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Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease
Mengel D, Soter E, Ott JM, Wacker M, Leyva A, Peters O, Hellmann-Regen J, Schneider LS et al.. Molecular psychiatry, 2025-04-18
Topic: Amyloid, tau and blood-test diagnosis
Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer's disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.
Key findings
- The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1).
- In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.
Why it matters
In 457 participants, elevated and faster-rising plasma p181 levels in amyloid-positive individuals with subjective cognitive decline predicted cognitive decline and transition to mild cognitive impairment. This is a biomarker study supporting staging and risk identification, not a test of any treatment, cure, or prevention for Alzheimer's disease.
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Study details
- Study designlongitudinal study
- Participants457
- Evidence strengthModerate
How this study scored 65/100
Published in a leading specialty 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. We have no data on senior author's track record, so that was left out: it earned 62 of the 96 points we could judge it on, which is 65 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | 3 / 4 | Molecular Psychiatry: journal h-index 318 (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 | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 457 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 | 3 / 7 | Cited 20 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 12.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 2 / 4 | Cited 20 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 | 2 / 3 | Imperial College London: institution h-index 1,744 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 31 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40247130) |
| Free to read | 2 / 2 | Free to read |
| Points | 62 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 62 of the 96 points we could judge it on is 65 out of 100. |
| Total | 65 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41380-025-03021-0
- PubMed: 40247130
- Original source →
- Free full text: Molecular Psychiatry →
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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Mengel, D., Soter, E., Ott, J. M., Wacker, M., Leyva, A., Peters, O., et al. (2025). Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease. Molecular psychiatry. https://doi.org/10.1038/s41380-025-03021-0
Vancouver
Mengel D, Soter E, Ott JM, Wacker M, Leyva A, Peters O, et al. Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease. Molecular psychiatry. 2025. doi:10.1038/s41380-025-03021-0. PMID: 40247130.
BibTeX
@article{mengel2025-40247130,
author = {Mengel, D. and Soter, E. and Ott, J. M. and Wacker, M. and Leyva, A. and Peters, O. and Hellmann-Regen, J. and Schneider, L. S. and others},
title = {{Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease}},
journal = {Molecular psychiatry},
year = {2025},
doi = {10.1038/s41380-025-03021-0},
pmid = {40247130},
url = {https://doi.org/10.1038/s41380-025-03021-0}
}
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