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Background: A population of >6 million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β‐amyloid‐(Aβ)‐precursor‐protein gene (APP). This is in contrast to non‐DS patients who inherit just the duplication of the APP gene (DupAPP), who develop EOAD with 100% penetrance, raising hypotheses of potential other AD‐suppressing genes on chromosome 21. Method: Cerebral organoids were grown in vitro from isogenic T21 and normal induced‐pluripotent‐stem‐cells (iPSCs), as well as a DupAPP patient. Trisomy of chromosome‐21 gene BACE2 was corrected to disomy by CRISPR/Cas9 editing. Organoids were analysed histologically and organoid pools profiled for β‐amyloid secretion by immunoprecipitation‐mass spectrometry (IP‐MS). Tissue‐quantity‐independent peptide ratios were compared between organoid conditioned media (CM) and cerebrospinal fluid (CSF) from DS and age‐matched euploid individuals. Result: We found that T21, but not DupAPP, organoids secrete increased proportions of putative BACE2‐θ‐secretase (Aβ1‐19) and BACE2‐Aβ‐degrading protease (AβDP or Aβ‐clearance) products (Aβ1‐20 and Aβ1‐34) compared to isogenic normal controls. Increased ratios of BACE2‐related to BACE2‐unrelated anti‐amyloidogenic cleavages were reproduced in CSF of people with DS, mirroring organoid secretions. Finally, CRISPR/SpCas9‐HF1‐reduction of BACE2 (3 to 2 copies) in T21‐iPSC significantly decreased AβDP/amyloidogenic ratio and triggered early and accelerated AD‐like pathology in T21 organoids. The pathology consisted of insoluble amyloid plaque‐like deposits, fibrillar aggregates, pathologically altered Tau, and premature neuronal loss, and was preventable by an early application of a combination of β‐secretase and γ‐secretase inhibitors. Conclusion: Our combined data demonstrate the role of BACE2 as a genetic‐dose‐dependent AD‐suppressor in human brain, and organoid technology as a potential assay for screening for other protective genes and disease‐preventive drugs. [ABSTRACT FROM AUTHOR]

This cross-sectional national survey used qualitative methodology to explore the views of surgical trainees about hand surgery in low-resource settings. Key concerns have been identified and recommendations are made for responsible organizations to promote equal access for the engagement of trainees in global surgery partnerships. [ABSTRACT FROM AUTHOR]