CT-derived brain volumes and plasma p-Tau217 for risk stratification of amyloid positivity in early-stage Alzheimer's disease.
Authors
Affiliations (28)
Affiliations (28)
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.
- BeauBrain Healthcare, Inc., Hakdong-ro, Gangnam-gu, Seoul, 06098, Korea.
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Jongno-Gu, Korea.
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, 1701 Divisadero St, San Francisco, CA, 94115, USA.
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenberg, Sweden.
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
- UK Dementia Research Institute, UCL, London, UK.
- Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
- Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
- Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
- Division of Life Sciences and Medicine, Department of Neurology, Institute on Aging and Brain Disorders, Neurodegenerative Disorder Research Center, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P. R. China.
- King's College London, Institute of Psychiatry, Psychology and Neuroscience Maurice Wohl Institute Clinical Neuroscience Institute, London, UK.
- NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
- Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
- Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea.
- Department of Neurology, KyungHee University College of Medicine, KyungHee University Hospital, Seoul, Korea.
- Department of Neurology, Yonsei University College of Medicine, 50-1, Yonsei-Ro, Seoul, Seodaemun-Gu, 03722, Korea.
- Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, 363 Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 16995, Korea.
- Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Korea.
- Alzheimer's Disease Convergence Research Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 115, Irwon-Ro, Gangnam-Gu, Seoul, 16419, Korea.
- Department of Digital Health, SAIHST, Sungkyunkwan University, 115, Irwon-Ro, Gangnam-Gu, Seoul, 16419, Korea.
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea. [email protected].
- Alzheimer's Disease Convergence Research Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea. [email protected].
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 115, Irwon-Ro, Gangnam-Gu, Seoul, 16419, Korea. [email protected].
- Department of Digital Health, SAIHST, Sungkyunkwan University, 115, Irwon-Ro, Gangnam-Gu, Seoul, 16419, Korea. [email protected].
- BeauBrain Healthcare, Inc., Hakdong-ro, Gangnam-gu, Seoul, 06098, Korea. [email protected].
Abstract
Early detection of amyloid-β (Aβ) pathology is critical for timely intervention in Alzheimer's disease (AD). While Aβ positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers are accurate, their high cost and limited accessibility hinder routine use. We developed a computed tomography (CT)-based, two-stage workflow combining CT-derived atrophy patterns with plasma phosphorylated tau 217 (p-Tau217) to predict Aβ PET positivity. In this cohort of 616 participants (521 with mild cognitive impairment (MCI], 95 with early dementia of Alzheimer's type (DAT]; age 60-93 years), CT, p-Tau217 assays, and Aβ PET were performed. A random forest model incorporating CT-derived regional W-scores and apolipoprotein E ε4 (APOE ε4) status stratified individuals into low-, intermediate-, and high-risk groups. p-Tau217 testing was reserved for the intermediate-risk group. At a 95% sensitivity/specificity threshold, CT-based stratification yielded a low-risk negative predictive value (NPV) of 95.8% (93.0-98.6%) and a high-risk positive predictive value (PPV) of 98.4% (96.8-100.0%), with 28.2% classified as intermediate-risk. Targeted plasma testing of intermediate-risk group improved the overall PPV to 92.8% (88.5-97.1%) and the overall NPV to 88.9% (78.6-99.2%), achieving an overall accuracy of 95.8% (94.2-97.4%). The CT-based workflow's accuracy was non-inferior to our MRI-based method (area under the curve 0.96 vs. 0.95; p = 0.14). This CT-based, two-stage approach is a cost-effective, scalable alternative to MRI-based strategies, leveraging routine CT and selective p-Tau217 testing to enhance early AD detection and optimize resource utilization in clinical practice.