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Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.64898\/2026.07.15.738801","type":"posted-content","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T20:50:14Z","timestamp":1784926214000},"source":"Crossref","is-referenced-by-count":1,"title":["APOE4 disrupts the central dogma by arresting neuronal proteome dynamics"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8232-5498","authenticated-orcid":false,"given":"Einar K.","family":"Krogsaeter","sequence":"first","affiliation":[{"name":"Gladstone Data Science and Biotechnology Institute, The J. David Gladstone Institutes, San Francisco CA 94158, USA"},{"name":"Quantitative Bioscience Institute, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-8288","authenticated-orcid":false,"given":"Justin","family":"McKetney","sequence":"additional","affiliation":[{"name":"Gladstone Data Science and Biotechnology Institute, The J. David Gladstone Institutes, San Francisco CA 94158, USA"},{"name":"Quantitative Bioscience Institute, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Arc Institute, Palo Alto CA94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia L.","family":"Richards","sequence":"additional","affiliation":[{"name":"Gladstone Data Science and Biotechnology Institute, The J. David Gladstone Institutes, San Francisco CA 94158, USA"},{"name":"Quantitative Bioscience Institute, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishvak","family":"Subramanyam","sequence":"additional","affiliation":[{"name":"Department of Urology, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Arc Institute, Palo Alto CA94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyi","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Urology, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Pharmacology, University of Texas Southwestern, Dallas TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Gordon","sequence":"additional","affiliation":[{"name":"Gladstone Data Science and Biotechnology Institute, The J. David Gladstone Institutes, San Francisco CA 94158, USA"},{"name":"Quantitative Bioscience Institute, University of California San Francisco, San Francisco CA 94158, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8472-8582","authenticated-orcid":false,"given":"Pedro","family":"Belio Mairal","sequence":"additional","affiliation":[{"name":"Gladstone Data Science and Biotechnology Institute, The J. 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