Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration. Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression. Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change -0.003 mm 95% confidence interval (CI) -0.005 to -0.001, p = .002), but not amyloid accumulation (0.003 95% CI -0.001 to 0.006, p = .107), or WMH increase (0.011 cm3 95% CI -0.001 to 0.023, p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (-0.004 mm 95% CI -0.008 to -0.001, p = .014); amyloid accumulation (0.010, 95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565). Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.