The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Harnessing Genetic Complexity to Enhance Translatability of Alzheimer’s Disease Mouse Models: A Path toward Precision Medicine
Open accessAbstract
An individual's genetic makeup plays a large role in determining susceptibility to Alzheimer's disease (AD) but has largely been ignored in preclinical studies. To test the hypothesis that incorporating genetic diversity into mouse models of AD would improve translational potential, we combined a well-established mouse model of AD with a genetically diverse reference panel to generate mice that harbor identical high-risk human mutations but differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of human AD mutations on both cognitive and pathological phenotypes. We then validate this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD. Overall, work here both introduces a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.
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“One source of differences may be that most studies have used only the C57BL/6J strain10, known to be relatively resistant to the transgenes effects.”
From Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice (2026) · cites this paper as [10]
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“On a positive note, the use of diverse AD-BXD F1 models10 avoids the risk of idiosyncratic effects caused by studying mutations and other transgenes on a single genetic background.”
From Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice (2026) · cites this paper as [10]
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“The protocol used matches that previously used in the AD-BXD F1s10 83.”
From Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice (2026) · cites this paper as [10]
In the citing paper
“a PRS derived from human LOAD GWAS [96] showed significant association with cognitive outcomes across genetically diverse AD mice at 14 months of age [288]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [288]
In the citing paper
“efforts to expand existing AD mouse models through the inclusion of genetic diversity [288, 289] have resulted in resources that show a more significant overlap with human AD transcriptional profiles than models on a single genetic background [288]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [288]
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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
The Molecular Signatures Database Hallmark Gene Set Collection
Liberzon, A., Birger, C., Thorvaldsdóttir, H., Ghandi, M., Mesirov, J. P., & Tamayo, P. (2015) · Cell Systems · doi:10.1016/j.cels.2015.12.004 · Cited by 13,807
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 8×
“This panel, which we term the AD-BXDs, combines two well-established resources: (1) the 5XFAD transgenic line on an otherwise fully inbred C57BL/6J (B6) background that recapitulates various aspects of the human disease, including amyloid-b42 accumulation, cognitive deficits, and neuron loss (Oakley et al., 2006) and…”
InfluentialComplement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708
Zerbino, D. R., Achuthan, P., Akanni, W., Amode, M. R., Barrell, D., Bhai, J., Billis, K., Cummins, C., Gall, A., Girón, C. G., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx1098 · Cited by 2,605
Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease
Zhang, B., Gaiteri, C., Bodea, L.-G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., Zhang, C., Xie, T., Tran, L., Dobrin, R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.030 · Cited by 1,657
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Items 201–202 of 202
Giffin, K. A., Puranik, N., Bustamante, A. C., Padilla, M., Zeng, Z., Randolph, G., Wheaton, L., Moore, S. J., Newstead, M. W., Denstaedt, S. J., et al. (2026) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2026.101309
Gene therapy in Alzheimer’s disease (AD)
Bemanalizadeh, M., Ashrafi, M., Eslami, M., Moein, S., Kazemi, A., & Mansouri, V. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-40467-2.00014-2
Metadata
- Authors
- Neuner, S. M., Heuer, S. E., Huentelman, M. J., O’Connell, K. M. S., & Kaczorowski, C. C.
- Affiliations
- University of Tennessee Health Science Center (US)
- Tufts University (US)
- Translational Genomics Research Institute (US)
- Jackson Laboratory (US)
- Corresponding author
- Kaczorowski, Catherine C.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 101
- Issue
- 3
- Pages
- 399-411.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6886697
- OpenAlex
- W2908182575
- Cited by
- 202
- References
- 51
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 27 · 2023: 31 · 2022: 31 · 2021: 27 · 2020: 30 · 2019: 30
- FWCI
- 14.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- NIA (R01AG057914)
- BrightFocus Foundation (A2016397S)
- National Institute on Aging (R01AG054180, F31AG050357, R01AG059778)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102918)
- Evnin family
- University of Tennessee Health Science Center Neuroscience Institute
- Translational Genomics Research Institute
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, mouse model, genetic diversity, translational research, precision medicine, cognitive phenotypes, amyloid pathology, transcriptomics, genetic susceptibility
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Female, Genotype, Male, Mice, Inbred C57BL, Species Specificity, Mice, Translational Research, Biomedical, Precision Medicine
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