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APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-β
Cicognola C, Salvadó G, Smith R, Palmqvist S, Stomrud E, Betthauser TJ, Johnson SC, Janelidze S et al.. Brain : a journal of neurology, 2025-07-01
Topic: Amyloid, tau and blood-test diagnosis
Although APOE4 is strongly associated with amyloid-β (Aβ), its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from Aβ load. We found no independent effects of APOE4 carriership on insoluble tau in either cohort (BioFINDER-2 or WRAP), on both cross-sectional and longitudinal tau-PET in the temporal meta-ROI, when Aβ was present in the model (P = 0.531-0.949). In BioFINDER-2, there was a significant interaction between APOE4 and Aβ (b = 0.166, P < 0.001) in the entorhinal cortex at baseline. Mediation analysis revealed that Aβ load fully mediated most associations between APOE4 and tau (46%-112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217). In the largest cohort (BioFINDER-2), looking at APOE4 groups by the number of ε4 alleles, we found an interaction between APOE4 homozygotes and Aβ on tau-PET levels at baseline and over time in the temporal meta-ROI, whereas in the entorhinal cortex this effect was observed only at baseline. In conclusion, although APOE4 is strongly associated with Aβ aggregation, it seems to be associated minimally with longitudinal changes in soluble or insoluble p-tau levels at a given level of Aβ pathology, confirming the primacy of Aβ in driving tau pathology.
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APA 7th
Cicognola, C., Salvadó, G., Smith, R., Palmqvist, S., Stomrud, E., Betthauser, T. J., et al. (2025). APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-β. Brain : a journal of neurology. https://doi.org/10.1093/brain/awaf016
Vancouver
Cicognola C, Salvadó G, Smith R, Palmqvist S, Stomrud E, Betthauser TJ, et al. APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-β. Brain : a journal of neurology. 2025. doi:10.1093/brain/awaf016. PMID: 39817469.
BibTeX
@article{cicognola2025-39817469,
author = {Cicognola, C. and Salvadó, G. and Smith, R. and Palmqvist, S. and Stomrud, E. and Betthauser, T. J. and Johnson, S. C. and Janelidze, S. and others},
title = {{APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-β}},
journal = {Brain : a journal of neurology},
year = {2025},
doi = {10.1093/brain/awaf016},
pmid = {39817469},
url = {https://doi.org/10.1093/brain/awaf016}
}
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.
Key findings
- Although APOE4 is strongly associated with amyloid-β (Aβ), its relationship with tau accumulation is less understood.
- Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from Aβ load.
- We found no independent effects of APOE4 carriership on insoluble tau in either cohort (BioFINDER-2 or WRAP), on both cross-sectional and longitudinal tau-PET in the temporal meta-ROI, when Aβ was present in the model (P = 0.531-0.949).
- In BioFINDER-2, there was a significant interaction between APOE4 and Aβ (b = 0.166, P < 0.001) in the entorhinal cortex at baseline.
- Mediation analysis revealed that Aβ load fully mediated most associations between APOE4 and tau (46%-112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217).
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Study details
- Study designcross-sectional
- Participants1,370
- Effect sizeor 40.2
- Evidence strengthModerate
How this study scored 72/100
Published in a leading specialty journal, and it is a snapshot of people at one point in time. Scored zero for 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 and multi-centre collaboration, so those were left out: it earned 42 of the 58 points we could judge it on, which is 72 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 4 / 12 | A snapshot of people at one point in 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 | 3 / 4 | 1,370 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 | — / 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 39817469) |
| Free to read | 2 / 2 | Free to read |
| Points | 42 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 42 of the 58 points we could judge it on is 72 out of 100. |
| Total | 72 / 100 | — |
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