Spaceflight reshapes Alzheimer's disease–associated molecular programs in human brain organoids

Spaceflight provides a unique environment to study neural responses relevant to neurodegenerative diseases. Here, human cortical organoids derived from induced pluripotent stem cells (iPSCs) that carry familial Alzheimer's disease (fAD) mutations in APP (p.V717G), PSEN1 (p.M233L), and PSEN2 (p.N141I) were cultivated at the International Space Station (ISS) alongside isogenic controls for 40 days. Multi-omic profiling, integrating transcriptomics, proteomics, and metabolic analyses, revealed a coordinated shift in neuronal and cellular states during spaceflight. AD-derived organoids showed altered glycolytic activity and altered lactate-to-malate ratios, consistent with metabolic and mitochondrial remodeling. Spaceflight was also associated with changes in amyloid-beta (AB) processing and tau phosphorylation, although the magnitude and direction of these responses varied across genetic backgrounds. Pathway analysis identified increased synaptic and neurotransmission-related signatures, particularly those associated with GABAergic and glutamatergic signaling. Integrative analysis further revealed convergent programs involving RNA processing, chromatin organization, cytoskeletal dynamics, and cellular stress responses. Proteomic and multi-omic analyses also identified changes in RNA-binding proteins, including CIRBP, consistent with altered post-transcriptional regulatory networks under spaceflight conditions. Collectively, these exploratory findings indicate that spaceflight reshapes neuronal and metabolic regulation in human brain organoids, revealing coordinated molecular responses relevant to AD biology.