Bryce, Sensi, Stefano L·2024·eLife
DOI 10.7554/elife.90633PMC PMC11434637
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Abstract

The recent, controversial approval of antibody-based treatments for Alzheimer’s disease (AD) is fueling a heated debate on the molecular determinants of this condition. The discussion should also incorporate a critical revision of the limitations of preclinical mouse models in advancing our understanding of AD. We critically discuss the limitations of animal models, stressing the need for careful consideration of how experiments are designed and results interpreted. We identify the shortcomings of AD models to recapitulate the complexity of the human disease. We dissect these issues at the quantitative, qualitative, temporal, and context-dependent levels. We argue that these models are based on the oversimplistic assumptions proposed by the amyloid cascade hypothesis (ACH) of AD and fail to account for the multifactorial nature of the condition. By shedding light on the constraints of current experimental tools, this review aims to foster the development and implementation of more clinically relevant tools. While we do not rule out a role for preclinical models, we call for alternative approaches to be explored and, most importantly, for a re-evaluation of the ACH.

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  • Most preclinical studies have examined Aβ and tau in isolation using either Aβ amyloidosis models or tauopathy models.

    “However, most preclinical studies have examined Aβ and tau in isolation, using either Aβ amyloidosis models that develop robust Aβ deposition without tau pathology, or tauopathy models that accumulate hyperphosphorylated tau in the absence of Aβ.”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [9]

    The Introduction’s Quantitative section says APP or tau-overexpressing mice remain the primary tools for AD research. Its Qualitative section describes the lack of tau pathology in APP models and hyperphosphorylated-tau inclusions in tau models. It does not establish the citing sentence’s further assertion that tauopathy models lack Aβ. (LLM, conf=0.83)

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Authors
Granzotto, A., Vissel, B., & Sensi, S. L.
Affiliations
  • University of Chieti-Pescara (IT)
  • UNSW Sydney (AU)
Corresponding author
Granzotto, Alberto
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-09-27
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.90633
PMC
PMC11434637
OpenAlex
W4402926058
Cited by
71
References
166
Citations by year
2026: 42 · 2025: 25 · 2024: 4
FWCI
4.05
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Horizon 2020 Framework Programme (841665)
  • European Union (D53D23019280001)
  • Alzheimer's Association (18PTC-19-602325, GEENA-Q-19-596282)
  • Italian Department of Health (RF-2013–02358785, NET-2011-02346784-1)
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, mouse model, amyloid hypothesis, preclinical models, translational research, complex diseases, experimental design, model limitations
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Humans, Mice

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