Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease

Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's disease (DSAD) to demographically matched cases of early onset AD and healthy ageing controls. We find dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that APOE expression was elevated in subtypes of astrocytes, endothelial cells, and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high risk of early onset dementia.

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Publication Details

Journal
Acta Neuropathologica
Published
2025-05-19
DOI
https://doi.org/10.1007/s00401-025-02889-0
Citations
4
Primary Topic
Down syndrome and intellectual disability research
Type
article
Field-Weighted Citation Impact
7.51

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article

Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease

Paige Mumford, Wendy Heywood, Christina E. Toomey, Vivek Swarup et al.
4 citations
Acta Neuropathologica
Down syndrome and intellectual disability research
7.51
article

Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease

Paige Mumford, Wendy Heywood, Christina E. Toomey, Vivek Swarup, Tammaryn Lashley, Clíona Farrell, Yazead Buhidma, Elizabeth Head, Elizabeth J. Andrews, Jenny Hällqvist, Ken Mills, Frances K. Wiseman, Orjona Stella Taso, Lisi Flores Aguilar, Eric Doran, Negin Rahimzadah
article en
4 citations

Abstract

Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's disease (DSAD) to demographically matched cases of early onset AD and healthy ageing controls. We find dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that APOE expression was elevated in subtypes of astrocytes, endothelial cells, and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high risk of early onset dementia.

Acta NeuropathologicaVol. 149(1)
University of California, Irvine (US), Great Ormond Street Hospital (GB), UK Dementia Research Institute (GB), National Hospital for Neurology and Neurosurgery (GB), University College London (GB)
Alzheimer's Association, Fondation Jérôme Lejeune, Alzheimer's Society, National Institute for Health and Care Research, University College London, Rosetrees Trust, Alzheimer’s Research UK, UK Dementia Research Institute, National Institutes of Health, Medical Research Council, NIHR Great Ormond Street Hospital Biomedical Research Centre, National Institute on Aging
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Openalex Percentile: Top 3%
Down syndrome and intellectual disability research
7.51
DOIOpen Access PDFOpenAlex
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