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Preprint WatchModerateOctober 30th, 2026

Differential endothelial cell remodeling in Down syndrome and APP duplication drives distinct blood brain barrier dysfunction

Valay, L.; Kasri, A.; Fontaine, V.; Camporesi, E.; Bigou, S.; Brinkmalm, G.; Piotrowska, D.; Dancette, L.; Lamontagne, M.; Lejeune, F.-X.; Halder, P.; Ravassard, P.; Irmler, M.; Zetterberg, H.; Beckers, J.; Potier, M.-C.

Equal APP gene dosage produces divergent endothelial remodelling and blood brain barrier outcomes in Down syndrome versus APP duplication, implying that other triplicated chromosome 21 genes modify cerebral amyloid angiopathy severity.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

A bioRxiv preprint compares induced pluripotent stem cell derived endothelial cells from Down syndrome and APP duplication carriers, reporting that both secrete more amyloid beta than isogenic controls while diverging in barrier function, with APP duplication cells showing increased permeability and Down syndrome cells showing increased junctional protein expression and reduced permeability. The Claidex graph holds one APP failure, valiltramiprosate-alz801-app-apoe4-alzheimers-phase3-efficacy-failure, a Phase 3 efficacy failure in APOE4 homozygotes, and that efficacy archetype sets severity at moderate. The preprint tests no therapeutic. It bears on the target because it argues that identical APP dosage yields different vascular outcomes depending on genetic background, which is an argument for stratifying any APP-directed programme by more than amyloid burden, and the prior failure was itself run in a genetically stratified population.

Abstract excerpt

An extra copy of the amyloid precursor protein gene (APP) is present in Down syndrome (DS) and APP duplication (APPdup), increasing the risk of Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). However, we reported greater vascular A{beta} deposition in APPdup than in DS with AD, suggesting that other triplicated chromosome 21 genes may mitigate CAA severity. We investigated endothelial cell (EC) function and blood brain barrier (BBB) integrity in DS and APPdup using human induced pluripotent stem cell-derived ECs (iECs), assessing their morphology, junctional proteins, A{beta} peptide secretion, barrier function, and transcriptomic profiles. Both DS and APPdup iECs secreted more A{beta}40 A{beta}42 compared with their respective isogenic controls but exhibited distinct A{beta} peptide profiles. DS iECs showed increased junctional protein expression and reduced permeability, whereas APPdup iECs displayed increased permeability. Transcriptomic analysis revealed extensive dysregulation in DS iECs, with enrichment of junctional, adhesion, angiogenic, immune, and apoptosis pathways, and reduced cell-cycle, proliferative, and membrane-targeting signatures. APPdup iECs showed milder changes, including impaired protein targeting and reduced adhesion-related pathways. Despite comparable APP dosage, DS iECs maintained greater junctional integrity and lower permeability than APPdup iECs, potentially contributing to differential CAA vulnerability. However, impaired proliferation and altered angiogenesis may reduce BBB resilience during ageing.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.