A decades-long study of postmenopausal women shows that a simple blood biomarker may help identify individuals at higher risk of cognitive decline and dementia years before symptoms appear.
Study: Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women. Image Credit: meeboonstudio / Shutterstock
In a recent study published in JAMA Network Open, researchers investigated associations between plasma phosphorylated tau 217 (p-tau217) and incident mild cognitive impairment (MCI) or probable dementia.
Plasma biomarkers offer new possibilities for early Alzheimer’s detection
Plasma biomarkers offer an accessible, minimally invasive approach to detecting Alzheimer’s disease-related pathology. In particular, plasma p-tau217 exhibits greater accuracy in Alzheimer’s disease detection than other biomarkers, with performance comparable to that of cerebrospinal fluid (CSF) p-tau217. Studies have reported associations between plasma p-tau217 and incident dementia in community cohorts.
However, few studies have evaluated associations with MCI and dementia in cognitively normal cohorts over decades of follow-up. In addition, although hormone therapy (HT) is reported to be associated with elevated tau accumulation, dementia, and amyloid deposition, no study has investigated whether p-tau217 associations with cognitive outcomes differ by HT exposure in a randomized clinical trial population.
Long-term analysis of WHIMS participants examines biomarker dementia links
In the present study, researchers evaluated the association between plasma p-tau217 and incident dementia or MCI in participants of the Women’s Health Initiative Memory Study (WHIMS). WHIMS included two randomized controlled trials examining HT effects on cognitive outcomes in cognitively unimpaired, postmenopausal females aged 65 to 79 years. Subjects were recruited between 1996 and 1999.
Participants were randomized to estrogen plus progestin among those with an intact uterus or estrogen alone among those with a hysterectomy compared to placebo. Trials ended in 2002 and 2004, with follow-up continuing through 2007. WHIMS transitioned to telephone-based cognitive assessments from 2008 onward and continued annual follow-up until 2021. Fasting blood was collected at baseline.
Plasma p-tau217 was measured using the ALZpath Simoa pTau217 assay in 2024. The primary outcome was a combined endpoint of incident MCI or probable dementia. Individual outcomes were also separately analyzed. Questionnaires were administered at baseline to collect information on race, ethnicity, age, smoking status, education, cardiovascular disease, diabetes, and energy expenditure from physical activity. APOE ε4 genotype data were available only for White participants.
Cox proportional hazards regression was used to estimate hazard ratios for the associations between p-tau217 and cognitive outcomes. Subgroup differences were assessed by age, race, APOE ε4 status, and HT. The discriminative ability of p-tau217 was ascertained using receiver operating characteristic curves, and the specificity and sensitivity were determined for p-tau217 alone or with demographics (age, ethnicity, and race).
Elevated p-tau217 levels linked to higher risk of cognitive decline
The study included 2,766 WHIMS participants selected from a larger biomarker case cohort sample with an average baseline age of 69.9 years. About 74% of participants were White, 18% were Black, and 7% were Latino or Hispanic. Individuals with higher plasma p-tau217 levels were more likely to be White, older, never smokers, APOE ε4 carriers, and have a lower body mass index (BMI). Plasma p-tau217 levels were lower in Black participants than in White participants.
In total, 1,311 participants developed the combined endpoint over a median follow-up of 14.1 years. Higher levels of p-tau217 were associated with incident MCI or dementia. When examining individual outcomes separately, dementia had the largest magnitude of association, while MCI had a lower magnitude of association. The dementia outcome represented probable all-cause dementia rather than Alzheimer’s disease-specific dementia.
Hormone therapy exposure may influence dementia risk associations
The association showed no significant difference in subjects randomized to estrogen alone compared with placebo. However, p-tau217 showed a larger association with dementia in participants assigned to estrogen plus progestin compared to placebo. Notably, the interaction between estrogen plus progestin and p-tau217 was not significant for MCI or the combined endpoint.
Associations vary by race, genetic risk, and age
The associations with the combined endpoint and dementia were larger among White participants compared to Black individuals. p-tau217 was associated with MCI in White females but not in Black individuals. However, the combination of age and p-tau217 demonstrated similar discrimination for dementia in both White and Black participants. The authors note that differences in MCI associations across racial groups may reflect multiple factors, including smaller subgroup sample sizes, differences in causes of cognitive impairment, and potential measurement or socioeconomic confounding.
Further, larger associations with the combined endpoint and MCI were observed in APOE ε4 carriers compared with non-carriers among White participants with available genotype data. Similarly, associations varied by age, with larger magnitudes observed in people aged 70 years or older compared with those aged 70 years or younger for dementia and the combined endpoint. p-tau217 exhibited better discrimination for dementia than demographics, and the combination of demographics and p-tau217 outperformed either alone.
Study highlights potential clinical value of plasma p-tau217
Together, elevated plasma p-tau217 was associated with incident dementia or MCI among older females. The association with incident dementia was larger in magnitude in participants assigned to estrogen plus progestin relative to placebo. In addition, the associations with dementia or MCI were larger in White participants, APOE ε4 carriers, and those older than 70 years. Because several subgroup analyses were exploratory and involved multiple comparisons, these findings should be interpreted cautiously. These results suggest that factors such as HT exposure, age, race, and APOE ε4 status may influence the strength of observed associations, though further studies are needed to confirm these potential modifying effects.
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