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Two-step detection of Lewy body pathology via smell-function testing and CSF α-synuclein seed amplification
Mastenbroek SE, Collij LE, Vogel JW, Caldera S, Serrano GE, Adler CH, Vargiu CM, Palmqvist S, Barkhof F, Parchi P, et al.. Nature Communications, 2025-08-05
Topic: Brain proteins, microglia and lab models
Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assays (SAAs) can detect Lewy body pathology (LBP) with high accuracy but are invasive and costly. To address these challenges, this study evaluated a two-step workflow combining prescreening via smell-function testing with confirmatory CSF α-syn SAA testing only in individuals with reduced smell, for predicting postmortem LBP status. Among 358 autopsied participants, the two-step workflow predicted brain LBP with high accuracy overall (94%), and within clinical subgroups (clinical parkinsonism=95%; clinical Alzheimer's disease [AD]=94%; clinically unimpaired [CU]=93%). It reduced the need for confirmatory CSF testing by 43% overall (23% clinical parkinsonism; 35% clinical AD; 80% CU). In an independent in vivo cohort (N=1209), the workflow predicted CSF α-syn SAA status with 79% accuracy and reduced CSF testing by 26%. This approach may reduce invasive CSF testing, alleviating patient burden and lowering healthcare costs.
Key findings
- Among 358 autopsied participants, the two-step workflow predicted brain LBP with high accuracy overall (94%), and within clinical subgroups (clinical parkinsonism=95%; clinical Alzheimer's disease [AD]=94%; clinically unimpaired [CU]=93%).
- It reduced the need for confirmatory CSF testing by 43% overall (23% clinical parkinsonism; 35% clinical AD; 80% CU).
Why it matters
This study evaluated a two-step approach combining smell-function testing with confirmatory CSF α-synuclein seed amplification to detect Lewy body pathology. Among 358 autopsied participants, the workflow predicted brain Lewy body pathology with 94% accuracy and reduced the need for confirmatory CSF testing by 43%, which the authors say may reduce invasive testing and lower healthcare costs.
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Study details
- Study designcohort
- Participants1,567
- Effect size94% accuracy vs autopsy; 43% reduction in CSF testing
- Evidence strengthEarly
Limitations
Autopsy cohort from a single brain bank; smell loss has many other causes, especially after COVID-19; accuracy in the living cohort was lower; not yet validated prospectively in clinical practice.
How this study scored 63/100
Published in a leading specialty journal, and it is a cohort study following people over time. Scored zero for randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 62 of the 98 points we could judge it on, which is 63 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Communications) |
| Journal's citation record | 4 / 4 | Nature Communications: journal h-index 747 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 2 / 5 | Rated “early” 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 | 3 / 4 | 1,567 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.4× 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 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Oskar Hansson: h-index 148 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 11 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40764485) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 62 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 62 of the 98 points we could judge it on is 63 out of 100. |
| Total | 63 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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
Mastenbroek, S. E., Collij, L. E., Vogel, J. W., Caldera, S., Serrano, G. E., Adler, C. H., et al. (2025). Two-step detection of Lewy body pathology via smell-function testing and CSF α-synuclein seed amplification. Nature Communications. https://doi.org/10.1038/s41467-025-62458-7
Vancouver
Mastenbroek SE, Collij LE, Vogel JW, Caldera S, Serrano GE, Adler CH, et al. Two-step detection of Lewy body pathology via smell-function testing and CSF α-synuclein seed amplification. Nature Communications. 2025. doi:10.1038/s41467-025-62458-7. PMID: 40764485.
BibTeX
@article{mastenbroek2025-40764485,
author = {Mastenbroek, S. E. and Collij, L. E. and Vogel, J. W. and Caldera, S. and Serrano, G. E. and Adler, C. H. and Vargiu, C. M. and Palmqvist, S. and Barkhof, F. and Parchi, P. and others},
title = {{Two-step detection of Lewy body pathology via smell-function testing and CSF α-synuclein seed amplification}},
journal = {Nature Communications},
year = {2025},
doi = {10.1038/s41467-025-62458-7},
pmid = {40764485},
url = {https://doi.org/10.1038/s41467-025-62458-7}
}
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