Reduced DTI-ALPS is associated with affected status rather than cumulative genetic and environmental risk in offspring of parents with schizophrenia

Reduced DTI-ALPS has been reported in schizophrenia, suggesting that it may capture disease-related neurobiological alterations. However, whether DTI-ALPS is linked to genetic and environmental liability remains unclear. Here, we compared the DTI-ALPS index across affected offspring (AO, n = 33), unaffected offspring (UO, n = 38), and healthy controls (HC, n = 41), and examined its association with a cumulative risk score (CRS) integrating polygenic and environmental risk. After adjusting for covariates, the DTI-ALPS index was lower in AO than in UO (difference - 0.132, 95% CI -0.189 to -0.076, Holm-adjusted p < 0.001) and HC (difference - 0.102, 95% CI -0.168 to -0.037, Holm-adjusted p = 0.004), whereas no significant UO-HC difference was detected. The CRS increased stepwise across groups, but no significant adjusted CRS-DTI-ALPS association was detected in the current sample. These findings suggest that lower DTI-ALPS is more closely associated with affected status than with measured genetic and environmental risk in this sample. Longitudinal and multimodal studies are needed to clarify the neurobiological significance of the observed DTI-ALPS difference in schizophrenia and determine whether it precedes or follows illness onset.