Observational Study

. 2023 Nov 2;15(1):189.

doi: 10.1186/s13195-023-01332-4.

Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study

Ilse Bader^{1

2}, Ilona Bader^{3

4}, Isadora Lopes Alves^{3

4

5}, David Vállez García^{3

4}, Bruno Vellas^{6

7}, Bruno Dubois⁸, Mercè Boada^{9

10}, Marta Marquié^{9

10}, Daniele Altomare¹¹, Philip Scheltens^{12

13}, Rik Vandenberghe¹⁴, Bernard Hanseeuw^{15

16

17

18}, Michael Schöll^{19

20

21}, Giovanni B Frisoni^{22

23}, Frank Jessen²⁴, Agneta Nordberg^{25

26

27}, Miia Kivipelto^{28

25

29}, Craig W Ritchie³⁰, Oriol Grau-Rivera³¹, José Luis Molinuevo^{31

32}, Lisa Ford³³, Andrew Stephens³⁴, Rossella Gismondi³⁴, Juan Domingo Gispert³¹, Gill Farrar³⁵, Frederik Barkhof^{3

4

36}, Pieter Jelle Visser^{12

13

37}, Lyduine E Collij^{3

4

38}; AMYPAD consortium

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands. ilse.bader@amsterdamumc.nl.
² Amsterdam Neuroscience, Neurodegeneration, 1081 HV, Amsterdam, The Netherlands. ilse.bader@amsterdamumc.nl.
³ Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, 1081 HZ, Amsterdam, The Netherlands.
⁴ Amsterdam Neuroscience, Brain Imaging, Amsterdam, 1081 HV, The Netherlands.
⁵ Brain Research Center, 1081 GN, Amsterdam, The Netherlands.
⁶ Gérontopole of Toulouse, University Hospital of Toulouse (CHU-Toulouse), 31300, Toulouse, France.
⁷ UMR INSERM 1027, University of Toulouse III, 31062, Toulouse, France.
⁸ Institute of Memory and Alzheimer's Disease (IM2A) and Brain Institute, Salpetriere Hospital, Sorbonne University, 75013, Paris, France.
⁹ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028, Barcelona, Spain.
¹⁰ Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.
¹¹ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25123, Brescia, Italy.
¹² Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands.
¹³ Amsterdam Neuroscience, Neurodegeneration, 1081 HV, Amsterdam, The Netherlands.
¹⁴ Laboratory for Cognitive Neurology, Leuven Brain Institute, KU Leuven, 3001, Louvain, Belgium.
¹⁵ Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium.
¹⁶ Department of Neurology, Clinique Universitaires Saint-Luc, 1200, Brussels, Belgium.
¹⁷ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, 02155, USA.
¹⁸ WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300, Wavre, Belgium.
¹⁹ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30, Gothenburg, Sweden.
²⁰ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30, Gothenburg, Sweden.
²¹ Dementia Research Centre, Queen Institute of Neurology, University College London, London, WC1N 3BG, UK.
²² Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, 1205, Geneva, Switzerland.
²³ Geneva Memory Center, Geneva University Hospitals, 1205, Geneva, Switzerland.
²⁴ German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.
²⁵ Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society (NVS), Karolinska Institutet, 171 77, Stockholm, Sweden.
²⁶ Theme Inflammation, Karolinska University Hospital, Stockholm, 171 77, Sweden.
²⁷ Theme Aging, Karolinska University Hospital, Stockholm, 171 77, Sweden.
²⁸ Kuopio University Hospital, 70210, Kuopio, Finland.
²⁹ Imperial College London, London, SW7 2AZ, UK.
³⁰ University of Edinburgh, Edinburgh, EH8 9YL, UK.
³¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005, Barcelona, Spain.
³² H. Lundbeck A/S, 2500, Copenhagen, Denmark.
³³ Janssen Research and Development, Titusville, NJ, 08560, USA.
³⁴ Life Molecular Imaging, 13353, Berlin, Germany.
³⁵ GE Healthcare, Pharmaceutical Diagnostics, Amersham, HP7 9LL, UK.
³⁶ Institutes of Neurology and Healthcare Engineering, UCL, London, WC1N 3BG, UK.
³⁷ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, 6229 ER, The Netherlands.
³⁸ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, 221 00, Malmö, Sweden.

PMID: 37919783
PMCID: PMC10621165
DOI: 10.1186/s13195-023-01332-4

Observational Study

Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study

Ilse Bader et al. Alzheimers Res Ther. 2023.

. 2023 Nov 2;15(1):189.

doi: 10.1186/s13195-023-01332-4.

Authors

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands. ilse.bader@amsterdamumc.nl.
² Amsterdam Neuroscience, Neurodegeneration, 1081 HV, Amsterdam, The Netherlands. ilse.bader@amsterdamumc.nl.
³ Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, 1081 HZ, Amsterdam, The Netherlands.
⁴ Amsterdam Neuroscience, Brain Imaging, Amsterdam, 1081 HV, The Netherlands.
⁵ Brain Research Center, 1081 GN, Amsterdam, The Netherlands.
⁶ Gérontopole of Toulouse, University Hospital of Toulouse (CHU-Toulouse), 31300, Toulouse, France.
⁷ UMR INSERM 1027, University of Toulouse III, 31062, Toulouse, France.
⁸ Institute of Memory and Alzheimer's Disease (IM2A) and Brain Institute, Salpetriere Hospital, Sorbonne University, 75013, Paris, France.
⁹ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028, Barcelona, Spain.
¹⁰ Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.
¹¹ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25123, Brescia, Italy.
¹² Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands.
¹³ Amsterdam Neuroscience, Neurodegeneration, 1081 HV, Amsterdam, The Netherlands.
¹⁴ Laboratory for Cognitive Neurology, Leuven Brain Institute, KU Leuven, 3001, Louvain, Belgium.
¹⁵ Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium.
¹⁶ Department of Neurology, Clinique Universitaires Saint-Luc, 1200, Brussels, Belgium.
¹⁷ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, 02155, USA.
¹⁸ WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300, Wavre, Belgium.
¹⁹ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30, Gothenburg, Sweden.
²⁰ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30, Gothenburg, Sweden.
²¹ Dementia Research Centre, Queen Institute of Neurology, University College London, London, WC1N 3BG, UK.
²² Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, 1205, Geneva, Switzerland.
²³ Geneva Memory Center, Geneva University Hospitals, 1205, Geneva, Switzerland.
²⁴ German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.
²⁵ Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society (NVS), Karolinska Institutet, 171 77, Stockholm, Sweden.
²⁶ Theme Inflammation, Karolinska University Hospital, Stockholm, 171 77, Sweden.
²⁷ Theme Aging, Karolinska University Hospital, Stockholm, 171 77, Sweden.
²⁸ Kuopio University Hospital, 70210, Kuopio, Finland.
²⁹ Imperial College London, London, SW7 2AZ, UK.
³⁰ University of Edinburgh, Edinburgh, EH8 9YL, UK.
³¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005, Barcelona, Spain.
³² H. Lundbeck A/S, 2500, Copenhagen, Denmark.
³³ Janssen Research and Development, Titusville, NJ, 08560, USA.
³⁴ Life Molecular Imaging, 13353, Berlin, Germany.
³⁵ GE Healthcare, Pharmaceutical Diagnostics, Amersham, HP7 9LL, UK.
³⁶ Institutes of Neurology and Healthcare Engineering, UCL, London, WC1N 3BG, UK.
³⁷ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, 6229 ER, The Netherlands.
³⁸ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, 221 00, Malmö, Sweden.

PMID: 37919783
PMCID: PMC10621165
DOI: 10.1186/s13195-023-01332-4

Abstract

Background: The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies.

Methods: Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests.

Results: 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = - 0.22, OR = 0.80, p < .05), more prior study visits (β = - 0.93, OR = 0.40, p < .001), and positive family history of dementia (β = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PC_research = 27.4%, PC_clinical = 9.0%, X² = 10.56, p = .001), and loss of research interest (PC_clinical = 46.3%, PC_research = 16.5%, X² = 32.34, p < .001).

Conclusions: The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site.

Keywords: Alzheimer’s disease; Amyloid PET; Clinical trial; Enrollment barriers; Preclinical; Recruitment.

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Conflict of interest statement

MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, Biogen, and Servier; and received fees for lectures and funds for research from Araclon, Esteve, Grifols, Janssen, Novartis, Nutricia, Piramal, Pfizer-Wyett, Roche, and Servier. Mercè Boada 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). MM 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 PI19/00335. DA received funding by the Fondation Recherche Alzheimer, and the Swiss National Science Foundation (project CRSK-3_196354 / 1). PS is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam University Medical Centers. Within his university affiliation he is global PI of the phase 1b study of AC Immune, Phase 2b study with FUJI-film/Toyama and phase 2 study of UCB. He is past chair of the EU steering committee of the phase 2b program of Vivoryon and the phase 2b study of Novartis Cardiology. Presently he co-chairs the phase 3 study with NOVO-Nordisk. RV his institution has Clinical Trial Agreements (as PI) with Alector, Biogen, Janssen Pharmaceuticals, NovoNordisk, Prevail, Roche, UCB. His institution has consultancy agreements (RV as DSMB member) with AC Immune and Novartis. PS has an editorial role for the Alzheimer’s Research & Therapy (AZRT) journal. RV was global PI of the Phase 1 and 2 18F-flutemetamol trials. RV institution had a material transfer agreement (RV as PI) with GEHC for free tracer delivery of the FPACK cohort baseline scans and with Avid Pharmaceuticals, an EliLilly subsidiary. BH received consulting fees from Biogen and Roche. The Belgian Foundation for Scientific Research supports his salary (FNRS CCL grant #40010417). He has received grants from the FNRS (including the WELBIO fund ##40010035), the Belgian Alzheimer Research Foundation (SAO-FRA), the Louvain and Saint-Luc Foundations, and the Queen Elizabeth Medical Foundation (QEMF-FMRE). MS has received fees for contributions to Advisory Boards from Roche, NovoNordisk and Servier and has received research support by Roche. MS has an editorial role for the AZRT journal. GBF reports grants from Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, IXICO, Merz Pharma, Nestlé, Novartis, Eisai, Piramal, Roche, Siemens, Teva Pharmaceutical Industries, and Vifor Pharma; he has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Biogen, Roche, Diadem, Neurodiem, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer, and TauRx Therapeutics. FJ reported receiving personal fees from Biogen, personal fees from Eisai, personal fees from Roche, personal fees from AC Immune, personal fees from Janssen, personal fees from Danone/Nutricia, personal fees from Lilly, personal fees from Grifols, and personal fees from Novo Nordisk outside the submitted work. FJ has an editorial role for the AZRT journal. AN received consulting fees from Hoffman La Roche. Patent: US patent alpha 7 nicotinic PET tracer. She is deputy chairman of Wennergren Foundations. MK has an editorial role for the AZRT journal. CWG has received fees for contributions to Advisory Boards from Biogen, Eisai, Eli Lilly, Roche, Roche Diagnostics, Actinogen, Alchemab, Merck, Kyowa Kirin, and Signant. His research has been supported by Janssen and Biogen. He was Chief Investigator of the IMI Funded EPAD project that had multiple EFPIA and SME partners. OG-R receives research support from Hoffmann La-Roche (paid to institution). JLM reported receiving grants from Innovative Medicines Initiative AMYPAD during the conduct of the study; being employed by Lundbeck and receiving consultancy fees from Genentech, Novartis, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, ProMIS Neurosciences, and Alector outside the submitted work. MS and LF are employees of Janssen Pharmaceuticals. AS and RG are employees of Life Molecular Imaging GmbH. JDG reported receiving grants from GE Healthcare, grants and personal fees from Roche Diagnostics, grants from Hoffmann La-Roche, personal fees from Biogen, and personal fees from Philips Nederland outside the submitted work. GF received research support from GE Healthcare (paid to institution). FB is in the steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics, FB h

Figures

**Fig. 1**
Classification of given reasons to decline participation in the AMYPAD-PNHS

**Fig. 2**
The AMYPAD-PNHS flowchart for recruitment and enrollment

**Fig. 3**
Absolute and relative frequency of reported reasons not to enroll in the AMYPAD-PNHS. Colored bars: the absolute number of times a reason is reported (% relative to the total number of subjects, n = 477). Gray bars: the remaining subjects that did not report this reason, truncated at 50% for visualization purposes (100% = the total number of 477 subjects). Each subject could provide ≥ 1 reason(s) supporting their refusal and may therefore be assigned to multiple main categories and/or to multiple sub-categories within a main category. A total of 509 main categories and 536 sub-categories have been reported

**Fig. 4**
Absolute and relative frequency of reasons not to enroll in the AMYPAD-PNHS for all PCs. Research PCs are EPAD-LCS, ALFA + , F-PACK, EMIF-AD 60 + + ; Clinical PCs are UCL-2010–412, EMIF-AD 90 + , AMYPAD DPMS, Microbiota, and FACEHBI. Abbreviations: 60 + + = EMIF-AD 60 + + /TWINS; UCL = UCL-2010–412; DPMS = AMYPAD DPMS; 90 + = EMIF-AD 90 +

See this image and copyright information in PMC

Cited by

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Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study

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Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study

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