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Multi-omics profiling reveals two distinct trajectories in the progression from mild cognitive impairment to Alzheimer's disease
Xiayao Guo, Hongwen Fu, Minghui Qin, Jiahui Kan, For the Alzheimer's Disease Neuroimaging Imitative. Journal of Alzheimer s Disease, 2025-08-06
Topic: Amyloid, tau and blood-test diagnosis
BackgroundAlzheimer's disease (AD) exhibits significant clinical and pathological heterogeneity, particularly during the mild cognitive impairment (MCI) transitional stage. Current understanding of the molecular drivers underlying distinct MCI progression trajectories remains incomplete, hindering the development of personalized interventions.ObjectiveThis study aims to integrate transcriptomic, epigenomic, and metabolomic data to identify distinct trajectories in the progression from MCI to AD, and to explore the underlying disease heterogeneity.MethodsWe integrated transcriptomic, epigenomic, and metabolomic data from MCI patients to model the progression to AD and stratified them into subtypes. We then examined molecular differences between MCI and AD within each subtype, identifying key immune microenvironments and regulatory pathways via immune cell infiltration analysis, WGCNA, and GO/KEGG analyses. Finally, we applied Cox regression to identify prognostic biomarkers and built a random forest prognostic model.ResultsOur analysis identified two distinct MCI-to-AD progression subtypes. Subtype 1 was marked by metabolic dysregulation and slower cognitive decline, while Subtype 2 was driven by chronic immune activation and exhibited faster cognitive decline. The trajectory subtypes captured molecular perturbations that were missed by traditional unclustered methods. Prognostic models based on these molecular signatures predicted disease progression over 1-5 years, with AUROC values ranging from 0.851 to 0.893 for Subtype 1 and from 0.878 to 0.927 for Subtype 2.ConclusionsOur findings highlight the importance of multi-omics trajectory stratification in understanding the heterogeneity of AD progression. The identification of two distinct progression trajectories provides insights into the underlying mechanisms of AD.
Key findings
- BackgroundAlzheimer's disease (AD) exhibits significant clinical and pathological heterogeneity, particularly during the mild cognitive impairment (MCI) transitional stage.
Why it matters
This study found two distinct molecular subtypes of progression from mild cognitive impairment to Alzheimer's disease: one with metabolic dysregulation and slower decline, and another with chronic immune activation and faster decline. These findings could help personalize interventions, but no treatment or cure is tested.
Study details
- Evidence strengthLow
How this study scored 33/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 32 of the 96 points we could judge it on, which is 33 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Alzheimer s Disease) |
| Journal's citation record | 2 / 4 | Journal of Alzheimer s Disease: journal h-index 218 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 3 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 0 / 3 | Southeast University: institution h-index 622 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40770955) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 32 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 32 of the 96 points we could judge it on is 33 out of 100. |
| Total | 33 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Guo, X., Fu, H., Qin, M., Kan, J., & Imitative, A. D. N. (2025). Multi-omics profiling reveals two distinct trajectories in the progression from mild cognitive impairment to Alzheimer's disease. Journal of Alzheimer s Disease. https://doi.org/10.1177/13872877251365210
Vancouver
Guo X, Fu H, Qin M, Kan J, Imitative ADN. Multi-omics profiling reveals two distinct trajectories in the progression from mild cognitive impairment to Alzheimer's disease. Journal of Alzheimer s Disease. 2025. doi:10.1177/13872877251365210. PMID: 40770955.
BibTeX
@article{guo2025-40770955,
author = {Guo, Xiayao and Fu, Hongwen and Qin, Minghui and Kan, Jiahui and Imitative, Alzheimer's Disease Neuroimaging},
title = {{Multi-omics profiling reveals two distinct trajectories in the progression from mild cognitive impairment to Alzheimer's disease}},
journal = {Journal of Alzheimer s Disease},
year = {2025},
doi = {10.1177/13872877251365210},
pmid = {40770955},
url = {https://doi.org/10.1177/13872877251365210}
}
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