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Background <p>Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer’s disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer’s Association (AA-2024) diagnostic framework, and to characterize clinical–biological discordance across the AD continuum.</p> Methods <p>We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [<sup>18</sup>F]florbetapir amyloid PET, [<sup>18</sup>F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL &gt; 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.</p> Results <p>Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21–60 (6.1%) but increased in CL 61–100 (22.6%) and &gt; 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical–biological discordance.</p> Conclusion <p>Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical–biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.</p>

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A clinically feasible framework to estimate tau pathology and clinical–biological discordance in the Alzheimer’s disease spectrum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Jung-Lung Hsu,
  • Shao-Yi Huang,
  • Hsiu-Chuan Wu,
  • Kun-Ju Lin,
  • Kuo-Lun Huang,
  • Chin-Chang Huang,
  • SangYun Kim,
  • Ing-Tsung Hsiao

摘要

Background

Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer’s disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer’s Association (AA-2024) diagnostic framework, and to characterize clinical–biological discordance across the AD continuum.

Methods

We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [18F]florbetapir amyloid PET, [18F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.

Results

Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21–60 (6.1%) but increased in CL 61–100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical–biological discordance.

Conclusion

Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical–biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.