Accelerated multi-organ proteomic aging is detectable decades before dementia onset

Recent developments in proteomics have connected organ aging with dementia risk. The present longitudinal study extends this line of research by demonstrating that midlife organ age and <i>pace of organ aging</i> 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 <i>pace of multi-decade brain aging</i> . Among these is tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), causally implicated in the accelerated <i>pace of brain, immune, muscle, and pancreas aging</i> . 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.