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Longitudinal plasma biomarkers and multimodal PET across APOE ε4 genotypes: a prospective cohort study
Koivumäki M, Snellman A, Ekblad L, Benedet A, Zetterberg H, Rinne J.. Research Square, 2026-11-01
Topic: Plasma and spinal-fluid biomarkers
Background In preclinical Alzheimer's disease (AD), longitudinal trajectories of blood-based biomarkers and their relationship to brain amyloid pathology, synaptic density and neuroinflammation in cognitively unimpaired individuals stratified by apolipoprotein E ( APOE ) ε4 genotype remain poorly characterized. Methods We measured plasma tau phosphorylated at threonine 217 (p-tau217), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), synaptosomal-associated protein 25 (SNAP25) and neurogranin (NRGN) using the nucleic acid-linked immuno-sandwich assay (NULISA) platform at baseline (n = 60) and after 4.4 years (n = 45) in cognitively unimpaired older adults ( APOE ε4/ε4, n = 19; ε4/ε3, n = 21; ε3/ε3, n = 20 at baseline). Longitudinal biomarker changes were analyzed using linear mixed-effects models. Associations with [ 11 C]PiB (amyloid) and [ 11 C]PK11195 (neuroinflammation) positron emission tomography (PET) at baseline and [ 11 C]UCB-J (synaptic density) PET were examined using multiple linear regression. Results GFAP increased over time in all genotype groups and NfL in the ε4/ε4 and ε3/ε3 groups, with no group differences in rate of change. Plasma p-tau217 was the only biomarker robustly associated with amyloid burden at both timepoints. Synaptic markers showed minimal longitudinal change and no association with synaptic density PET. Conclusions These findings support a model in which p-tau217 specifically tracks amyloid-driven pathological progression, while markers of neurodegeneration reflect broader age-related processes that are not associated with APOE genotype.
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APA 7th
Koivumäki, M., Snellman, A., Ekblad, L., Benedet, A., Zetterberg, H., & Rinne, J. (2026). Longitudinal plasma biomarkers and multimodal PET across APOE ε4 genotypes: a prospective cohort study. Research Square. https://doi.org/10.21203/rs.3.rs-11294615/v1
Vancouver
Koivumäki M, Snellman A, Ekblad L, Benedet A, Zetterberg H, Rinne J. Longitudinal plasma biomarkers and multimodal PET across APOE ε4 genotypes: a prospective cohort study. Research Square. 2026. doi:10.21203/rs.3.rs-11294615/v1.
BibTeX
@article{koivumaki2026-19abfe03,
author = {Koivumäki, M. and Snellman, A. and Ekblad, L. and Benedet, A. and Zetterberg, H. and Rinne, J.},
title = {{Longitudinal plasma biomarkers and multimodal PET across APOE ε4 genotypes: a prospective cohort study}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11294615/v1},
url = {https://doi.org/10.21203/rs.3.rs-11294615/v1}
}
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Key findings
- Results GFAP increased over time in all genotype groups and NfL in the ε4/ε4 and ε3/ε3 groups, with no group differences in rate of change.
- Plasma p-tau217 was the only biomarker robustly associated with amyloid burden at both timepoints.
- Conclusions These findings support a model in which p-tau217 specifically tracks amyloid-driven pathological progression, while markers of neurodegeneration reflect broader age-related processes that are not associated with APOE genotype.
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Study details
- Study designlongitudinal study
- Participants60
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 42 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on 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 26 of the 62 points we could judge it on, which is 42 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 1 / 4 | 60 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 26 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 26 of the 62 points we could judge it on is 42 out of 100. |
| Total | 42 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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