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Why do people with Down syndrome develop Alzheimer’s?

For the first time, researchers carried out single-cell transcriptomic analysis and long-read sequencing in Down syndrome brains to better understand the link with early onset Alzheimer’s disease.

Down syndrome is a condition that occurs when a person has an extra copy of chromosome 21, hence the alternative name ‘trisomy 21’. It is the most common chromosomal disorder and occurs in around 1 in 700 births. The condition is associated with intellectual disability, a characteristic facial appearance (flattened face, upslanting palpebral fissures, small ears and a tongue that tends to stick out of the mouth) and weak muscle tone in infancy.

Individuals with Down syndrome have an increased risk of developing several medical conditions, including gastroesophageal reflux, celiac disease and hyperthyroidism. Additionally, Down syndrome is associated with an increased risk of developing early onset Alzheimer’s disease. By the time that people with Down syndrome are over the age of 40, most will already experience some type of Alzheimer’s pathology. Whilst some of the genes and molecular pathways involved in Alzheimer’s disease progression in people with Down syndrome have been studied, the underlying mechanisms triggering these events remains a mystery.

Investigating Alzheimer’s in Down syndrome

Recently, Jerold Chun, Professor and Senior Vice President of Neuroscience Drug Discovery at Sanford Burnham Prebys, and his team investigated neurodegeneration in individuals with Down syndrome. Excitingly, this was the first study to carry out single-cell transcriptomic analysis on Down syndrome brains and to use long-read sequencing in the human brain. The findings were published in the Proceedings of the National Academy of Science.

The team analysed 29 post-mortem Down syndrome brains and found several unique features that may explain the origin of cognitive challenges and the onset of neurodegeneration in these individuals. For example, in the Down syndrome brains there were more inhibitory neurons than excitatory neurons, and early sustained increases in activated microglia were common. Interestingly, these microglial features were found in young brains before Alzheimer’s had occurred, suggesting that they are a prominent and early player in Down syndrome brains. Additionally, thousands of RNA intra-exonic junctions were found, which have previously been proposed to act in Alzheimer’s disease.

Further researching neurodegeneration in Down syndrome

Overall, uncovering the molecular changes within ageing brains of individuals with Down syndrome could help to explain their cognitive challenges and the development of Alzheimer’s disease earlier on in life. This study is a critical step forward in understanding the neurobiology of Down syndrome and could help to pave the way for new therapies to aid people with the condition and Alzheimer’s disease in the future.

Professor Chun said:

“Our study revealed unappreciated changes in brain cell types involving hundreds of thousands of never-before-seen RNAs that can’t be seen using standard techniques. These can now be considered toward understanding the brain and provide new avenues for understanding both Down syndrome and Alzheimer’s disease. It will take more studies to confirm whether these novel RNAs reflect somatic gene recombination or come from some other source, but given what we’ve found before in Alzheimer’s brains, this new Down syndrome evidence points in that direction, and we are excited to investigate it further. We are grateful to the brain donors, as well as their families, for helping our team and other researchers continue to shape our understanding of both Down syndrome and Alzheimer’s disease.”

Altered cell and RNA isoform diversity in aging Down syndrome brains, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2114326118.

Image credit: Pixels