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Are mouse models of Alzheimer's disease truly flawed, or are we misusing them?

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Τίτλος: Are mouse models of Alzheimer's disease truly flawed, or are we misusing them?
Συγγραφείς: Calon F; Faculté de pharmacie, Université Laval, Québec, Canada; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada. Electronic address: Frederic.Calon@pha.ulaval.ca., Otaegui L; Faculté de pharmacie, Université Laval, Québec, Canada; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada., Bouali ML; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada; Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Québec, Canada., Hébert SS; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada; Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Québec, Canada.
Πηγή: Neuroscience [Neuroscience] 2026 Oct 15; Vol. 614, pp. 43-46. Date of Electronic Publication: 2026 Aug 02.
Τύπος έκδοσης: Journal Article; Review
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Science Country of Publication: United States NLM ID: 7605074 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7544 (Electronic) Linking ISSN: 03064522 NLM ISO Abbreviation: Neuroscience Subsets: MEDLINE
Imprint Name(s): Publication: [New York?] : Elsevier Science
Original Publication: Oxford, Elmsford, N. Y., Pergamon Press
Ιατρικοί όροι (MeSH): Alzheimer Disease* , Disease Models, Animal* , Mice, Transgenic*, Animals ; Mice ; Male ; Female ; Translational Research, Biomedical
Περίληψη: The first transgenic mouse models of Alzheimer's disease (AD) developed in the 1990 s were hailed as a major breakthrough. As newer generations of models have emerged over the decades after, they still face growing criticism for translating poorly into clinical outcomes, even if the effects of newer therapeutic compounds, including monoclonal antibodies, align well with those seen in mice. Like any disease model, AD mice have substantial limitations. The real issue is that they are often treated as miniature humans with AD, which they are not. Overreliance on specific pathogen-free (SPF) housing may also blunt immune-related endpoints and compromise translational relevance. The impact of biological sex and ambient temperature may also differ between animal models and humans. In this review, we argue that despite these limitations, they remain highly useful for specific scientific questions and preclinical development. They are far better suited for pharmacokinetic and biodistribution studies, and for testing target engagement in vivo on well-defined neuropathological processes. Thus, while criticisms of these models are justified, researchers have often used them with misaligned objectives. As discussed herein, these models should not be discarded, but used more thoughtfully, in ways that align with their true strengths.
(Copyright © 2026. Published by Elsevier Inc.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Pharmacodynamics; Pharmacokinetics; Target engagement; Transgenic mouse models; Translational neuroscience
Entry Date(s): Date Created: 20260802 Date Completed: 20260908 Latest Revision: 20260908
Update Code: 20260908
DOI: 10.1016/j.neuroscience.2026.07.069
PMID: 42543113
Βάση Δεδομένων: MEDLINE
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  Data: Are mouse models of Alzheimer's disease truly flawed, or are we misusing them?
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  Data: <searchLink fieldCode="AU" term="%22Calon+F%22">Calon F</searchLink>; Faculté de pharmacie, Université Laval, Québec, Canada; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada. Electronic address: Frederic.Calon@pha.ulaval.ca.<br /><searchLink fieldCode="AU" term="%22Otaegui+L%22">Otaegui L</searchLink>; Faculté de pharmacie, Université Laval, Québec, Canada; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada.<br /><searchLink fieldCode="AU" term="%22Bouali+ML%22">Bouali ML</searchLink>; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada; Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Québec, Canada.<br /><searchLink fieldCode="AU" term="%22Hébert+SS%22">Hébert SS</searchLink>; Axe Neurosciences - Centre de recherche du CHU de Québec - Université Laval, Québec, Canada; Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Québec, Canada.
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  Data: The first transgenic mouse models of Alzheimer's disease (AD) developed in the 1990 s were hailed as a major breakthrough. As newer generations of models have emerged over the decades after, they still face growing criticism for translating poorly into clinical outcomes, even if the effects of newer therapeutic compounds, including monoclonal antibodies, align well with those seen in mice. Like any disease model, AD mice have substantial limitations. The real issue is that they are often treated as miniature humans with AD, which they are not. Overreliance on specific pathogen-free (SPF) housing may also blunt immune-related endpoints and compromise translational relevance. The impact of biological sex and ambient temperature may also differ between animal models and humans. In this review, we argue that despite these limitations, they remain highly useful for specific scientific questions and preclinical development. They are far better suited for pharmacokinetic and biodistribution studies, and for testing target engagement in vivo on well-defined neuropathological processes. Thus, while criticisms of these models are justified, researchers have often used them with misaligned objectives. As discussed herein, these models should not be discarded, but used more thoughtfully, in ways that align with their true strengths.<br /> (Copyright © 2026. Published by Elsevier Inc.)
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