Olfactory and Neural Deficits in Late-Onset Alzheimer’s Mouse Model
Publication Title: Behavioral deficits and exacerbated neural and hemodynamic odor responses during lifespan of a mouse model of late onset Alzheimer’s disease expressing humanized APOEε4 and Trem2*R47H
Summary
- Question
- This study investigated the effects of age and genetic mutations on behavioral and neural changes in a mouse model of late-onset Alzheimer’s disease (LOAD). The researchers focused on mice carrying humanized APOEε4 and TREM2*R47H genes, both of which are linked to increased risk of Alzheimer’s in humans. They aimed to assess whether this mouse model could mimic age-dependent features of LOAD, including behavioral deficits and changes in neural and blood flow responses in the brain's olfactory system.
- Why it Matters
- Alzheimer’s disease, the leading cause of dementia, predominantly occurs in older adults and lacks effective early diagnostic tools. Most current animal models mimic early-onset Alzheimer’s, which is rare compared to the more common late-onset form. The development of a reliable animal model for LOAD can aid in identifying early biomarkers, testing interventions, and better understanding disease progression. The researchers highlight that olfactory dysfunction, an early sign of Alzheimer’s, may offer a non-invasive way to detect the disease early, potentially through smell tests or imaging techniques.
- Methods
- The researchers studied mice with humanized APOEε4 and TREM2*R47H genes, along with wild-type controls, across three age groups. Behavioral tests assessed anxiety, memory, and olfactory function. Neural activity and blood flow responses in the dorsal olfactory bulb (a brain region critical for smell) were measured using optical imaging during exposure to different odors. The study also evaluated neurovascular coupling, which refers to the relationship between neural activity and blood flow.
- Key Findings
- The APOEε4.TREM2 mice exhibited age-dependent deficits in anxiety, spatial memory, and odor-guided foraging. Neural and blood flow responses to odors in the olfactory bulb were significantly heightened compared to controls, particularly in older mice. Despite these changes, the coupling between neural activity and blood flow remained stable, indicating that vascular hyperactivity might be a compensatory mechanism for declining brain function. Importantly, the mice did not show signs of anhedonia (loss of pleasure), nest-building impairments, or sleep disturbances.
- Implications
- These findings suggest that the APOEε4.TREM2 mouse model replicates key aspects of LOAD, including age-related behavioral and neural changes. The observed olfactory deficits and vascular hyperresponsiveness align with early symptoms in human Alzheimer’s patients, supporting the use of this model for studying disease progression and testing potential treatments. Additionally, the results highlight the potential of using smell tests and functional imaging to detect Alzheimer’s in its early stages.
- Next Steps
- The authors recommend further research to refine the APOEε4.TREM2 model by addressing limitations, such as reduced TREM2 expression due to the R47H mutation. Future studies should explore the molecular mechanisms underlying vascular hyperresponsiveness and evaluate the potential of olfactory-based functional imaging as an early diagnostic tool for LOAD.
- Funding Information
- This research was supported by the National Science Foundation (awards NSF BRAIN 1555880 and NSF/CIHR/DFG/FRQ/UKRI-MRC Next Generation Networks for Neuroscience Program #2014217). It also received funding from the National Institute on Aging (awards R21AG085366, 1R21AG091590, and 5R01AG084681). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Yale University also provided funding and support for this research.
Full Citation
Izydorczak M, Oumov M, Udhwani M, Fostok F, Coronas-Samano G, Sanganahalli B, Herman P, Hyder F, Verhagen J. Behavioral deficits and exacerbated neural and hemodynamic odor responses during lifespan of a mouse model of late onset Alzheimer’s disease expressing humanized APOEε4 and Trem2*R47H. Frontiers In Aging Neuroscience 2026, 18: 1622135. PMID: 41777674, PMCID: PMC12950773, DOI: 10.3389/fnagi.2026.1622135.
This AI-assisted summary has been reviewed and approved by at least one of the study's authors to ensure it accurately reflects the research.
Authors
Misha Izydorczak
First AuthorJustus Verhagen, PhD
Last AuthorAssociate Research Scientist