p-Tau231 or p-Tau217? STARTER Reveals the Truth!

p-Tau231 and p-Tau217

Alzheimer's disease (AD) is pathologically characterized by β-amyloid (Aβ) plaque deposition and neurofibrillary tangles (NFTs) formed by abnormal tau phosphorylation. In recent years, different variants of phosphorylated tau (p-tau), particularly p-tau231 and p-tau217, have emerged as key biomarkers for early AD diagnosis and disease monitoring. These two p-tau forms exhibit significant differences in dynamic changes, diagnostic performance, and clinical application value during AD progression. Understanding their characteristics is crucial for precise diagnosis and personalized therapy. This article systematically compares the molecular properties, pathological mechanisms, detection technologies, and clinical applications of p-tau231 and p-tau217, and explores their diagnostic efficacy differences across various AD stages (preclinical, mild cognitive impairment [MCI], and dementia), providing a scientific basis for clinical decision-making and future research directions.

Comparison of Molecular Characteristics and Pathological Mechanisms

Structural differences between p-Tau231 and p-Tau217 determine their distinct roles in AD pathology. p-Tau231 refers to phosphorylation at threonine 231 (Thr231) of tau, while p-Tau217 involves Thr217 phosphorylation. Structurally, Thr231 is located near tau’s microtubule-binding repeat region, and its phosphorylation significantly reduces tau-microtubule binding, impairing neuronal cytoskeleton stability. In contrast, Thr217 resides in tau’s proline-rich region, where phosphorylation not only affects tau conformation but also promotes oligomerization and NFT formation. Notably, p-Tau231 abnormally elevates in the early AD pathological stage (initial Aβ deposition), whereas p-Tau217 changes more closely correlate with tau pathology spread and cognitive decline.

Their generation and regulatory mechanisms also differ significantly. Studies show p-Tau231 elevation is detectable at the lowest Aβ pathological burden, suggesting it may reflect the earliest Aβ-related tau pathological changes. A study by Kaj Blennow’s team at the University of Gothenburg, Sweden, found that in the ALFA+ cohort, plasma p-Tau231 showed the most significant elevation in preclinical AD (Aβ-positive but cognitively normal) and highly correlated with early Aβ-PET accumulation regions. In contrast, p-Tau217 elevates slightly later, but its dynamic changes closely associate with worsening Aβ deposition, cognitive decline, and brain atrophy progression. Longitudinal studies show only p-Tau217 levels continue to rise with increasing Aβ pathology, while p-Tau231 plateaus at high Aβ burdens without further changes.

In terms of pathological specificity, p-Tau231 excels in distinguishing AD from non-AD tauopathies (e.g., frontotemporal lobar degeneration [FTLD]), but its diagnostic efficacy weakens with disease progression. p-Tau217, however, maintains high specificity in early AD and more accurately reflects tau pathology spread and neurodegeneration. For example, in corticobasal syndrome (CBS) patients, p-Tau217 effectively differentiates AD pathology (CBS-AD) from 4R tauopathy (CBS-FTLD) with an area under the curve (AUC) of 0.93, significantly superior to p-Tau231. Additionally, p-Tau217 highly correlates with tau-PET temporal lobe standardized uptake value ratio (SUVR) (R=0.82), further supporting its central role in tau pathology monitoring.

Regarding humoral dynamics, p-Tau231 and p-Tau217 exhibit different concentration change patterns in cerebrospinal fluid (CSF) and blood. p-Tau231 elevates in CSF earlier than in blood, while p-Tau217 plasma concentrations highly align with CSF levels, making it more suitable as a noninvasive biomarker. Developments in ultrasensitive detection technologies (e.g., single-molecule array [Simoa]) have enabled plasma p-Tau217 detection sensitivity at the fg/mL level, whereas p-Tau231 detection relies more on mass spectrometry or highly specific antibodies. These differences suggest p-Tau231 may be better for ultra-early screening, while p-Tau217 offers greater advantages in comprehensive disease monitoring.

Comparison of Detection Technologies and Diagnostic Efficacy

Differences in antibody technology and detection platforms influence the clinical application of p-Tau231 and p-Tau217. p-Tau231 detection faces greater challenges due to its lower concentration in body fluids and structural similarity to other phosphorylated tau variants (e.g., p-Tau181). Hangzhou Boyin Biotechnology has developed a high-affinity rabbit monoclonal antibody via hybridoma technology that precisely recognizes the Thr231 phosphorylated epitope, but its commercial kit popularity still lags behind p-Tau217 detection. In contrast, p-Tau217 detection technology is more mature—for example, the monoclonal antibody mAb2A7 developed by Yingjun Zhao’s team at Xiamen University not only enables diagnosis but also targets and clears brain p-Tau217 deposits via intranasal administration, demonstrating therapeutic potential.

Head-to-head comparisons of diagnostic performance show p-Tau231 has optimal discrimination in preclinical AD (low Aβ burden). In the ALFA+ cohort, plasma p-Tau231 distinguished Aβ-positive from negative cognitively normal individuals with an AUC of 0.854, slightly higher than p-Tau217 (AUC=0.81). However, as the disease progresses to MCI and dementia stages, p-Tau217’s diagnostic efficacy significantly surpasses p-Tau231. For instance, in predicting Aβ-PET positivity, p-Tau217 achieves an AUC of 0.92–0.97, while p-Tau231’s AUC drops to 0.75–0.85. This difference may stem from p-Tau231’s plateau effect at high Aβ loads, whereas p-Tau217 continuously reflects tau pathology spread.

Multimarker combined detection strategies further highlight their complementary value. In preclinical AD screening, the combination of p-Tau231 and Aβ42/40 improves early detection sensitivity, while p-Tau217 combined with neurofilament light chain (NfL) or glial fibrillary acidic protein (GFAP) is more suitable for monitoring disease progression. For example, the Canadian PREVENT-AD cohort study found that individuals with positive plasma p-Tau217 and abnormal Aβ42/40 had a 681% increased risk of developing MCI within 10 years, whereas p-Tau231 alone showed weaker predictive efficacy. Additionally, p-Tau217 dynamic changes significantly correlate with brain atrophy rate (β=−0.012, P<0.001) and cognitive decline (MMSE score reduction, β=−0.308, P=0.0008), while p-Tau231 shows weaker longitudinal associations.

In terms of standardization and accessibility, p-Tau217 detection has gradually achieved clinical translation. The National Institute on Aging and Alzheimer’s Association (NIA-AA) 2024 revised AD diagnostic criteria list plasma p-Tau217 as a "core biomarker," on par with PET and CSF testing. In contrast, p-Tau231 detection remains primarily in research settings, partly due to unresolved antibody specificity and batch-to-batch consistency issues. The fully synthesized p-Tau231 calibrator developed by Sun Yat-sen University team is expected to advance its standardization, but large-scale clinical validation is still needed.

Differences in Clinical Applications and Therapeutic Potential

For early diagnosis and risk assessment, p-Tau231 and p-Tau217 have distinct focuses. p-Tau231 significantly elevates in preclinical AD (Aβ-positive but cognitively normal), making it suitable for ultra-early risk stratification. For example, in the ALFA+ cohort, p-Tau231 abnormalities appeared earlier than p-Tau217 and highly correlated with early Aβ-PET retention regions. In contrast, p-Tau217 elevates slightly later but more accurately predicts subsequent cognitive decline. The PREVENT-AD study showed that cognitively normal older adults with positive plasma p-Tau217 had a 280% increased risk of developing MCI within 5 years, while p-Tau231 had weaker predictive efficacy. Thus, p-Tau231 may be better for initial screening of clinical trial participants, and p-Tau217 for individualized prognosis assessment.

In disease monitoring and treatment response evaluation, p-Tau217 demonstrates unique advantages. Longitudinal studies show p-Tau217 levels continue to rise with AD progression and highly correlate with cognitive decline and brain atrophy rates. In clinical trials of anti-Aβ therapy (e.g., Lecanemab), dynamic p-Tau217 changes serve as early indicators of treatment response. In contrast, p-Tau231 plateaus at high Aβ loads, making it difficult to reflect pathological improvement after treatment. Additionally, immunotherapy targeting p-Tau217 (e.g., mAb2A7) has shown significant efficacy in animal models, reducing tau pathology, inhibiting neuronal death, and improving cognition without causing motor dysfunction common in total tau-targeted antibodies. These findings suggest p-Tau217 is not only a diagnostic marker but also a potential therapeutic target.

Regarding differential diagnosis value, p-Tau217 performs better in distinguishing AD from non-AD tauopathies (e.g., FTLD, progressive supranuclear palsy [PSP]). In CBS patients, p-Tau217 accurately differentiates AD pathology (CBS-AD) from 4R tauopathy (CBS-FTLD) with an AUC of 0.93, while p-Tau231 has lower discriminative efficacy (AUC=0.75–0.85). Similarly, in Huntington’s disease (HD), CSF p-Tau231 correlates with cognitive phenotypes and posterior cortical atrophy, but p-Tau217 shows stronger disease specificity. These differences may arise from p-Tau217’s close association with tau pathology spread, whereas p-Tau231 more reflects early Aβ-driven tau phosphorylation.

In public health and cost-effectiveness, p-Tau217 detection has demonstrated significant advantages. Compared with traditional AD diagnostic methods (e.g., PET or CSF testing), plasma p-Tau217 detection costs less (approximately 1/10 of PET) and requires no complex equipment. The Swedish BioFINDER study showed that p-Tau217-based screening reduced CSF testing needs by 85.9%, significantly lowering healthcare burdens. In contrast, p-Tau231 detection standardization and popularity still need improvement, but its unique value in ultra-early screening may drive its clinical application in the future. Large cohorts like China’s Guangdong-Hong Kong-Macao Greater Bay Area Healthy Aging Brain Study (GHABS) have started integrating p-Tau231 and p-Tau217 detection to optimize early AD detection and intervention strategies.

Future Research Directions and Challenges

Multi-omics integration and artificial intelligence may further optimize the application of p-Tau231 and p-Tau217. By combining genomics (e.g., APOE ε4 status), proteomics (e.g., GFAP, NfL), and radiomics (e.g., Aβ-PET, tau-PET), more precise AD prediction models can be constructed. For example, machine learning analysis shows that when p-Tau217 is used in combination with Aβ42/40, the AUC for predicting cognitive decline risk over the next 10 years reaches 0.81, but p-Tau217 alone approaches the upper limit (AUC=0.77–0.82). In contrast, p-Tau231 may provide additional value in ultra-early models, especially in individuals with extremely low Aβ loads. Future research could explore dynamic biomarker combinations to cover the complete AD pathological process.

Standardization and detection consistency remain major challenges for p-Tau231. Current p-Tau231 detection methods (e.g., Simoa, MSD, mass spectrometry) used in different laboratories vary significantly, making results difficult to compare directly. In contrast, p-Tau217 detection has gradually achieved methodological uniformity, with standardized kits provided by multiple manufacturers. The fully synthesized p-Tau231 calibrator from Sun Yat-sen University team is an important advance, but global multicenter validation will take time. Additionally, issues such as establishing reference intervals for special populations (e.g., chronic kidney disease patients) and interpretation standards for long-term monitoring remain to be addressed.

In therapeutic development, p-Tau217-targeted immunotherapy has made breakthroughs. The mAb2A7 antibody developed by Yingjun Zhao’s team at Xiamen University crosses the blood-brain barrier via intranasal administration, selectively clearing p-Tau217 aggregates and significantly reducing pathology and improving cognition in tau transgenic mice (PS19). In contrast, therapeutic research targeting p-Tau231 remains in the early stage, partly due to its pathological role being more limited to ultra-early AD. Future strategies may explore kinase regulation (e.g., GSK-3β inhibitors) to intervene in p-Tau231 generation or develop bispecific antibodies targeting both Aβ and tau phosphorylation sites.

Optimizing clinical application scenarios requires clearer guidelines. Current evidence supports the following strategies: (1) Combine p-Tau231 and Aβ42/40 for ultra-early screening in middle-aged populations or individuals at high AD risk; (2) Prioritize p-Tau217 for diagnosis and differentiation in MCI or suspected AD patients; (3) Use dynamic p-Tau217 monitoring to evaluate treatment response in clinical trials. With the popularization of detection technologies, plasma p-Tau217 is expected to become a routine health check for middle-aged and elderly people, while p-Tau231 may be more suitable for research settings or specific high-risk groups.

Conclusion

As AD biomarkers, p-Tau231 and p-Tau217 each have unique characteristics in pathological mechanisms, diagnostic efficacy, and clinical applications. p-Tau231 is a sensitive indicator of ultra-early Aβ pathology, while p-Tau217 excels in comprehensive disease monitoring, differential diagnosis, and treatment evaluation. Future AD management may adopt a "stage-based" strategy: p-Tau231 for initial screening, p-Tau217 for confirmation and monitoring, and integration with other markers for precision medicine. With the resolution of standardization issues and advancement of therapeutic development, these two markers will jointly promote early AD diagnosis and targeted intervention, bringing hope to tens of millions of patients worldwide.

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