Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women.
Level 3 - non-randomized controlled study
Prospective cohort study assessing a prognostic biomarker over long-term follow-up
PubMed 41805953 · doi:10.1001/jamanetworkopen.2026.1295
What was done
This cohort study evaluated 2,766 cognitively unimpaired women aged 65 to 79 years recruited between 1996 and 1999 across 39 US clinical sites in the Women's Health Initiative Memory Study (who were randomized to estrogen alone vs placebo or estrogen plus progestin vs placebo). Baseline plasma p-tau217 was measured in 2024 using the ALZpath Simoa assay. Participants were followed for up to 25 years through 2021 for the primary outcome of incident mild cognitive impairment (MCI) or probable dementia, analyzed via Cox proportional hazards regression.
What was found
During follow-up, 1,311 participants developed MCI or dementia (849 MCI, 752 dementia). Each 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR 2.43; 95% CI, 2.18–2.71), MCI alone (HR 1.94; 95% CI, 1.72–2.20), and dementia alone (HR 3.17; 95% CI, 2.79–3.61). The association with dementia was stronger for women randomized to estrogen plus progestin (HR 4.18; 95% CI, 3.41–5.13) vs placebo (HR 3.07; 95% CI, 2.41–3.91; P for interaction = .04), but did not differ for estrogen alone vs placebo. Biomarker associations with MCI or dementia were larger in women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared to Black women (P for interaction < .001). P-tau217 was not associated with incident MCI in Black women, though the combination of p-tau217 and age showed similar discrimination in White women (AUC 72.0%; 95% CI, 70.3%–73.6%) and Black women (AUC 70.4%; 95% CI, 64.0%–78.0%).
Why it matters
Baseline plasma p-tau217 predicts incident MCI and dementia up to 25 years prior to diagnosis, though its prognostic strength is modified by age, race, APOE ε4 status, and hormone therapy exposure.
Limits
The study included only older postmenopausal women, limiting generalizability to men and younger populations. Non-White subgroups were smaller (486 Black and 196 Hispanic women), and blood samples were stored for over two decades prior to assay measurement.
Cited by
- supports Plasma p-tau217 levels begin to rise 20 years before the onset of mild cognitive impairment.