ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Tau pathology differs by sex in Alzheimer's disease in Down syndrome.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- A Researcher's guide to rodent models of Down syndrome: Recent insights and translational perspectives.STAR protocols · 2026Review
- Intraindividual cognitive variability predicts amyloid beta, tau PET, and dementia conversion in Down syndrome: a potential marker of cognitive resilience.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Neuron-specific epigenetic repression ofbioRxiv : the preprint server for biology · 2026Article
- Use of anti-amyloid-β monoclonal antibodies in persons with Down syndrome Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Tau pathology differs by sex in Alzheimer's disease in Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
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Authors and funding
3 authors.
Funding
Abstract
introductionAlzheimer'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.
methodsWe 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.
resultsPHF1 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.
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