. 2024 May;20(5):3429-3441.

doi: 10.1002/alz.13761. Epub 2024 Apr 4.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Ariane Bollack¹, Lyduine E Collij^{2

3

4}, David Vállez García², Mahnaz Shekari^{5

6

7}, Daniele Altomare⁸, Pierre Payoux^{9

10}, Bruno Dubois¹¹, Oriol Grau-Rivera⁵, Mercè Boada^{12

13}, Marta Marquié^{12

13}, Agneta Nordberg^{14

15}, Zuzana Walker^{16

17}, Philip Scheltens¹⁸, Michael Schöll^{19

20

21}, Robin Wolz²², Jonathan M Schott²³, Rossella Gismondi²⁴, Andrew Stephens²⁴, Christopher Buckley²⁵, Giovanni B Frisoni⁸, Bernard Hanseeuw^{26

27

28}, Pieter Jelle Visser^{2

14

29}, Rik Vandenberghe³⁰, Alexander Drzezga^{31

32

33}, Maqsood Yaqub², Ronald Boellaard^{2

34}, Juan Domingo Gispert^{5

6

35}, Pawel Markiewicz^{1

36}, David M Cash^{37

38}, Gill Farrar²⁵, Frederik Barkhof^{1

2

37}; AMYPAD consortium

Affiliations

¹ Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, London, UK.
² Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
³ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴ Amsterdam Neuroscience, Brain Imaging, VU University Amsterdam, Amsterdam, The Netherlands.
⁵ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
⁶ Universitat Pompeu Fabra, Barcelona, Spain.
⁷ Instituto de investigaciones médicas Hospital del Mar (IMIM), Barcelona, Spain.
⁸ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹ Department of Nuclear Medicine, Imaging Pole, Toulouse University Hospital, Toulouse, France.
¹⁰ Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, CHU Purpan, Pavillon Baudot, Place du Docteur Joseph Baylac, Toulouse, France.
¹¹ Department of Neurology, Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France.
¹² Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.
¹³ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹⁴ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Theme Inflammation and Aging, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Division of Psychiatry, University College London, London, UK.
¹⁷ Essex Partnership University NHS Foundation Trust, The Lodge, Wickford, UK.
¹⁸ Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Alzheimercentrum Amsterdam, Amsterdam, The Netherlands.
¹⁹ Wallenberg Centre for Molecular and Translational Medicine, The University of Gothenburg, Gothenburg, Sweden.
²⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²² IXICO Plc, London, UK.
²³ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
²⁴ Life Molecular Imaging, GmbH, Berlin, Germany.
²⁵ GE HealthCare, Buckinghamshire, UK.
²⁶ Department of Neurology, Institute of Neuroscience, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
²⁷ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁸ WELBIO Department, WEL Research Institute, Wavre, Belgium.
²⁹ Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
³⁰ Laboratory for Cognitive Neurology, LBI - KU Leuven Brain Institute, Leuven, Belgium.
³¹ Department of Nuclear Medicine, University Hospital Cologne, Universitätsklinikums Köln, Köln, Germany.
³² Molecular Organization of the Brain, Institute for Neuroscience and Medicine, INM-2), Forschungszentrum Jülich GmbH, Jülich, Germany.
³³ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
³⁴ Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁵ Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, Spain.
³⁶ Computer Science and Informatics, School of Engineering, London South Bank University, London, UK.
³⁷ Queen Square Institute of Neurology, University College London, London, UK.
³⁸ UK Dementia Research Institute at University College London, London, UK.

PMID: 38574374
PMCID: PMC11095430
DOI: 10.1002/alz.13761

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Ariane Bollack et al. Alzheimers Dement. 2024 May.

. 2024 May;20(5):3429-3441.

doi: 10.1002/alz.13761. Epub 2024 Apr 4.

Authors

Affiliations

¹ Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, London, UK.
² Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
³ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴ Amsterdam Neuroscience, Brain Imaging, VU University Amsterdam, Amsterdam, The Netherlands.
⁵ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
⁶ Universitat Pompeu Fabra, Barcelona, Spain.
⁷ Instituto de investigaciones médicas Hospital del Mar (IMIM), Barcelona, Spain.
⁸ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹ Department of Nuclear Medicine, Imaging Pole, Toulouse University Hospital, Toulouse, France.
¹⁰ Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, CHU Purpan, Pavillon Baudot, Place du Docteur Joseph Baylac, Toulouse, France.
¹¹ Department of Neurology, Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France.
¹² Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.
¹³ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹⁴ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Theme Inflammation and Aging, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Division of Psychiatry, University College London, London, UK.
¹⁷ Essex Partnership University NHS Foundation Trust, The Lodge, Wickford, UK.
¹⁸ Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Alzheimercentrum Amsterdam, Amsterdam, The Netherlands.
¹⁹ Wallenberg Centre for Molecular and Translational Medicine, The University of Gothenburg, Gothenburg, Sweden.
²⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²² IXICO Plc, London, UK.
²³ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
²⁴ Life Molecular Imaging, GmbH, Berlin, Germany.
²⁵ GE HealthCare, Buckinghamshire, UK.
²⁶ Department of Neurology, Institute of Neuroscience, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
²⁷ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁸ WELBIO Department, WEL Research Institute, Wavre, Belgium.
²⁹ Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
³⁰ Laboratory for Cognitive Neurology, LBI - KU Leuven Brain Institute, Leuven, Belgium.
³¹ Department of Nuclear Medicine, University Hospital Cologne, Universitätsklinikums Köln, Köln, Germany.
³² Molecular Organization of the Brain, Institute for Neuroscience and Medicine, INM-2), Forschungszentrum Jülich GmbH, Jülich, Germany.
³³ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
³⁴ Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁵ Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, Spain.
³⁶ Computer Science and Informatics, School of Engineering, London South Bank University, London, UK.
³⁷ Queen Square Institute of Neurology, University College London, London, UK.
³⁸ UK Dementia Research Institute at University College London, London, UK.

PMID: 38574374
PMCID: PMC11095430
DOI: 10.1002/alz.13761

Abstract

Introduction: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-β (Aβ) accumulation based on Centiloids (CL) in pre-dementia populations.

Methods: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [¹⁸F]flutemetamol, [¹⁸F]florbetaben or [¹⁸F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95^th percentile of longitudinal measurements in sub-populations (N_PNHS = 101/750, N_Insight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models.

Results: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education.

Discussion: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Keywords: Alzheimer's; Centiloid; amyloid; longitudinal PET; quantification; reliable accumulation.

PubMed Disclaimer

Conflict of interest statement

A.B., C.B., and G.F. are employees of GE HealthCare. L.C. has received research support from GE HealthCare (paid to institution). D.A. received funding by the Swiss National Science Foundation (project CRSK‐3_196354/1). OG‐R receives research support from F. Hoffmann‐La Roche Ltd. and has given lectures in symposia sponsored by Roche Diagnostics. M.B. received research funding from the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER‐Una manera de hacer Europa) grant PI17/01474, and the European Union/EFPIA Innovative Medicines Initiative Joint MOPEAD project (grant number 115985). M.M. reports research funding from the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—Una manera de hacer Europa) grant PI19/00335, travel support from F. Hoffmann‐La Roche Ltd. and participation on the Spanish Scientific Advisory Board for biomarkers from Araclon‐biotech—Grífols. M.Sch. has served on scientific advisory boards for Servier Pharmaceuticals, NovoNordisk and Roche, and has received funding from Roche, Novo Nordisk and Bioarctic (paid to institution), all outside the scope of this study. RW is an employee of IXICO. J.M.S. has received research funding and PET tracer from AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Alliance Medical; has consulted for Roche, Eli Lilly, Biogen, AVID, Merck, and GE; and received royalties from Oxford University Press and Henry Stewart Talks. He is Chief Medical Officer for Alzheimer's Research UK, and Medical Advisor to UK Dementia Research Institute. R.G. is a full‐time employee of Life Molecular Imaging GmbH, Berlin, Germany. A.D. reports the following: Research support from Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA, Ariceum Therapeutics; Speaker Honorary/Advisory Boards: Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital; Stock: Siemens Healthineers, Lantheus Holding, Structured therapeutics, ImmunoGen; Patents: Patent for 18F‐JK‐PSMA‐ 7 (PSMA PET imaging tracer, Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021). J.D.G. reports research support from GE Healthcare, Roche Diagnostics, and Hoffmann‐La Roche; has given lectures in symposia sponsored by General Electrics, Philips Nederlands, Life Molecular Imaging, and Biogen; has served on scientific advisory boards or as a consultant for Prothena Biosciences and Roche Diagnostics; and is the inventor, founder, and co‐owner of BetaScreen. F.B. is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. He is a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics and has research agreements with Merck, Biogen, GE Healthcare, Roche. He is co‐founder and shareholder of Queen Square Analytics LTD. The remaining authors have no conflicts of interest to declare. Author disclosures are available in the Supporting information.

Figures

**FIGURE 1**
Definition of reliable accumulation using two approaches. (A) Reliable accumulation based on the 95^th percentile of the annualized CL rate of change in a reference group (i.e., >3.0 CL/year), represented by the orange dotted lines. The plot displays longitudinal CL trajectories within the PNHS exploratory subset, for Aβ‐accumulators (individuals that showed reliable accumulation, in purple) and non‐accumulators (in gray). (B) Reliable accumulation based on gaussian mixture modeling (k = 2) using the whole PNHS cohort. The orange vertical line represents the 99th percentile of the first Gaussian distribution and corresponds to 2.2 CL/year. ARC, annualized rates of change; CL, Centiloid; PNHS, Prognostic and Natural History Study.

**FIGURE 2**
Number of subjects in each category within the exploratory cohort. Aβ‐Accumulators based on the 95^th percentile of the annualized CL rate of change in a reference group (i.e., >3.0 CL/year). Aβ, amyloid‐β; CL, Centiloid; VR, visual reads.

**FIGURE 3**
(A) Precision‐Recall curve using baseline CL load as predictor to identify Aβ‐Accumulators. In blue, the maximum F1 score corresponds to a baseline amyloid load of 15.7 [12.4, 19.4] CL; Bootstrap resampling was used both to optimize the threshold (500 repetitions) and derive its 95% confidence interval (CI; validation using out‐of‐sample predictions from 1000 repetitions). (B) ARC versus baseline CL load. The blue line represents a baseline threshold of 15.7 CL. The shaded blue area defines the boundaries of the 95% CI around the threshold. The orange line represents the limit above which subjects are considered Aβ‐Accumulators (ARC > 3.0 CL/year). The purple curve represents the data fitted with a quadratic polynomial. Aβ, amyloid‐β; ARC, annualized rate of change; CI, confidence interval; CL, Centiloid; VR, visual read.

**FIGURE 4**
Summary of Precision‐Recall Analysis using baseline CL to predict reliable accumulation. The optimal baseline CL threshold is determined by maximizing the F1‐score. (A) Three additional scenarios were investigated by adding a constraint on precision, recall or specificity (minimum value = 0.7 for precision and recall, 0.9 for specificity). Bootstrap resampling was used both to optimize the threshold (500 repetitions) and derive its 95% confidence interval (CI; validation using out‐of‐sample predictions from 1000 repetitions). (B, C, D) Precision‐Recall curves according to APOE ε4 carriership, tracer, and level of education respectively. APOE, apolipoprotein E; AUC, area under the curve; CL, Centiloid.

**FIGURE 5**
Longitudinal trajectories of amyloid accumulation (A) by tracer and (B) based on VR over time. CL, Centiloid scale; VR, visual reads.

**FIGURE 6**
Overview of CL thresholds with a focus in the “gray zone,” between 10 and 30 CL. CL, Centiloid; VR, visual reads.

See this image and copyright information in PMC

References

1. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013;12:357‐367. doi: 10.1016/S1474-4422(13)70044-9 - DOI - PubMed
1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388:9‐21. doi: 10.1056/NEJMoa2212948 - DOI - PubMed
1. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021;384:1691‐1704. doi: 10.1056/NEJMoa2100708 - DOI - PubMed
1. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: the TRAILBLAZER‐ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512‐527. doi: 10.1001/jama.2023.13239 - DOI - PMC - PubMed
1. Rafii MS, Sperling RA, Donohue MC, et al. The AHEAD 3‐45 Study: design of a prevention trial for Alzheimer's disease. Alzheimers Dement. 2023;19(4):1227‐1233. doi: 10.1002/alz.12748 - DOI - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

Grants and funding

115952/Innovative Medicines Initiative 2

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Affiliations

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous