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Aβ positive, tau biomarker negative cognitive impairment is associated with significant non‐Alzheimer's disease neuropathologies
Konstantinos Ioannou, Richard J. Perrin, Khadidzha Abdullaieva, Marina Blūma, Konstantinos Poulakis, Antoine Leuzy, Dorota Religa, Elena Rodriguez‐Vieitez et al.. Alzheimer s & Dementia, 2025-12-01
Topic: Amyloid, tau and blood-test diagnosis
Abstract Background This study leverages biomarker and autopsy data with the aim to evaluate the impact of mixed pathologies on interpreting cognitive impairment within the Αβ and tau (AT) biomarker system. Method Individuals with at least one instance of antemortem CSF AD biomarkers measurement (Roche, Elecsys ®) and a full postmortem assessment were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Previously validated cut‐offs were used to define A+ (Aβ42 ≤ 981 pg/mL) and T+ ( p ‐tau181 ≥ 24.3 pg/mL). Aβ PET burden was quantified in‐house using the Centiloid pipeline. AT groups were compared with respect to cognitive performance, CSF α‐synuclein positivity (Amprion, SYNTap ®), Aβ PET burden, clinical comorbidities, and neuropathological evidence of proteinopathies associated with cognitive impairment or vascular brain injury (VBI). Mixed AD was defined as the copresence of Alzheimer's disease neuropathologic change (ADNC) and at least another non‐AD proteinopathy at autopsy. Result We identified and grouped 77 individuals by AT status (median [IQR] interval from CSF sampling to death = 3.13 [1.45, 5.69] years). Both A+T‐ and A+T+ groups were more severely cognitively impaired than the A‐T‐ group at CSF sampling (Table 1). The A+T‐ and A+T+ groups had similar demographics, frequency of CSF α‐synuclein positivity, Aβ PET burden and frequency of clinical comorbidities. The two A+ groups showed differences in APOE ε4 frequency (79% in A+T+ vs. 22% in A+T‐, p ‐value < 0.001) (Table 1). The A+T+ group showed a higher frequency of ADNC (100% vs. 78%, p ‐value = 0.008) than the A+T‐ group. When ADNC was present, the A+T‐ group exhibited a higher frequency of mixed AD (79% vs. 28%, p ‐value = 0.002) than the A+T+ group, even when taking VBI into consideration (Figure 1). Conclusion Cognitive impairment associated with Aβ positivity and low tau (A+T‐) is linked to mixed AD. These cases deviate from the expected disease path, as proposed by the most recent criteria (Jack CR Jr, et al. Alzheimers Dement. 2024) (Figure 2), and highlight the need for specific biomarkers for non‐AD proteinopathies.
Key findings
- AT groups were compared with respect to cognitive performance, CSF α‐synuclein positivity (Amprion, SYNTap ®), Aβ PET burden, clinical comorbidities, and neuropathological evidence of proteinopathies associated with cognitive impairment or vascular brain injury (VBI).
- Result We identified and grouped 77 individuals by AT status (median [IQR] interval from CSF sampling to death = 3.13 [1.45, 5.69] years).
- Conclusion Cognitive impairment associated with Aβ positivity and low tau (A+T‐) is linked to mixed AD.
Why it matters
Among 77 individuals with autopsy data, those who were Aβ positive but tau biomarker negative (A+T-) were as cognitively impaired as A+T+ individuals, and this group was linked to significant non-Alzheimer's disease neuropathologies. The findings suggest that cognitive impairment with Aβ positivity and low tau may often be due to mixed or non-Alzheimer's pathologies, which matters for interpreting biomarker results but does not offer a treatment or cure.
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Study details
- Participants77
- Evidence strengthLow
How this study scored 37/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| 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 | 1 / 5 | Rated “low” 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 | 77 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 0 / 6 | Cited 0.0× 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 | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Konstantinos Chiotis: h-index 27 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 2 countries |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Total | 37 / 100 | — |
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Read the original
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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
Ioannou, K., Perrin, R. J., Abdullaieva, K., Blūma, M., Poulakis, K., Leuzy, A., et al. (2025). Aβ positive, tau biomarker negative cognitive impairment is associated with significant non‐Alzheimer's disease neuropathologies. Alzheimer s & Dementia. https://doi.org/10.1002/alz70856_104812
Vancouver
Ioannou K, Perrin RJ, Abdullaieva K, Blūma M, Poulakis K, Leuzy A, et al. Aβ positive, tau biomarker negative cognitive impairment is associated with significant non‐Alzheimer's disease neuropathologies. Alzheimer s & Dementia. 2025. doi:10.1002/alz70856_104812.
BibTeX
@article{ioannou2025-256d8475,
author = {Ioannou, Konstantinos and Perrin, Richard J. and Abdullaieva, Khadidzha and Blūma, Marina and Poulakis, Konstantinos and Leuzy, Antoine and Religa, Dorota and Rodriguez‐Vieitez, Elena and others},
title = {{Aβ positive, tau biomarker negative cognitive impairment is associated with significant non‐Alzheimer's disease neuropathologies}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz70856_104812},
url = {https://doi.org/10.1002/alz70856_104812}
}
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