For the first time, the Hospital of Sant Pau, the Catalan Foundation for Down and the University of Cambridge describe the natural history of Alzheimer’s disease in people with Down syndrome

One of the world’s leading medical journals, The Lancet, published the article ‘Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study’, led by the Alzheimer-Down Unit of Hospital de la Santa Creu i Sant Pau and the Fundación Catalana Síndrome de Down, in collaboration with researchers of the University of Cambridge, United Kingdom, promoted by Fundació “la Caixa”.

Link to the article


This work describes, for the first time, the natural history of Alzheimer’s disease in people with Down syndrome. It determines the order and temporality of the changes in different biomarkers preceding the cognitive impairment due to Alzheimer’s disease in 388 participants with Down syndrome and in a control group of 242 cognitively healthy individuals.

Life expectancy in people with Down syndrome has increased exponentially in recent decades due to a better medical treatment of the comorbidities associated with the syndrome. Unfortunately, this increased life expectancy has revealed a very high risk of developing Alzheimer’s disease in this population. This risk is due to the third copy of chromosome 21, which contains the amyloid precursor protein gene. The onset of Alzheimer´s disease dementia usually occurs when a person is in their early 50s, and the cumulative risk of suffering Alzheimer’s disease dementia in the 60s is in excess of 90%.

The results of the research show that the changes in cognitive, biochemical and imaging biomarkers in adults with Down syndrome occur for more than 20 years before clinical symptom onset. In this very long preclinical phase, the biomarkers follow a predictable sequence of changes. The order and temporality of these changes is surprisingly similar to those described in autosomal dominant Alzheimer’s disease, a very rare hereditary form of the disease caused by a mutations in some genes (including the amyloid precursor protein gene), and which also has an early onset (often before the age of 55).

The earliest changes found in the study started in adults with Down syndrome at age 30, with a decrease of cerebrospinal fluid (CSF) beta-amyloid levels and an increase in plasma neurofilament light chain levels (a marker of neurodegeneration). These changes are followed by an increase in CSF tau levels and reduced brain metabolism. Brain atrophy, together with cognitive impairment, occurs after the age of 40, eventually leading to symptom onset and prodromal Alzheimer’s disease diagnosis at the age of 50.

This long preclinical phase offers a unique window of opportunity for intervening before symptoms develop. The understanding of this sequence of changes is essential in the design of clinical trials aimed towards preventing or moderating the progression of Alzheimer’s disease in Down syndrome. These biomarkers will be used in the selection of the therapeutic targets and for monitoring the progression of the disease or the response to a potential treatment.

Consequently, the results and conclusions of this study have several important implications:

First, they support the concept of Down syndrome as a genetically determined form of Alzheimer’s disease in which changes in the brain develop for decades before the first symptoms become evident. This concept assimilates people with Down syndrome with those people carrying mutations in the three genes that cause autosomal dominant Alzheimer’s disease. This concept has important implications in the medical treatment and counselling of adults with Down syndrome and their families.

Second, the results show that Alzheimer’s disease in Down syndrome is qualitatively the same to that in the general population, and that the sequence of biomarker changes is strikingly similar to that described in sporadic and autosomal dominant Alzheimer’s disease.

Third, the increases in plasma neurofilament light chain levels and brain hypometabolism, reflecting neurodegeneration, occur years earlier than previously hypothesized, thus emphasising the need for earlier interventions.

Fourth, this study shows that Down syndrome might be an appropriate model for the study of Alzheimer´s disease in the general population. Clinical trials to prevent Alzheimer’s disease are essential for people with Down syndrome, but they might prove beneficial for the general population.

In conclusion, this study shows that the pattern and temporality of the Alzheimer’s disease biomarker changes in adults with Down syndrome are the same as those in the general population. A better understanding of the long preclinical phase of the disease is essential in the design of future clinical trials aiming to delay or prevent Alzheimer’s disease in Down syndrome.
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