MULTI-OMIC PROFILING OF RETROTRANSPOSON-LINKED MECHANISMS DRIVING ACCELERATED ALZHEIMER’S DISEASE IN DOWN SYNDROME

Retrotransposable elements (RTEs) are repetitive genomic sequences capable of copying and reinserting into the genome. In humans, only LINE-1 (L1) elements and endogenous retroviruses (ERVs) retain this activity, but they are normally repressed by constitutive heterochromatin. Loss of this repression leads to RTE activation, triggering innate immune responses and promoting epigenetic and genomic erosion. Down syndrome (DS), caused by trisomy 21, is characterised by early-onset Alzheimer’s disease (AD), chromatin instability, and constitutive activation of interferon pathways driven by interferon-receptor overdosage. We hypothesised that RTE activation, favoured by extensive chromatin and immune dysregulation in DS, contributes to the accelerated AD trajectory in DS and may represent a broader pathogenic mechanism relevant to AD in the general population.
We performed spatial transcriptomics, single-nucleus RNA-seq, and ATAC-seq on high-quality human postmortem samples (preserved cytoarchitecture, intact tissue integrity, RIN≥7) from DS across different stages of AD pathology and euploid controls. Preliminary analyses reveal coordinated erosion of constitutive heterochromatin and incomplete compensatory cellular responses, creating a permissive environment for L1 activation. Chromatin erosion and L1 accumulation appear to promote ERV transcription, and RTE-derived nucleic acids activate RTE-specific defence pathways. The hippocampus emerges as particularly vulnerable compared to the prefrontal cortex, with excitatory neurons showing the strongest signatures of RTE activation.
Ongoing work includes multi-omic integration and long-read DNA sequencing with ONT to enable detection of RTE activation along with histological validation. Although preliminary, our findings support a model in which chromatin instability and RTE dysregulation contribute to early AD vulnerability in DS.