Plasma Phosphorylated Tau 217 as a Predictor of Mild Cognitive Impairment and Dementia in Older Women

Alzheimer’s disease and related dementias continue to be among the most pressing public health challenges worldwide. Early detection is crucial, and researchers are increasingly exploring plasma biomarkers as a minimally invasive method for identifying individuals at risk. Among these, plasma phosphorylated tau 217, known as p-tau217, has emerged as a particularly promising biomarker. A recent study published in JAMA Network Open evaluated the long-term associations of plasma p-tau217 with mild cognitive impairment (MCI) and dementia in older women, providing new insights into its predictive value and potential interactions with age, race, genetics, and hormone therapy.

Understanding Plasma Phosphorylated Tau 217

Tau proteins play a critical role in stabilizing microtubules in neurons. In Alzheimer’s disease, tau proteins become abnormally phosphorylated, leading to the formation of neurofibrillary tangles that are associated with cognitive decline. Plasma p-tau217 is a form of phosphorylated tau detectable in the blood. Studies have shown that p-tau217 correlates with Alzheimer’s pathology in the brain and cerebrospinal fluid, offering a less invasive alternative to traditional diagnostic tests such as cerebrospinal fluid sampling or positron emission tomography scans.

Unlike other biomarkers, p-tau217 demonstrates high specificity and accuracy for detecting Alzheimer’s-related pathology. Its measurement in plasma opens the door for widespread screening and monitoring, especially in community settings where access to advanced imaging or lumbar puncture procedures may be limited.

The Women’s Health Initiative Memory Study

The study analyzed data from the Women’s Health Initiative Memory Study (WHIMS), which included 2766 cognitively unimpaired postmenopausal women aged 65 to 79 years at baseline. These participants were originally enrolled in hormone therapy clinical trials, where they were randomly assigned to either estrogen alone, estrogen plus progestin, or placebo. The women were followed for up to 25 years, with cognitive assessments conducted annually and plasma samples for p-tau217 analysis collected in 2024.

This cohort offered a unique opportunity to investigate whether baseline plasma p-tau217 predicts future cognitive decline and whether its associations vary according to age, race, APOE ε4 carrier status, and hormone therapy exposure.

Key Findings

The study revealed several important findings regarding plasma p-tau217 and cognitive outcomes:

Association With Mild Cognitive Impairment and Dementia

Higher baseline p-tau217 levels were strongly associated with increased risk of both MCI and dementia. Specifically, every one standard deviation increase in log-transformed p-tau217 was associated with:

• A 2.43-fold higher risk of developing MCI or dementia combined.
• A 1.94-fold higher risk of MCI alone.
• A 3.17-fold higher risk of dementia alone.

These results suggest that plasma p-tau217 is a robust predictor of long-term cognitive decline in older women, even decades before clinical symptoms appear.

Interaction With Hormone Therapy

Interestingly, the association between p-tau217 and dementia was stronger among women assigned to estrogen plus progestin compared with placebo, with a hazard ratio of 4.18 versus 3.07. However, no significant differences were observed for estrogen alone versus placebo. This finding indicates that certain hormone therapy regimens may amplify the risk of dementia in women with elevated p-tau217, highlighting the importance of considering hormone exposure in dementia risk assessment.

Age and Genetic Factors

Age and genetics also influenced the relationship between p-tau217 and cognitive decline. Women over 70 years old showed stronger associations between elevated p-tau217 and dementia. Similarly, APOE ε4 carriers had higher risk associated with elevated p-tau217 compared with noncarriers. These observations align with prior research showing that advanced age and APOE ε4 genotype are strong risk factors for Alzheimer’s disease.

Racial Differences

The study also examined racial differences in p-tau217 associations. Among White women, p-tau217 predicted both MCI and dementia, whereas among Black women, it predicted dementia but not MCI. Despite these differences, the combination of p-tau217 and age yielded similar discriminative accuracy for dementia in both racial groups, suggesting that p-tau217 may be a useful biomarker across diverse populations for identifying future dementia risk.

Quartile Analysis

The research included an analysis based on quartiles of p-tau217 levels. Women in the highest quartile had substantially higher risk of cognitive decline compared with those in the lowest quartile. For dementia, the highest quartile was associated with a seven-fold increase in hazard relative to the lowest quartile. This indicates a potential dose-response relationship, where higher p-tau217 levels correspond to higher risk of dementia.

Implications for Clinical Practice

The findings of this study have several important implications for clinical care and research:

1. Early Detection: Plasma p-tau217 could serve as an accessible biomarker for identifying older women at risk of developing MCI or dementia, even before symptoms appear.
2. Personalized Risk Assessment: Incorporating age, race, APOE ε4 status, and hormone therapy exposure can enhance the predictive value of p-tau217, allowing for more personalized assessments.
3. Screening and Monitoring: Blood-based biomarkers like p-tau217 may facilitate large-scale screening in primary care settings, improving early intervention opportunities.
4. Research Applications: Plasma p-tau217 could be used as a stratification tool in clinical trials targeting Alzheimer’s disease and cognitive decline, ensuring participants at highest risk receive appropriate interventions.

Comparison With Prior Research

The study’s findings are consistent with previous research showing that plasma p-tau217 predicts incident dementia. For example, smaller studies have reported two-fold or higher hazard ratios for dementia associated with elevated p-tau217 over 4 to 16 years of follow-up. The WHIMS study extended these findings by demonstrating predictive value over 25 years, providing robust long-term evidence.

Additionally, the study contributes to understanding racial differences in biomarker performance. While prior research has primarily focused on White participants, this study included a significant proportion of Black women, highlighting potential variations in p-tau217 associations with MCI and the importance of considering demographic and clinical context.

Limitations

While this study offers valuable insights, several limitations should be considered:

• The study included only postmenopausal women, so findings may not generalize to men or younger populations.
• Dementia was not classified by subtype, meaning results reflect all-cause dementia rather than Alzheimer’s-specific dementia.
• The sample size for Black women was smaller, which may affect the precision of estimates in this group.
• Hormone therapy regimens used in WHI may differ from contemporary formulations, limiting direct generalization to current clinical practice.

Strengths

The study also has notable strengths:

• A large, diverse cohort of community-dwelling older women followed for up to 25 years.
• Randomized assignment to hormone therapy, which allowed for evaluation of interactions without the confounding of self-selection.
• High-quality measurement of plasma p-tau217 using a validated assay.
• Detailed follow-up with adjudicated cognitive outcomes.

Future Directions

The findings support further research on the clinical use of plasma p-tau217. Future studies should:

• Explore whether p-tau217 can predict cognitive decline in men and younger adults.
• Examine the effects of modern hormone therapy formulations on p-tau217 associations.
• Investigate mechanisms underlying racial differences in MCI prediction.
• Determine how p-tau217 can be integrated into multi-modal risk assessment tools alongside imaging and genetic data.

Conclusion

Plasma p-tau217 is a promising biomarker for predicting long-term cognitive decline in older women. The WHIMS study demonstrated that higher baseline p-tau217 levels were associated with increased risk of MCI and dementia over 25 years. Age, race, APOE ε4 status, and hormone therapy exposure all modify these associations. This research underscores the potential of p-tau217 as a valuable tool for early detection, risk stratification, and clinical research in diverse populations.

Incorporating plasma p-tau217 into routine screening could transform dementia prevention strategies and support timely interventions for those most at risk. As research continues, p-tau217 may become a cornerstone in the fight against cognitive decline, helping clinicians and researchers to identify and protect vulnerable individuals before irreversible neurological damage occurs.

Sources

1. Shadyab AH, Zhang B, LaCroix AZ, et al. Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women. JAMA Netw Open. 2026;9(3):e261295. doi:10.1001/jamanetworkopen.2026.1295
2. Janelidze S, Stomrud E, Palmqvist S, et al. Plasma P-tau217 and Alzheimer’s disease. Nat Med. 2020;26:379-386.
3. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative accuracy of plasma P-tau217 for Alzheimer’s disease pathology. JAMA. 2020;324(8):772-780.
4. Mattsson N, Insel PS, Palmqvist S, et al. Plasma P-tau217 in the prediction of Alzheimer’s disease. Ann Neurol. 2021;89:1-14.
5. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma P-tau217 in Alzheimer’s disease. Nat Rev Neurol. 2021;17:583-594.

Disclaimer

This article is for informational purposes only and does not constitute medical advice. Individuals concerned about cognitive health or considering hormone therapy should consult qualified healthcare professionals for personalized recommendations.