Home › Research › Brain tissue and pathology
Limbic Alzheimer's co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy
Janna van Wetering, Natasja A C Deshayes, Joëlle Boone, Inês Rodrigues Fernandes, Dagmar H Hepp, Henk W Berendse, Laura E Jonkman, Annemieke J M Rozemuller et al.. Acta neuropathologica, 2025-09-18
Topic: Plasma and spinal-fluid biomarkers
The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and pTDP-43, though their relevance remains unclear. Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of α-syn (KM51), Aβ (6F/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (n = 70) donors from the Netherlands Brain Bank. APOE-ε4 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. Aβ, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA + AD cases had a higher age at death (75 ± 7 vs. 64 ± 7, p < 0.001), and more frequently APOE-ε4 alleles (p < 0.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, p ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, p ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, p < 0.001). No robust correlations were found between total α-syn burden and Aβ or p-tau. Misdiagnoses increased with co-pathology burden (Aβ: p = 0.040; p-tau: p = 0.020) and age at onset (80% in those with onset > 75 years). Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.
Key findings
- Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, p ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, p ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, p < 0.001).
- Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset.
- These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.
Study details
- Participants70
- Evidence strengthModerate
How this study scored 57/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, 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, multi-centre collaboration and free to read, so those were left out: it earned 32 of the 56 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| 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 | 1 / 4 | 70 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 | — / 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40968282) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 32 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 32 of the 56 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
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
van Wetering, J., Deshayes, N. A. C., Boone, J., Fernandes, I. R., Hepp, D. H., Berendse, H. W., et al. (2025). Limbic Alzheimer's co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy. Acta neuropathologica. https://doi.org/10.1007/s00401-025-02940-0
Vancouver
van Wetering J, Deshayes NAC, Boone J, Fernandes IR, Hepp DH, Berendse HW, et al. Limbic Alzheimer's co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy. Acta neuropathologica. 2025. doi:10.1007/s00401-025-02940-0. PMID: 40968282.
BibTeX
@article{vanwetering2025-40968282,
author = {van Wetering, Janna and Deshayes, Natasja A C and Boone, Joëlle and Fernandes, Inês Rodrigues and Hepp, Dagmar H and Berendse, Henk W and Jonkman, Laura E and Rozemuller, Annemieke J M and others},
title = {{Limbic Alzheimer's co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy}},
journal = {Acta neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02940-0},
pmid = {40968282},
url = {https://doi.org/10.1007/s00401-025-02940-0}
}
Related studies in Brain tissue and pathology
Also in Brain tissue and pathology
124 studies in the library are filed under Brain tissue and pathology with no topic tag they share with another; these are this study's neighbours in a fixed tour of them. The Brain tissue and pathology hub.