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Plasma phosphorylated tau 217 concentrations, APOE genotype, and timing of cognitive impairment in individuals across diverse racial and ethnic groups: a pooled analysis of prospective cohort studies
Yuexuan Xu, Tamil Iniyan Gunasekaran, Yian Gu, Dolly Reyes-Dumeyer, Angel Piriz, Danurys Sanchez, Diones Rivera Mejia, Martin Medrano, et al.. The Lancet. Neurology, 2026-09-09
Topic: Brain proteins, microglia and lab models
Methods We did a pooled analysis of participant-level data from seven multi-ethnic prospective cohorts of older adults, including individuals with no cognitive impairment at increased risk of dementia and individuals with mild cognitive impairment or dementia, recruited through academic research centres and community-based settings in Canada, Dominican Republic, and USA. We evaluated whether APOE-ε4 carrier status modified the risk and timing of cognitive impairment associated with plasma p-tau217 concentration modelled as a continuous variable. At baseline, higher p-tau217 concentrations were associated with cognitive impairment (odds ratio 1·77, 95% CI 1·42-2·20) and this association was stronger in APOE-ε4 carriers (2·25, 1·52-3·34) than in non-carriers (1·52, 1·35-1·72). Higher p-tau217 concentrations at baseline were also associated with incident cognitive impairment (hazard ratio 1·41, 95% CI 1·22-1·64; for 1-SD increase of p-tau217 levels), with a stronger association in APOE-ε4 carriers (1·76, 1·36-2·26) than in non-carriers (1·26, 1·12-1·42). Each 1-SD increase in p-tau217 concentration was associated with a 24% shorter time to cognitive impairment among APOE-ε4 carriers, compared with 13% among non-carriers. Interpretation Plasma p-tau217 concentrations, considered together with APOE genotype, might help stratify risk and estimate the timing of future cognitive impairment in asymptomatic individuals who are at increased risk for Alzheimer's disease, such as those with a family history of dementia or known APOE-ε4 carrier status. These findings support the use of biomarker-informed approaches to guide monitoring and therapeutic intervention in appropriately selected at-risk individuals before the onset of clinical symptoms.
Key findings
- Methods We did a pooled analysis of participant-level data from seven multi-ethnic prospective cohorts of older adults, including individuals with no cognitive impairment at increased risk of dementia and individuals with mild cognitive impairment or dementia, recruited through academic research centres and community-based settings in Canada, Dominican Republic, and USA.
- We evaluated whether APOE-ε4 carrier status modified the risk and timing of cognitive impairment associated with plasma p-tau217 concentration modelled as a continuous variable.
- At baseline, higher p-tau217 concentrations were associated with cognitive impairment (odds ratio 1·77, 95% CI 1·42-2·20) and this association was stronger in APOE-ε4 carriers (2·25, 1·52-3·34) than in non-carriers (1·52, 1·35-1·72).
- Higher p-tau217 concentrations at baseline were also associated with incident cognitive impairment (hazard ratio 1·41, 95% CI 1·22-1·64; for 1-SD increase of p-tau217 levels), with a stronger association in APOE-ε4 carriers (1·76, 1·36-2·26) than in non-carriers (1·26, 1·12-1·42).
- Each 1-SD increase in p-tau217 concentration was associated with a 24% shorter time to cognitive impairment among APOE-ε4 carriers, compared with 13% among non-carriers.
Why it matters
Across seven multi-ethnic cohorts, higher blood p-tau217 levels were linked to cognitive impairment and to a shorter time until impairment, with stronger links in people carrying the APOE-ε4 gene. The authors suggest p-tau217 together with APOE genotype might help estimate risk and timing of future cognitive impairment.
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Study details
- Study designcohort
- Participants8,582
- Effect sizeHazard ratio for incident cognitive impairment per 1-SD p-tau217: 1.41 (95% CI 1.22-1.64) overall; 1.76 (1.36-2.26) in APOE-e4 carriers vs 1.26 (1.12-1.42) in non-carriers
- Evidence strengthHigh
Limitations
Cohorts used different recruitment and assays, harmonised statistically; many participants were at elevated familial risk; outcome was a clinical diagnosis without uniform biomarker confirmation.
How this study scored 59/100
Published in a leading specialty journal, and it is a cohort study following people over time. Scored zero for randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 58 of the 98 points we could judge it on, which is 59 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (The Lancet. Neurology) |
| Journal's citation record | 3 / 4 | The Lancet Neurology: journal h-index 457 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 8,582 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 2 year(s) since 2026 |
| 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 | 4 / 4 | Last-listed author Richard P Mayeux: h-index 158 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Columbia University: institution h-index 1,824 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42716078) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 58 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 58 of the 98 points we could judge it on is 59 out of 100. |
| Total | 59 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/S1474-4422(26)00313-3
- PubMed: 42716078
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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
Xu, Y., Gunasekaran, T. I., Gu, Y., Reyes-Dumeyer, D., Piriz, A., Sanchez, D., et al. (2026). Plasma phosphorylated tau 217 concentrations, APOE genotype, and timing of cognitive impairment in individuals across diverse racial and ethnic groups: a pooled analysis of prospective cohort studies. The Lancet. Neurology. https://doi.org/10.1016/S1474-4422(26)00313-3
Vancouver
Xu Y, Gunasekaran TI, Gu Y, Reyes-Dumeyer D, Piriz A, Sanchez D, et al. Plasma phosphorylated tau 217 concentrations, APOE genotype, and timing of cognitive impairment in individuals across diverse racial and ethnic groups: a pooled analysis of prospective cohort studies. The Lancet. Neurology. 2026. doi:10.1016/S1474-4422(26)00313-3. PMID: 42716078.
BibTeX
@article{xu2026-42716078,
author = {Xu, Yuexuan and Gunasekaran, Tamil Iniyan and Gu, Yian and Reyes-Dumeyer, Dolly and Piriz, Angel and Sanchez, Danurys and Mejia, Diones Rivera and Medrano, Martin and others},
title = {{Plasma phosphorylated tau 217 concentrations, APOE genotype, and timing of cognitive impairment in individuals across diverse racial and ethnic groups: a pooled analysis of prospective cohort studies}},
journal = {The Lancet. Neurology},
year = {2026},
doi = {10.1016/S1474-4422(26)00313-3},
pmid = {42716078},
url = {https://doi.org/10.1016/S1474-4422(26)00313-3}
}
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