Review
Dementia in Down's syndrome

https://doi.org/10.1016/S1474-4422(16)00063-6Get rights and content

Summary

Down's syndrome is the most common genetic cause of learning difficulties, and individuals with this condition represent the largest group of people with dementia under the age of 50 years. Genetic drivers result in a high frequency of Alzheimer's pathology in these individuals, evident from neuroimaging, biomarker, and neuropathological findings, and a high incidence of cognitive decline and dementia. However, cognitive assessment is challenging, and diagnostic methods have not been fully validated for use in these patients; hence, early diagnosis remains difficult. Evidence regarding the benefits of cholinesterase inhibitors and other therapeutic options to treat or delay progressive cognitive decline or dementia is very scarce. Despite close similarities with late-onset Alzheimer's disease, individuals with Down's syndrome respond differently to treatment, and a targeted approach to drug development is thus necessary. Genetic and preclinical studies offer opportunities for treatment development, and potential therapies have been identified using these approaches.

Introduction

Down's syndrome affects 5·8 million people worldwide and is the most common genetic cause of learning difficulties.1 The incidence of age-related cognitive decline and dementia is higher in individuals with the syndrome than in the general population, and progressive cognitive impairment develops at a far earlier age: the median age of dementia onset across all reported studies is below 60 years (table 1),2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and Down's syndrome dementia is the most common form of dementia in individuals under the age of 50 years.1 Dementia in Down's syndrome presents a major diagnostic and clinical management challenge because of the combination of learning disabilities, progressive cognitive and functional decline, and associated neuropsychiatric and behavioural symptoms. Incidence of Down's syndrome has decreased by 1% in the UK since the introduction of antenatal screening in the early 1990s, although an increase in birth rates of babies with Down's syndrome has been reported in the USA as a result of older maternal age.18 With more people living beyond age 60 years,19 dementia in Down's syndrome is likely to be an increasing challenge.

In the past decade, substantial progress has been made in the search for genetic risk factors for dementia in people with Down's syndrome, and in understanding the neuropathological similarities and differences between Down's syndrome dementia and Alzheimer's disease without Down's syndrome. In turn, this progress has led to opportunities in drug development, including the use of transcriptional analysis to identify treatment targets, and the emergence of potential new targets based on knowledge of neurogenesis pathways and genes such as DYRK1A.20 Additionally, studies of new potential therapies are underway, such as the use of vitamin E to target oxidative stress (NCT01594346), and repurposing of existing therapies is a valuable opportunity for treatment development.

In this Review, we summarise published work on progressive dementia in people with Down's syndrome and explore potential avenues for future research. We first briefly describe the epidemiological and clinical characteristics of dementia in Down's syndrome, and then focus on the most recent developments in the neurobiology of dementia in this population, including imaging and pathophysiological changes and genetic risk factors. Additionally, we discuss existing treatment strategies and the most innovative and promising opportunities for drug development in the context of emerging knowledge from neuropathological and genetic research. A developmental approach that considers the effect on neuronal development, prodromal pathologies, and symptoms in young people with Down's syndrome is also an important area, although the focus of this Review is on the progressive cognitive impairment that is associated with Alzheimer's disease in people with Down's syndrome older than 40 years.

Section snippets

Epidemiology

Results from cross-sectional and longitudinal studies2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 show a wide range in prevalence, and substantial variability in the age of onset, of clinically significant cognitive impairment and dementia in people with Down's syndrome across all age groups (table 1). A clear age-related trend exists for emergence of impairment.4, 5, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17 Results from eight studies4, 6, 7, 9, 10, 13, 15, 17 show rising prevalence from

Clinical presentation and assessment

For people older than 40 years with Down's syndrome, dementia development follows a similar course to that seen in Alzheimer's disease,6, 8 with declines in recall and explicit memory21 and in receptive language function22 usually preceding dementia. However, when dementia emerges in younger individuals (aged 30–40 years), it often initially manifests as changes in behaviour and personality,6, 8 including onset of apathy, increasing impulsivity, and executive dysfunction.

Of note, some reports

Imaging findings

Perhaps the most striking parallels between Alzheimer's disease and Alzheimer's disease in Down's syndrome are common neuropathologies, including the characteristic accumulation of amyloid-β (Aβ).28 In MRI and PET studies of people with Down's syndrome, changes in hippocampal volume, glucose metabolism, and amyloid burden have been identified across a large age range. For example, in a study of individuals (aged 34–52 years) with Down's syndrome but not dementia,29 reduced grey matter volume on

Genetic risk factors

The wide variation in age of dementia onset in individuals with Down's syndrome suggests that substantial differences exist between alleles of key genes for Alzheimer's disease on chromosome 21, or in other genes that regulate dementia risk, or both. Understanding these differences could be the key to the identification of new approaches to delay and treat Alzheimer's disease in people with Down's syndrome.

Existing treatments for Alzheimer's disease

The UK National Institute for Health and Care Excellence recommends treatment with cholinesterase inhibitors and the NMDA receptor antagonist memantine for people with moderate to severe Alzheimer's disease and their use is also approved in the context of learning disability. The US guidelines for treatment of people with learning disabilities are more nuanced and recommend decisions based on individual patient assessments.119, 120 Although evidence from preclinical models suggests that

Conclusions

In this Review, we have focused on new findings in the genetic and neuropathological manifestations of Down's syndrome, and examined how this knowledge might be applied to the development and design of treatments. We are in an encouraging, but preliminary, position in this regard. A large RCT of vitamin E is still in progress, but other clinical trials are preliminary. Results from studies in mouse models of Down's syndrome suggest that some targets of Alzheimer's disease might be of particular

Search strategy and selection criteria

We searched PubMed for articles published between Jan 1, 1969, and Jan 21, 2016, with the search terms “Down OR Downs OR Down's”, “syndrome”, “dementia”, “cognitive”, and “Alzheimer OR Alzheimer's”. Additional search terms were used for specific sections of the Review: “prevalence”, “incidence”, “epidemiology”, “frequency”, “diagnosis”, “assessment”, “identification”, “neuroimaging”, “biomarker”, “pathology”, “neuropathology”, “genetic”, “gene”, “genotype”, “GWAS”, “transgenic”,

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