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MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer’s disease
Kotredes KP, Pandey RS, Reagan AM, Sarica Z, O'Rourke R, Herrick S, Davis A, Garceau D et al.. Research Square, 2026-10-09
Topic: Genetics and APOE
Background Late-onset Alzheimer’s disease (LOAD) comprises more than 95% of all AD cases. Transgenic, overexpression animal models have off-target side effects, do not effectively produce the heterogeneity observed clinically in LOAD patients, and are therefore not best suited for preclinical therapeutic development. The Model Organism Development and Evaluation for Late-onset Alzheimer’s Disease (MODEL-AD) Consortium was established to develop novel mouse strains to model human-relevant genetic and environmental risk factors for LOAD. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in the MTHFR gene, notably 677C > T , are associated with ADRD, and we have previously shown the Mthfr 677C>T mouse model phenocopies humans carrying the variant and develops cerebrovascular deficits. Methods To examine the contributions of Mthfr 677C>T in the context of late-onset Alzheimer’s disease (LOAD), MODEL-AD created a novel mouse strain on the C57BL/6J (B6) background that was homozygous for Mthfr 677C>T , in combination with humanized Aβ , APOEe4 , and Trem2*R47H ( referred to as LOAD2.Mthfr 677C>T ) . Mice were assessed over multiple ages for disease-relevant phenotypes. Regular behavior measurements and biometric samples were collected longitudinally to 24 months of age. Blood and brain tissue were collected for transcriptomics, proteomics, human disease correlation, and neuropathology. Results Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr 677C>T mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients. Conclusions These data further support the use of the LOAD2.Mthfr 677C>T mouse model to study aspects of ADRD such as cerebrovascular compromise.
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APA 7th
Kotredes, K. P., Pandey, R. S., Reagan, A. M., Sarica, Z., O'Rourke, R., Herrick, S., et al. (2026). MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer’s disease. Research Square. https://doi.org/10.21203/rs.3.rs-11166891/v1
Vancouver
Kotredes KP, Pandey RS, Reagan AM, Sarica Z, O'Rourke R, Herrick S, et al. MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer’s disease. Research Square. 2026. doi:10.21203/rs.3.rs-11166891/v1.
BibTeX
@article{kotredes2026-6da14e5f,
author = {Kotredes, K. P. and Pandey, R. S. and Reagan, A. M. and Sarica, Z. and O'Rourke, R. and Herrick, S. and Davis, A. and Garceau, D. and others},
title = {{MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer’s disease}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11166891/v1},
url = {https://doi.org/10.21203/rs.3.rs-11166891/v1}
}
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Key findings
- Variants in the MTHFR gene, notably 677C > T , are associated with ADRD, and we have previously shown the Mthfr 677C>T mouse model phenocopies humans carrying the variant and develops cerebrovascular deficits.
- Results Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr 677C>T mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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