ArticleMolecular psychiatry2021
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 80 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
80 citing papers in PubMed, 2 syntheses or guidelines pooled it, 120 citations in OpenAlex.
- Mapping the Cerebral Organoid Landscape: A Systematic Review of Preclinical 3D Models in Neuroscience.Advanced healthcare materials · 2026Pooled it
- A beginner's guide on the use of brain organoids for neuroscientists: a systematic review.Stem cell research & therapy · 2023Pooled it
- Stem cell derived neural organoid approaches for neurological diseases.Neural regeneration research · 2026Article
- Abnormal neuronal and synaptic morphology in Down syndrome brains reproduces in human isogenic cellular models.Cell death & disease · 2026Article
- Age-related behavioral and molecular landmarks in new mouse models for studying Alzheimer's disease in Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B.American journal of human genetics · 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
- Interplay between DYRK1A dosage and aneuploidy-induced neuropathology in Down syndrome.Communications biology · 2026Article
- Single-cell atlas of the developing Down syndrome brain cortex.Nature medicine · 2026Article
- Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome.Nature communications · 2026Article
- Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.Proteomics · 2026Article
- The role for artificial intelligence in identifying combination therapies for Alzheimer's disease.The journal of prevention of Alzheimer's disease · 2025Review
- Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B.bioRxiv : the preprint server for biology · 2025Article
- Towards a quality control framework for cerebral cortical organoids.Scientific reports · 2025Article
- Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome-Alzheimer's disease.Acta neuropathologica · 2025Article
- The potential of brain organoids in addressing the heterogeneity of synucleinopathies.Cellular and molecular life sciences : CMLS · 2025Review
- Current Development of iPSC-Based Modeling in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Resistance and resilience to Alzheimer's disease in Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease.Scientific reports · 2025Article
- Total cell N-glycosylation is altered during differentiation of induced pluripotent stem cells to neural stem cells and is disturbed by trisomy 21.BBA advances · 2025Article
20 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
43 authors at 14 institutions in 8 countries.
Funding
Abstract
A population of more than six 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. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.