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Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease
Bernhardt AM, Rodríguez-Baz Í, Aldecoa I, Arranz J, Arriola-Infante JE, Maure-Blesa L, Carmona-Iragui M, Longen S et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-06-01
Topic: Amyloid, tau and blood-test diagnosis
Introduction Alpha-synuclein (αSyn) seed amplification assay (SAA) enables in vivo study of αSyn but remains underexplored in Down syndrome-associated Alzheimer's disease (DSAD). Methods We analyzed αSyn-SAA in cerebrospinal fluid (CSF) from 270 adults with Down syndrome, from the Down Alzheimer Barcelona Neuroimaging Initiative and from the AD21 cohort from the Department of Neurology at the University Hospital, Ludwig Maximilian University of Munich, Germany. Neuropathological examinations were conducted in 19 brain donors (five with ante mortem CSF). Participants were classified as asymptomatic or symptomatic (prodromal/dementia) Alzheimer's disease (AD). CSF Aβ1-42/1-40, CSF and plasma p-Tau181, and neurofilament light chain (NfL) levels were measured. Neuropathological evaluations assessed AD neuropathological changes and Lewy body pathology (LBP). Results ΑSyn-SAA was positive in 9.2% of cases, independent of age or cognitive status. Symptomatic αSyn-positive cases exhibited higher plasma NfL levels than αSyn-negative cases (31 vs 21 pg/mL, p = 0.027). LBP was observed in 47% of necropsies. The individual with severe neocortical LBP was αSyn-SAA-positive. Discussion These findings highlight LBP prevalence in DSAD but suggest current SAA may fail to detect limited αSyn deposition. Highlights αSyn-SAA positivity in DSAD is 9.2%, similar to ADAD but lower than sporadic AD. Misfolded αSyn was detectable from early ages in individuals with DS. Positivity rates did not vary with age or clinical status in DS. Plasma NfL levels are higher in symptomatic αSyn-SAA positive versus negative cases. CSF αSyn seeding activity was associated with high neocortical LBP at necropsy.
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APA 7th
Bernhardt, A. M., Í, R.-B., Aldecoa, I., Arranz, J., Arriola-Infante, J. E., Maure-Blesa, L., et al. (2025). Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.70342
Vancouver
Bernhardt AM, Í R.-B, Aldecoa I, Arranz J, Arriola-Infante JE, Maure-Blesa L, et al. Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.70342. PMID: 40528443.
BibTeX
@article{bernhardt2025-40528443,
author = {Bernhardt, A. M. and Í, Rodríguez-Baz and Aldecoa, I. and Arranz, J. and Arriola-Infante, J. E. and Maure-Blesa, L. and Carmona-Iragui, M. and Longen, S. and others},
title = {{Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.70342},
pmid = {40528443},
url = {https://doi.org/10.1002/alz.70342}
}
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Key findings
- Results ΑSyn-SAA was positive in 9.2% of cases, independent of age or cognitive status.
- Discussion These findings highlight LBP prevalence in DSAD but suggest current SAA may fail to detect limited αSyn deposition.
- Plasma NfL levels are higher in symptomatic αSyn-SAA positive versus negative cases.
- CSF αSyn seeding activity was associated with high neocortical LBP at necropsy.
Why it matters
In cerebrospinal fluid from 270 adults with Down syndrome, an alpha-synuclein seed amplification assay was positive in 9.2% of cases, and Lewy body pathology was found in 47% of necropsies. The authors suggest the current assay may fail to detect limited alpha-synuclein deposition, so this is about measuring co-pathology, not treating or preventing Alzheimer's disease.
Study details
- Participants270
- Effect size9.2%
- Evidence strengthModerate
How this study scored 54/100
Published in a leading specialty journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (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 | 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 | 270 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 8 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 4.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Johannes Levin: h-index 72 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Ludwig-Maximilians-Universität München: institution h-index 1,224 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 13 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40528443) |
| Free to read | 2 / 2 | Free to read |
| Total | 54 / 100 | — |
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