Tau pathology differs by sex in Alzheimer's disease in Down syndrome

INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia, is more common in females. Although sex differences in tau pathology have been reported in AD, findings remain inconsistent. Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of AD (DS-AD) and features tau pathology, but sex effects in DS-AD remain unclear. METHODS: We examined post mortem brain samples from individuals with DS-AD, DS without AD, and a rare partial trisomy 21 (PT) case with only two amyloid precursor protein (APP) gene copies. PHF1 tau, total tau, and sarkosyl-soluble and insoluble fractions were quantified by group and sex. RESULTS: PHF1 tau was significantly elevated in DS-AD, especially in females. Lower total tau in DS-AD males explained the absence of sex differences after normalization. Sarkosyl-insoluble tau was also higher in DS-AD females. DS without AD, and the PT case showed minimal pathology. DISCUSSION: These findings suggest sex-specific tau dynamics in DS-AD and support a role for APP dosage. HIGHLIGHTS: Tau pathology is significantly elevated in individuals with DS-AD, especially in females. Female DS-AD brains show markedly higher PHF1 (S396/404) and sarkosyl-insoluble tau levels compared to males. The observed sex difference in phosphorylated tau is driven by lower total tau in DS-AD males. Minimal tau pathology is present in DS without AD and in a rare partial trisomy 21 case. These findings implicate APP gene dosage in tau pathology in DS-AD.