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The number of U1\u201070K lightly labeled cells was only greater in layer III in DSD+. U1A intensely stained nuclei decreased significantly in layer III in DSD+, whereas those lightly labeled significantly increased in layers III and V\u2013VI in DSD+. U1\u00a0mislocalization and\u00a0tangles appeared in each laminae examined in both DS groups but were significantly greater in DSD+. Mislocalized U1s that co\u2010localized with AT8, and not TauC3, were significantly increased in DSD+.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>U1 splicing proteins play a key role in tau pathogenesis in individuals with DS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>U1 mislocalization and tangle\u2010like profiles appeared in frontal cortex layer III and V\u2013VI neurons in Down syndrome (DS).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Frontal cortex hnRNPA2B1 nuclear morphometric values decreased in layer III in DS with dementia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Frontal cortex SRSF2 and CLK1 nuclear proteins were unchanged in DSD+ and without dementia 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