Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women

TL;DR

Higher levels of plasma phosphorylated tau 217 in older women are linked to a greater risk of developing mild cognitive impairment or dementia, with differences based on age, race, and hormone therapy.

Contribution

This study is the first to show how plasma p-tau217's association with cognitive decline varies by race, hormone therapy, and age in older women.

Findings

Higher p-tau217 levels strongly predict dementia, especially in women over 70, APOE ε4 carriers, and White women.

Hormone therapy with estrogen plus progestin increases dementia risk more in women with higher p-tau217.

P-tau217 was not associated with MCI in Black women, highlighting racial differences in biomarker relevance.

Abstract

This cohort study examines associations of baseline plasma phosphorylated tau 217 with incident mild cognitive impairment (MCI) or dementia and whether associations vary by age, race, APOE ε4 carrier status, or hormone therapy use among older men and women.

Do associations of plasma phosphorylated tau 217 (p-tau217) with incident mild cognitive impairment (MCI) and dementia vary by race, hormone therapy, age, or APOE ε4 carrier status?

In this cohort study among 2766 older women, associations of p-tau217 with incident dementia were larger in magnitude among women assigned to estrogen plus progestin vs placebo but did not vary for estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years, APOE ε4 carriers, and White compared with Black women.

These findings underscore the value of p-tau217 and show that many factors should be considered when examining its associations with cognitive outcomes.

There is limited research on the long-term associations of plasma phosphorylated tau 217 (p-tau217) with mild cognitive impairment (MCI) and dementia. No study has evaluated whether such associations vary by race or hormone therapy (HT) use.

To examine associations of baseline plasma p-tau217 with incident MCI and dementia and determine whether associations vary by age, race, APOE ε4 carrier status, or HT use.

This cohort study examined women recruited from 39 US clinical sites between 1996 and 1999 into the Women’s Health Initiative Memory Study who were randomized to either estrogen alone vs placebo or estrogen plus progestin vs placebo. Women were assessed for up to 25 years through 2021. Baseline plasma p-tau217 was measured in 2024 and analyzed between February and August 2025. Women aged 65 to 79 years who were cognitively unimpaired at baseline were included for this analysis.

Plasma p-tau217, quantified using the ALZpath Simoa assay.

The primary outcome was the combined end point of incident MCI or probable dementia. Secondary outcomes included MCI and dementia examined separately. Cause-specific hazard ratios (HRs) and 95% CIs for the association of p-tau217 with MCI or dementia were estimated using Cox proportional hazards regression models.

Among 2766 participants (mean [SD] age, 69.9 [3.8] years; 486 [17.9%] Black, 196 [7.1%] Hispanic, and 2007 [73.9%] White), 1311 developed the combined end point of MCI or dementia (849 participants with MCI and 752 participants with dementia). Every 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR, 2.43; 95% CI, 2.18-2.71) and each individual outcome (MCI: HR, 1.94; 95% CI, 1.72-2.20; dementia: HR, 3.17; 95% CI, 2.79-3.61). Associations of p-tau217 with dementia were larger in magnitude 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 significantly vary by estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared with Black women (P for interaction < .001). However, the combination of p-tau217 and age performed similarly in White women (area under the curve = 72.0%; 95% CI, 70.3%-73.6%) and Black women (area under the curve = 70.4%; 95% CI, 64.0%-78.0%). P-tau217 was not associated with incident MCI in Black women.

In this cohort study of cognitively unimpaired older women, p-tau217 was associated with incident MCI or dementia up to 25 years later. These findings suggest that age, race, APOE ε4, and HT use should be considered when examining associations of p-tau217 with cognitive outcomes.

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