Chromosome 21 gene dosage and Alzheimer's disease in Down syndrome: DYRK1A mechanism and its translation to blood-based biomarkers

Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of early-onset Alzheimer's disease (AD). Virtually all individuals with DS develop AD neuropathology by the fourth decade of life, and the majority develop clinical dementia by the seventh decade. Triplication of the APP gene on chromosome 21 (HSA21) is the established central driver of the substantial amyloid burden in this population. However, HSA21 contains hundreds of genes, and additional triplicated genes may compound DS-associated AD (DSAD) risk. This narrative review examines DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase 1A), a triplicated HSA21 kinase overexpressed approximately 1.5-fold in DS brains, as a potential complementary contributor to DSAD. Evidence from cell and animal models proposes three mechanistic axes: (1) phosphorylation of amyloid-β protein precursor at Thr668, promoting amyloidogenic processing; (2) phosphorylation of tau at Thr212, the site corresponding to the p-tau212 epitope, priming downstream GSK3β-mediated hyperphosphorylation; and (3) transcriptional suppression of neprilysin, impairing amyloid-β clearance. Direct human mechanistic evidence for these pathways remains limited. Because DYRK1A has been implicated in broader tau-regulatory pathways, individuals with DS may exhibit distinct plasma p-tau profiles compared with euploid AD populations. Recent cohort studies have reported DS-specific plasma p-tau217 and p-tau212 thresholds substantially higher than euploid references. Dedicated quantitative syntheses of plasma p-tau217 and p-tau212 diagnostic accuracy specifically in DS remain limited, representing a key translational gap.