Temporal Dynamics and Biological Variability of Alzheimer Biomarkers

Jihwan Yun¹, Daeun Shin², Eun Hye Lee², Jun Pyo Kim², Hongki Ham^{2

3

4

5}, Yuna Gu^{2

6}, Min Young Chun^{7

8}, Sung Hoon Kang⁹, Hee Jin Kim^{2

3

4

6}, Duk L Na^{2

10}, Chi-Hun Kim¹¹, Ko Woon Kim¹², Si Eun Kim¹³, Yeshin Kim¹⁴, Jaeho Kim¹⁵, Na-Yeon Jung¹⁶, Yeo Jin Kim¹⁷, Soo Hyun Cho¹⁸, Henrik Zetterberg^{19

20

21

22

23

24}, Kaj Blennow^{19

20

25

26}, Fernando Gonzalez-Ortiz^{19

20}, Nicholas J Ashton^{19

27

28

29}, Joseph Therriault^{30

31}, Nesrine Rahmouni^{30

31}, Pedro Rosa-Neto^{30

31

32

33}, Michael W Weiner³³, Sang Won Seo^{2

3

4

5

6}, Hyemin Jang³⁴; ADNI, TRIAD, and K-ROAD study groups

Collaborators, Affiliations

Collaborators

ADNI, TRIAD, and K-ROAD study groups:
Youngsoo Kim, Sun-Ho Han, JoonKyung Seong, Jun-Kyu Choi, Eek-Sung Lee, Tak-Kyeong Lee, Juhee Chin, Chi-Hun Kim, Hee Jin Kim, Haesook Bok, Hang-Rai Kim, Seung Joo Kim, Seunghee Na, Geon Ha Kim, Jin San Lee, Hanna Cho, Byeong C Kim, Dong Young Lee, So Young Moon, Min Soo Byun, Giijung Jung, Dahyun Yi, Han Na Lee, Jae-Won Jang, Jee Hyang Jeong, Young Hee Jung, Jong Hun Kim, Youngju Kim, Bo Kyoung Cheon, Jinkyu Seo, Young Noh, Hyunjung Yang, Youngji Ha, Hae-Eun Shin, Kyunghun Kang, SungHui Eom, Ki Young Shin, Yeongshin Kim, Jisung Jang, Changsik Yoon, Do Kyung Lee, Hongki Ham, Yu Hyun Park, Soo-Jong Kim, Byunghyun Byun, Yejoo Choi, Na Kyung Lee, Hong-Hee Won, Minyoung Cho, Sang-Hyuk Jung, Dong Hyun Lee, Beomsu Kim, Paul Aisen, Ronald Petersen, Clifford R Jack Jr, William Jagust, John Q Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Andrew J Saykin, John Morris, Leslie M Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M Marcel Mesulam, William Potter, Peter Snyder, Veronika Logovinsky, Tom Montine, Gustavo Jimenez, Michael Donohue, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCarli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarchi, Chad Ward, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C Morris, Nigel J Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Neil Buckholtz, Marilyn Albert, Richard Frank, John Hsiao, Cecile Tissot, Gleb Bezgin, Stijn Servaes, Jenna Stevenson, Serge Gauthier, Paolo Vitali

Affiliations

¹ Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea.
² Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
³ Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, South Korea.
⁴ Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University. Seoul, South Korea.
⁵ Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, South Korea.
⁶ Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
⁷ Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.
⁸ Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea.
⁹ Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea.
¹⁰ Happymid Clinic, Seoul, South Korea.
¹¹ Department of Neurology, Hallym University Sacred Heart Hospital, Anyang, South Korea.
¹² Department of Neurology, Jeonbuk National University Medical School and Hospital, Jeonju, Korea.
¹³ Department of Neurology, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea.
¹⁴ Department of Neurology, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea.
¹⁵ Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Republic of Korea.
¹⁶ Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea.
¹⁷ Department of Neurology, Kangwon National University College of Medicine, Chuncheon-si, Korea.
¹⁸ Department of Neurology, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Korea.
¹⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom.
²² UK Dementia Research Institute at UCL, London, United Kingdom.
²³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
²⁴ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
²⁵ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁶ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, People's Republic of China.
²⁷ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, United Kingdom.
²⁸ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom.
²⁹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
³⁰ McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre Intégré Universitaire de Santé et de Services Sociaux de l'Ouest-de-l'Île-de-Montréal.
³¹ Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
³² Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
³³ Department of Radiology and Biomedical Imaging, University of California, San Francisco.
³⁴ Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

PMID: 39960728
PMCID: PMC11833660 (available on 2026-02-17)
DOI: 10.1001/jamaneurol.2024.5263

Temporal Dynamics and Biological Variability of Alzheimer Biomarkers

Jihwan Yun et al. JAMA Neurol. 2025.

. 2025 Feb 17;82(4):384-396.

doi: 10.1001/jamaneurol.2024.5263. Online ahead of print.

Authors

Collaborators

ADNI, TRIAD, and K-ROAD study groups:
Youngsoo Kim, Sun-Ho Han, JoonKyung Seong, Jun-Kyu Choi, Eek-Sung Lee, Tak-Kyeong Lee, Juhee Chin, Chi-Hun Kim, Hee Jin Kim, Haesook Bok, Hang-Rai Kim, Seung Joo Kim, Seunghee Na, Geon Ha Kim, Jin San Lee, Hanna Cho, Byeong C Kim, Dong Young Lee, So Young Moon, Min Soo Byun, Giijung Jung, Dahyun Yi, Han Na Lee, Jae-Won Jang, Jee Hyang Jeong, Young Hee Jung, Jong Hun Kim, Youngju Kim, Bo Kyoung Cheon, Jinkyu Seo, Young Noh, Hyunjung Yang, Youngji Ha, Hae-Eun Shin, Kyunghun Kang, SungHui Eom, Ki Young Shin, Yeongshin Kim, Jisung Jang, Changsik Yoon, Do Kyung Lee, Hongki Ham, Yu Hyun Park, Soo-Jong Kim, Byunghyun Byun, Yejoo Choi, Na Kyung Lee, Hong-Hee Won, Minyoung Cho, Sang-Hyuk Jung, Dong Hyun Lee, Beomsu Kim, Paul Aisen, Ronald Petersen, Clifford R Jack Jr, William Jagust, John Q Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Andrew J Saykin, John Morris, Leslie M Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M Marcel Mesulam, William Potter, Peter Snyder, Veronika Logovinsky, Tom Montine, Gustavo Jimenez, Michael Donohue, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCarli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarchi, Chad Ward, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C Morris, Nigel J Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Neil Buckholtz, Marilyn Albert, Richard Frank, John Hsiao, Cecile Tissot, Gleb Bezgin, Stijn Servaes, Jenna Stevenson, Serge Gauthier, Paolo Vitali

Affiliations

¹ Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea.
² Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
³ Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, South Korea.
⁴ Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University. Seoul, South Korea.
⁵ Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, South Korea.
⁶ Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
⁷ Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.
⁸ Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea.
⁹ Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea.
¹⁰ Happymid Clinic, Seoul, South Korea.
¹¹ Department of Neurology, Hallym University Sacred Heart Hospital, Anyang, South Korea.
¹² Department of Neurology, Jeonbuk National University Medical School and Hospital, Jeonju, Korea.
¹³ Department of Neurology, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea.
¹⁴ Department of Neurology, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea.
¹⁵ Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Republic of Korea.
¹⁶ Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea.
¹⁷ Department of Neurology, Kangwon National University College of Medicine, Chuncheon-si, Korea.
¹⁸ Department of Neurology, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Korea.
¹⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom.
²² UK Dementia Research Institute at UCL, London, United Kingdom.
²³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
²⁴ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
²⁵ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁶ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, People's Republic of China.
²⁷ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, United Kingdom.
²⁸ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom.
²⁹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
³⁰ McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre Intégré Universitaire de Santé et de Services Sociaux de l'Ouest-de-l'Île-de-Montréal.
³¹ Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
³² Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
³³ Department of Radiology and Biomedical Imaging, University of California, San Francisco.
³⁴ Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

PMID: 39960728
PMCID: PMC11833660 (available on 2026-02-17)
DOI: 10.1001/jamaneurol.2024.5263

Abstract

Importance: Understanding the characteristics of discordance between plasma biomarkers and positron emission tomography (PET) results in Alzheimer disease (AD) is crucial for accurate interpretation of the findings.

Objective: To compare (1) medical comorbidities affecting plasma biomarker concentrations, (2) imaging and clinical features, and (3) cognitive changes between plasma biomarker and PET discordant and concordant cases.

Design, setting, and participants: This multicenter cohort study, conducted between 2016 and 2023, included individuals with unimpaired cognition, mild cognitive impairment, or Alzheimer-type dementia, who had both amyloid β (Aβ) PET imaging and plasma biomarkers. A subset of participants also underwent tau PET imaging.

Exposures: Participants were categorized into 4 groups based on their plasma and PET biomarker results: plasma-/PET-, plasma+/PET-, plasma-/PET+, and plasma+/PET+.

Main outcomes and measures: Clinical characteristics were compared between the 4 groups, focusing on the discordant groups.

Results: A total of 2611 participants (mean [SD] age was 71.2 [8.7] years; 1656 female [63.4%]), of whom 124 additionally underwent tau PET, were included. Among the plasma biomarkers, phosphorylated tau (p-tau) 217 exhibited the highest concordance rate with Aβ (2326 of 2571 [90.5%]) and tau (100 of 120 [83.3%]) PET. The p-tau217+/Aβ PET- group was older (mean [SD] age, 75.8 [7.2] years vs 70.0 [8.8] years; P < .001) with a higher prevalence of hypertension (56 of 152 [36.8%] vs 266 of 1073 [25.0%]), diabetes (40 of 152 [26.3%] vs 156 of 1059 [14.7%]), and chronic kidney disease (17 of 152 [11.2%] vs 21 of 1073 [2.0%]) compared with the p-tau217-/Aβ PET- group (P < .001 for all). Body mass index was higher in p-tau217-/Aβ PET+ than in p-tau217+/Aβ PET+ (mean [SD], 24.1 [2.8] vs 23.1 [3.1], respectively; P = .001; calculated as weight in kilograms divided by height in meters squared). The p-tau217+/Aβ PET- group had lower hippocampal volume (mean [SD], 2555.4 [576.9] vs 2979.1 [545.8]; P < .001) and worse clinical trajectory compared with p-tau217-/Aβ PET- (β = -0.53; P < .001). In contrast, tau PET discordant cases did not show significant differences in medical comorbidities or clinical outcomes compared with the p-tau217-/tau PET- group. Only the p-tau 217+/tau PET+ group demonstrated faster cognitive deterioration compared with the p-tau 217-/tau PET- group (β = -1.66; P < .001).

Conclusions and relevance: Results of this cohort study suggest that the mechanisms underlying the discordance between plasma biomarkers and PET findings may be multifaceted, underscoring the need to consider the temporal dynamics and biological variability of plasma biomarkers.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Zetterberg reported receiving advisory board fees from AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave Scientific; lecture fees from Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD; and being cofounder and stockholder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the submitted work. Dr Blennow reported receiving consultant and advisory board fees from AbbVie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, Sanofi, and Siemens Healthineers; serving on data monitoring committees for Julius Clinical and Novartis; giving lectures, producing educational materials, and participating in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and being a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work. Dr Therriault reported receiving personal fees from Alzheon and Neurotorium outside the submitted work. Dr Weiner reported receiving grants from the National Institutes of Health/National Institute on Aging, the Department of Defense, the California Department of Public Health, Siemens, Biogen, Hillblom Foundation, Alzheimer's Association, Johnson & Johnson, Kevin & Connie Shanahan, GE, VUmc, Australian Catholic University, The Stroke Foundation, and Veterans Administration; consulting, travel, and/or lecture fees from Boxer Capital, Cerecin, Clario/BioClinica, Dementia Society of Japan, Eisai, Guidepoint, Health & Wellness Partners, Indiana University, LCN Consulting, Merck, Sharpe & Dohme, Duke University, Prova Education, T3D Therapeutics, University of Southern CA, WebMD, MEDA Corp, China Association for Alzheimer’s Disease, Taipei Medical University, Cleveland Clinic, AD/PD Congress, Foundation of Learning, Health Society Japan, Korean Dementia Society, National Center for Geriatrics & Gerontology Japan, INSPIRE Project, University of Toulouse, CTAD Congress; and stock options from Alzeca, Alzheon, ALZpath, and Anven outside the submitted work. No other disclosures were reported.

References

1. Teunissen CE, Verberk IMW, Thijssen EH, et al. . Blood-based biomarkers for Alzheimer disease: towards clinical implementation. Lancet Neurol. 2022;21(1):66-77. doi:10.1016/S1474-4422(21)00361-6 - DOI - PubMed
1. Thijssen EH, Verberk IMW, Kindermans J, et al. . Differential diagnostic performance of a panel of plasma biomarkers for different types of dementia. Alzheimers Dement (Amst). 2022;14(1):e12285. doi:10.1002/dad2.12285 - DOI - PMC - PubMed
1. Hansson O. Biomarkers for neurodegenerative diseases. Nat Med. 2021;27(6):954-963. doi:10.1038/s41591-021-01382-x - DOI - PubMed
1. Thijssen EH, La Joie R, Strom A, et al. ; Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators . Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol. 2021;20(9):739-752. doi:10.1016/S1474-4422(21)00214-3 - DOI - PMC - PubMed
1. Mielke MM, Frank RD, Dage JL, et al. . Comparison of plasma phosphorylated tau species with amyloid and tau positron emission tomography, neurodegeneration, vascular pathology, and cognitive outcomes. JAMA Neurol. 2021;78(9):1108-1117. doi:10.1001/jamaneurol.2021.2293 - DOI - PMC - PubMed

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Temporal Dynamics and Biological Variability of Alzheimer Biomarkers

Collaborators

Affiliations

Temporal Dynamics and Biological Variability of Alzheimer Biomarkers

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

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