We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD). Plasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD. •Plasma biomarkers offer a noninvasive means of studying pathological differences in Alzheimer's disease (AD).•Plasma markers of neuronal injury, astrocytic activation, systemic inflammation, and cellular plasticity were quantified in EOAD and LOAD.•Markers of neuronal injury and astrocytic activation were elevated in AD groups in comparison with controls, with larger effect sizes in EOAD.•Markers of cellular plasticity were elevated in AD and especially associated with functional decline in EOAD.•Systemic inflammation correlated with age across groups, reflecting the well-described phenomenon of age-associated sterile chronic inflammation.