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The present longitudinal study extends this line of research by demonstrating that midlife organ age and\n                  <jats:italic>pace of organ aging<\/jats:italic>\n                  over multiple decades from midlife to late life are associated with future dementia risk and neurodegeneration, independent of the late-life organ age. We show further that advanced multi-organ aging, especially the combination of brain and heart\/muscle aging, acts synergistically as a risk factor for dementia. Midlife proteome-wide analysis and Mendelian randomization identified a set of mostly non-brain-specific proteins driving or slowing the\n                  <jats:italic>pace of multi-decade brain aging<\/jats:italic>\n                  . Among these is tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), causally implicated in the accelerated\n                  <jats:italic>pace of brain, immune, muscle, and pancreas aging<\/jats:italic>\n                  . Two other proteins associated with pace of brain aging, GM2 ganglioside activator (GM2A) and limbic system-associated membrane protein (LSAMP), showed putative causal roles in multiple neurologic diseases.\n                <\/jats:p>","DOI":"10.64898\/2026.01.16.26344299","type":"posted-content","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T22:15:12Z","timestamp":1768860912000},"source":"Crossref","is-referenced-by-count":0,"title":["Accelerated multi-organ proteomic aging is detectable decades before dementia onset"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1554-1478","authenticated-orcid":false,"given":"Fangyu","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, US"},{"name":"Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, US"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Teal Rise, Inc, Palo Alto, CA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-5980","authenticated-orcid":false,"given":"Aditya","family":"Surapaneni","sequence":"additional","affiliation":[{"name":"Department of Medicine, NYU Grossman School of Medicine, New York, NY, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingsha","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cassandra","family":"Joynes","sequence":"additional","affiliation":[{"name":"Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8460-0462","authenticated-orcid":false,"given":"Pascal","family":"Schlosser","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US"},{"name":"Institute of Epidemiology and Prevention, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, DE"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0720-384X","authenticated-orcid":false,"given":"Zulema","family":"Rodriguez-Hernandez","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Prevention, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, DE"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5470-2161","authenticated-orcid":false,"given":"Endre","family":"Sebesty\u00e9n","sequence":"additional","affiliation":[{"name":"Teal Rise, Inc, Palo Alto, CA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-7593","authenticated-orcid":false,"given":"Hamilton Se-Hwee","family":"Oh","sequence":"additional","affiliation":[{"name":"The Bioinformatics CRO, Inc. 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