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Multiplex Cerebrospinal Fluid Proteomics Identifies Biomarkers Predicting Neuropsychiatric Symptom Progression in Mild Cognitive Impairment and Alzheimer's Disease
Xue Han, Shouqiang Zhu, Heng Zhang, Tianjiao Xia, Xiaoping Gu. The FASEB Journal, 2026-01-19
Topic: Brain proteins, microglia and lab models
Neuropsychiatric symptoms (NPS), commonly concomitant with Alzheimer's disease (AD), substantially impair the quality of life and accelerate disease progression, yet reliable biomarkers for early identification of individuals at high NPS risk remain elusive. In this study, we leveraged the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), incorporating longitudinal data from 509 participants diagnosed with mild cognitive impairment (MCI) or mild AD at baseline and followed up for 1 and 2 years. The dataset included cerebrospinal fluid (CSF) proteomic profiles comprising 6361 proteins, along with comprehensive data on NPS diagnosis, cognitive function, and AD pathology. LASSO regression and recursive feature elimination were applied to identify NPS-related CSF proteins, followed by random forest modeling to predict NPS risk at baseline, 1 year, and 2 years. Incorporating selected CSF proteins significantly improved NPS prediction compared to the reference model, with AUCs increasing from 0.64 to 0.76 at baseline, 0.63 to 0.80 at 1 year, and 0.63 to 0.81 at 2 years. Notably, Cyclin-Dependent Kinase-Like 2 (CDKL2), Nidogen 2 (NID2), and Lin-7 Homolog B (LIN7B) were consistently associated with NPS across all time points. Among them, CDKL2 and NID2 were significantly associated with AD biomarkers and cognitive scores, and their expression changes were independently validated in cerebrospinal fluid from a mouse model, highlighting their potential as stable predictive biomarkers. Our findings highlight CSF proteomic signatures that robustly predict NPS progression in individuals with MCI and mild AD, offering a framework for early risk stratification and precision intervention in NPS.
Key findings
- Incorporating selected CSF proteins significantly improved NPS prediction compared to the reference model, with AUCs increasing from 0.64 to 0.76 at baseline, 0.63 to 0.80 at 1 year, and 0.63 to 0.81 at 2 years.
- Notably, Cyclin-Dependent Kinase-Like 2 (CDKL2), Nidogen 2 (NID2), and Lin-7 Homolog B (LIN7B) were consistently associated with NPS across all time points.
- Among them, CDKL2 and NID2 were significantly associated with AD biomarkers and cognitive scores, and their expression changes were independently validated in cerebrospinal fluid from a mouse model, highlighting their potential as stable predictive biomarkers.
- Our findings highlight CSF proteomic signatures that robustly predict NPS progression in individuals with MCI and mild AD, offering a framework for early risk stratification and precision intervention in NPS.
Why it matters
Adding selected cerebrospinal fluid proteins improved prediction of neuropsychiatric symptom risk in people with mild cognitive impairment or mild Alzheimer's disease over two years. This is a biomarker prediction study and does not test any treatment, cure or prevention.
Study details
- Study designlongitudinal study
- Participants509
- Evidence strengthModerate
How this study scored 54/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The FASEB Journal) |
| Journal's citation record | 3 / 4 | The FASEB Journal: journal h-index 401 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 509 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 19.0× 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 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Xiaoping Gu: h-index 7 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Nanjing University: institution h-index 850 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41553038) |
| Free to read | 2 / 2 | Free to read |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Han, X., Zhu, S., Zhang, H., Xia, T., & Gu, X. (2026). Multiplex Cerebrospinal Fluid Proteomics Identifies Biomarkers Predicting Neuropsychiatric Symptom Progression in Mild Cognitive Impairment and Alzheimer's Disease. The FASEB Journal. https://doi.org/10.1096/fj.202504014r
Vancouver
Han X, Zhu S, Zhang H, Xia T, Gu X. Multiplex Cerebrospinal Fluid Proteomics Identifies Biomarkers Predicting Neuropsychiatric Symptom Progression in Mild Cognitive Impairment and Alzheimer's Disease. The FASEB Journal. 2026. doi:10.1096/fj.202504014r. PMID: 41553038.
BibTeX
@article{han2026-41553038,
author = {Han, Xue and Zhu, Shouqiang and Zhang, Heng and Xia, Tianjiao and Gu, Xiaoping},
title = {{Multiplex Cerebrospinal Fluid Proteomics Identifies Biomarkers Predicting Neuropsychiatric Symptom Progression in Mild Cognitive Impairment and Alzheimer's Disease}},
journal = {The FASEB Journal},
year = {2026},
doi = {10.1096/fj.202504014r},
pmid = {41553038},
url = {https://doi.org/10.1096/fj.202504014r}
}
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