Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. Amyloid-β accumulates in the brain across the lifespan of people with DS, which provides a unique opportunity to understand the temporal progression of AD and the epigenetic factors that contribute to the age of dementia onset. This age dependency in the development of AD in DS can inform research into the presentation of AD in the general population, in whom a longitudinal perspective of the disease is not often available. Comparison of the risk profiles, biomarker profiles and genetic profiles of adults with DS with those of individuals with AD in the general population can help to determine common and distinct pathways as well as mechanisms underlying increased risk of dementia. This Review evaluates the similarities and differences between the pathological cascades and genetics underpinning DS and AD with the aim of providing a platform for common exploration of these disorders.
Virtually all people with Down syndrome (DS) have Alzheimer disease (AD) pathology by 40 years of age; this association facilitates an increased understanding of the temporal progression of AD pathogenesis and provides unique insights for AD in the general population.
Understanding the role of amyloid precursor protein in DS might lead to a greater understanding of its role in both sporadic AD and familial AD in the general population.
The study of neuroinflammation in DS might provide unique insights into AD in the general population and highlight key pathways that might be amenable to therapeutic intervention.
Investigation of cerebrovascular pathology and its role in dementia might be simplified by the study of DS cohorts and lead to novel hypotheses regarding the causes and consequences of cerebral amyloid angiopathy.
Comorbidities in DS, such as sleep disturbances, seizures and psychiatric conditions, overlap with those conditions seen in AD in the general population.
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The authors are supported by the US National Institute on Aging grants U01AG051412 and P50AG16573 to I.T.L. and the US NIH grant R01HD064993 to E.H. The authors are grateful to N. Schupf and J. Lee at Columbia University, New York, NY, USA, for their helpful comments on this manuscript.
Nature Reviews Neurology thanks A.C. Granholm, W. Mobley and other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
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Lott, I.T., Head, E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol 15, 135–147 (2019). https://doi.org/10.1038/s41582-018-0132-6
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