Increased APOE abundance in the brain in Down syndrome - Alzheimer’s disease compared with early onset-Alzheimer's disease is associated with elevated APP and C- terminal fragment abundance

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 proteome of the frontal cortex of people who have Down syndrome-Alzheimer’s disease (DSAD) with demographically matched cases of early-onset AD and healthy ageing controls from the general population. We find the abundance of several chromosome 21 encoded proteins are increased in DSAD compared to both comparative groups. Moreover, wider dysregulation of the proteome occurs beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD protein APOE, in people with DSAD compared to matched cases of early-onset AD. To understand the cell-types which may contribute to these changes in protein abundance we undertook a single-nuclei RNA-sequencing study on the same cases. This demonstrated that trisomy of chromosome 21 altered transcription of these proteins in a range of cell-types. Specifically, APOE expression was raised in subtypes of astrocytes, endothelial cells and pericytes. In our case series, we also found that the abundance of APOE correlates with the abundance of full-length APP and C-terminal-fragments-α but not with amyloid-β, the key constituent of AD plaque pathology. Having increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people who have DSAD, altering the disease mechanisms, with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people who have DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this important group of individuals who are at high risk of early-onset dementia.