Abstract
BackgroundAdults 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.DiscussionIn 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.SummaryObservational 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.
Highlights
Aging people with Down syndrome (DS) are at increased risk for cognitive decline, dementia, and Alzheimer’s disease (AD)
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
In DS adults ranging from 40 to years of age, up to 55% may be demented, and between and 59 years, prevalence ranges from 4% to 55% [1,2]
Summary
Diagnosing dementia in down syndrome and clinical trial outcome measures Systematic diagnostic criteria for mild cognitive impairment or dementia in DS have not been clearly established [5,6,7]. We will focus on Aβ-targeted therapies (many different prevention approaches that are vaccinebased or pharmacological could be considered) and challenges for clinical trials for adults with DS that are, we suggest, unique to this vulnerable cohort. It is important to remember that chromosome 21 contains over 200 genes, affecting multiple protein pathways and domains that have not been fully explored in relation to aging and that could significantly, and possibly adversely, affect clinical trial outcomes. Overall, establishing appropriate clinical outcome measures and considering possible complications related to the fact that multiple genes are overexpressed in DS that can affect inflammation, oxidative stress, mitochondrial dysfunction, and other mechanisms are important to consider in terms of both efficacy and adverse events. Competing interests The authors declare that they have no competing interests
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