Alzheimer's disease in Down syndrome: An overlooked population for prevention trials

doi:10.1016/j.trci.2018.10.006

Review

. 2018 Dec 13:4:703-713.

doi: 10.1016/j.trci.2018.10.006. eCollection 2018.

Alzheimer's disease in Down syndrome: An overlooked population for prevention trials

André Strydom^{1

2

3

4}, Antonia Coppus^{5

6}, Rafael Blesa^{7

8}, Adrian Danek⁹, Juan Fortea^{7

8

10}, John Hardy^{3

11

12}, Johannes Levin^{9

13}, Georg Nuebling⁹, Anne-Sophie Rebillat¹⁴, Craig Ritchie¹⁵, Cornelia van Duijn¹⁶, Shahid Zaman^{17

18}, Henrik Zetterberg^{11

19

20

21}

Affiliations

¹ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, UK.
² Division of Psychiatry, University Collee London, London, UK.
³ The London Down Syndrome Consortium (LonDownS), UK.
⁴ South London and Maudsley NHS Foundation Trust, London, UK.
⁵ Dichterbij, Center for Intellectual Disabilities, Gennep, the Netherlands.
⁶ Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau-Universitat Autònoma de Barcelona, Barcelona, Spain.
⁸ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Spain.
⁹ Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
¹⁰ Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain.
¹¹ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
¹² Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.
¹³ German Center for Neurodegenerative Diseases (DZNE) site Munich, Munich, Germany.
¹⁴ Institut Jérôme Lejeune, Paris, France.
¹⁵ Centre for Clinical Brain Sciences, Dementia Prevention Research Group, University of Edinburgh.
¹⁶ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹⁷ Cambridge Intellectual & Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁸ Cambridgeshire & Peterborough NHS Foundation Trust (CBFT), Fulbourn Hospital, Cambridge, UK.
¹⁹ UK Dementia Research Institute at UCL, London, UK.
²⁰ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

PMID: 30581976
PMCID: PMC6296162
DOI: 10.1016/j.trci.2018.10.006

Review

Alzheimer's disease in Down syndrome: An overlooked population for prevention trials

André Strydom et al. Alzheimers Dement (N Y). 2018.

. 2018 Dec 13:4:703-713.

doi: 10.1016/j.trci.2018.10.006. eCollection 2018.

Authors

Affiliations

¹ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, UK.
² Division of Psychiatry, University Collee London, London, UK.
³ The London Down Syndrome Consortium (LonDownS), UK.
⁴ South London and Maudsley NHS Foundation Trust, London, UK.
⁵ Dichterbij, Center for Intellectual Disabilities, Gennep, the Netherlands.
⁶ Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau-Universitat Autònoma de Barcelona, Barcelona, Spain.
⁸ Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Spain.
⁹ Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
¹⁰ Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain.
¹¹ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
¹² Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.
¹³ German Center for Neurodegenerative Diseases (DZNE) site Munich, Munich, Germany.
¹⁴ Institut Jérôme Lejeune, Paris, France.
¹⁵ Centre for Clinical Brain Sciences, Dementia Prevention Research Group, University of Edinburgh.
¹⁶ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹⁷ Cambridge Intellectual & Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁸ Cambridgeshire & Peterborough NHS Foundation Trust (CBFT), Fulbourn Hospital, Cambridge, UK.
¹⁹ UK Dementia Research Institute at UCL, London, UK.
²⁰ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

PMID: 30581976
PMCID: PMC6296162
DOI: 10.1016/j.trci.2018.10.006

Abstract

The discovery that adults with Down syndrome (DS) have neuropathological features identical to individuals with sporadic Alzheimer's disease (AD) played a key role in the identification of the amyloid precursor protein gene on chromosome 21 and resulted in the amyloid cascade hypothesis. Individuals with DS have a lifetime risk for dementia in excess of 90%, and DS is now acknowledged to be a genetic form of AD similar to rare autosomal-dominant causes. Just as DS put the spotlight on amyloid precursor protein mutations, it is also likely to inform us of the impact of manipulating the amyloid pathway on treatment outcomes in AD. Ironically, however, individuals with DS are usually excluded from AD trials. This review will discuss primary and secondary prevention trials for AD in DS and the potential barriers and solutions to such trials and describe the Europe-wide Horizon21 Consortium to establish a DS-AD prevention clinical trials network.

Keywords: APP; Alzheimer's disease; Amyloid; Biomarkers; Dementia; Down syndrome; Prevention; Randomized controlled trials; Trisomy 21.

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Figures

**Fig. 1**
Cross-sectional data showing the distribution of age at dementia diagnosis in people with DS. Graph based on Sinai et al., 2018 . Abbreviation: DS, Down syndrome.

**Fig. 2**
(A) Cross-sectional data showing the performance (z-score) of adults with DS on object memory test across age, split by *APOE* status (2/2, 2/3; 3/3; 3/4, 4/4). Data from the London Down Syndrome Consortium (LonDownS), as yet unpublished. (B) Cumulative incidence of mortality, split by *APOE* status (2/2, 2/3, 2/4; 3/3; 3/4, 4/4). Data from the Rotterdam group, as yet unpublished. Abbreviation: DS, Down syndrome.

**Fig. 3**
Flow diagram showing existing DS trial-ready cohorts. Abbreviation: DS, Down syndrome.

**Fig. 4**
Neurofilament light concentration (ng/L) by age and dementia status of adults with DS. Graph based on Strydom et al., 2018 . Abbreviation: DS, Down syndrome.

See this image and copyright information in PMC

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Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.
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[1] Dubois B., Hampel H., Feldman H.H., Scheltens P., Aisen P., Andrieu S. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016;12:292–323. - PMC - PubMed

[2] Dubois B., Hampel H., Feldman H.H., Scheltens P., Aisen P., Andrieu S. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016;12:292–323. - PMC - PubMed

[3] Ritchie K., Ropacki M., Albala B., Harrison J., Kaye J., Kramer J. Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project. Alzheimers Dement. 2017;13:186–195. - PubMed

[4] Ritchie K., Ropacki M., Albala B., Harrison J., Kaye J., Kramer J. Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project. Alzheimers Dement. 2017;13:186–195. - PubMed

[5] Bateman R.J., Benzinger T.L., Berry S., Clifford D.B., Duggan C., Fagan A.M. The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement. 2017;13:8–19. - PMC - PubMed

[6] Bateman R.J., Benzinger T.L., Berry S., Clifford D.B., Duggan C., Fagan A.M. The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement. 2017;13:8–19. - PMC - PubMed

[7] European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease 2018.

[8] European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease 2018.

[9] U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Early Alzheimer's Disease: Developing Drugs for Treatment Guidance for Industry 2018.

[10] U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Early Alzheimer's Disease: Developing Drugs for Treatment Guidance for Industry 2018.

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Alzheimer's disease in Down syndrome: An overlooked population for prevention trials

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Alzheimer's disease in Down syndrome: An overlooked population for prevention trials

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