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Few studies have investigated which pathological features, including systemic vascular disease (VD), associate with younger age at death in multiple sclerosis (MS) and this constitutes the aim of the present study.A post mortem MS brain autopsy tissue was studied for 1)systemic VD scores 2)% brain plaque area and activity from a)frontal plus occipital white matter(WM), b)pons, and c)basal ganglia(BG), 3)frontal plus occipital cortex. These pathology measures, sex, disease duration (DD), and cause of death, were fitted into a regression model to explain age at death.34 MS cases (mean age 61.6±13.05 years, 58.8% females, DD 20.2±13.45 years) were included. Age at death decreased with increasing WM+pons+ BG (r=−0.382, r=0.02) and cortical (r=−0.299, p=0.03) demyelination, and WM+pons+ BG active plaques (r=−0.326, p=0.011) but increased with DD(r=0.298, p=0.016) and VD(r=0.329, p<0.0001). In the regression model only cortical demyelination (b=−0.39, p=0.014), DD (b=0.36, p=0.009) and VD (b=0.64, p=0.001) persisted.Higher cortical demyelination associated with younger age at death. Systemic VD did not associate with younger age at death in this MS cohort.