Top

Alzheimer's Research & Therapy

Published in:

Open Access 01-10-2014 | Debate

Con: are we ready to translate Alzheimer’s disease-modifying therapies to people with down syndrome?

Authors: Elizabeth Head, Frederick A Schmitt

Published in: Alzheimer's Research & Therapy | Issue 5-8/2014

Abstract

Background

Adults with Down syndrome develop Alzheimer’s disease neuropathology in an age-dependent manner. This unique feature provides an opportunity to test interventions targeted for prevention of Alzheimer’s disease neuropathology and dementia in Down syndrome.

Discussion

In considering clinical trial designs, however, there are several challenges that we believe will be critical to examine further. These include: accuracy in dementia, mild cognitive impairment and preclinical Alzheimer’s disease diagnoses in Down syndrome; clinical trial outcome measures appropriate for individuals with Down syndrome; in vivo imaging outcome measures (and practical considerations); and contributions of medical co-morbidities to disease progression. Also, when studies are designed, the molecular target may appear to be obvious (for example, targeting beta-amyloid pathology), but chromosome 21 has over 200 additional genes that could influence both positive and negative clinical trial outcomes.

Summary

Observational longitudinal studies of aging in Down syndrome will be critically important as there is a need to establish sensitive clinical outcome measures and understand the consequences of gene overexpression in relation to specific interventions.

Head E, Powell D, Gold BT, Schmitt FA: Alzheimer’s disease in Down syndrome. Eur J Neurodegener Dis 2012, 1: 353-363.PubMedPubMedCentral

Schupf N, Sergievsky GH: Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry 2002, 180: 405-410. 10.1192/bjp.180.5.405PubMedCrossRef

Wisniewski K, Wisniewski H, Wen G: Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985, 17: 278-282. 10.1002/ana.410170310PubMedCrossRef

Zigman WB: Atypical aging in Down syndrome. Dev Disabil Res Rev 2013, 18: 51-67. 10.1002/ddrr.1128PubMedCrossRef

Nieuwenhuis-Mark RE: Diagnosing Alzheimer’s dementia in Down syndrome: problems and possible solutions. Res Dev Disabil 2009, 30: 827-838. 10.1016/j.ridd.2009.01.010PubMedCrossRef

Strydom A, Livingston G, King M, Hassiotis A: Prevalence of dementia in intellectual disability using different diagnostic criteria. Br J Psychiatry 2007, 191: 150-157. 10.1192/bjp.bp.106.028845PubMedCrossRef

Krinsky-McHale SJ, Silverman W: Dementia and mild cognitive impairment in adults with intellectual disability: issues of diagnosis. Dev Disabil Res Rev 2013, 18: 31-42. 10.1002/ddrr.1126PubMedCrossRef

Schneider LS, Sano M: Current Alzheimer’s disease clinical trials: methods and placebo outcomes. Alzheimers Dement 2009, 5: 388-397. 10.1016/j.jalz.2009.07.038PubMedPubMedCentralCrossRef

Teipel SJ, Hampel H: Neuroanatomy of Down syndrome in vivo: a model of preclinical Alzheimer’s disease. Behav Genet 2006, 36: 405-415. 10.1007/s10519-006-9047-xPubMedCrossRef

10.

Landt J, D’Abrera JC, Holland AJ, Aigbirhio FI, Fryer TD, Canales R, Hong YT, Menon DK, Baron JC, Zaman SH: Using positron emission tomography and carbon 11-labeled Pittsburgh compound B to image brain fibrillar beta-amyloid in adults with Down syndrome: safety, acceptability, and feasibility. Arch Neurol 2011, 68: 890-896. 10.1001/archneurol.2011.36PubMedCrossRef

11.

DS-ConnectTM: The Down Syndrome Registry.., [https://dsconnect.nih.gov/]

12.

Lott IT, Doran E, Nguyen VQ, Tournay A, Movsesyan N, Gillen DL: Down syndrome and dementia: seizures and cognitive decline. J Alzheimers Dis 2012, 29: 177-185.PubMedPubMedCentral

13.

Powell D, Caban-Holt A, Jicha G, Robertson W, Davis R, Gold BT, Schmitt FA, Head E: Frontal white matter integrity in adults with Down syndrome with and without dementia. Neurobiol Aging 2014, 35: 1562-1569. 10.1016/j.neurobiolaging.2014.01.137PubMedPubMedCentralCrossRef

14.

Wilcock DM, Griffin WS: Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation 2013, 10: 84. 10.1186/1742-2094-10-84PubMedPubMedCentralCrossRef

15.

Yan R, Vassar R: Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 2014, 13: 319-329. 10.1016/S1474-4422(13)70276-XPubMedPubMedCentralCrossRef

16.

Ness S, Rafii M, Aisen P, Krams M, Silverman W, Manji H: Down’s syndrome and Alzheimer’s disease: towards secondary prevention. Nat Rev Drug Discov 2012, 11: 655-656. 10.1038/nrd3822PubMedCrossRef

Title: Con: are we ready to translate Alzheimer’s disease-modifying therapies to people with down syndrome?
Authors: Elizabeth Head
Frederick A Schmitt
Publication date: 01-10-2014
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 5-8/2014
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-014-0061-6

At a glance: The STEP trials

Springer Medicine

Con: are we ready to translate Alzheimer’s disease-modifying therapies to people with down syndrome?

Abstract

Background

Discussion

Summary

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Discussion

Summary

Please log in to get access to this content

Other articles of this Issue 5-8/2014

Advocacy, education, and the role of not-for-profit organizations in Lewy body dementias

Pro: Are we ready to translate Alzheimer's disease modifying therapies to people with Down syndrome?

Moving beyond the pros and cons of automating cognitive testing in pathological aging and dementia: the case for equal opportunity

Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson’s disease

Comorbidity profile in dementia with Lewy bodies versus Alzheimer’s disease: a linkage study between the Swedish Dementia Registry and the Swedish National Patient Registry

A systematic review of cognitive decline in dementia with Lewy bodies versus Alzheimer’s disease