Clinical Manifestations

BACKGROUND: Reduced white-matter integrity, detectable before other brain imaging findings in individuals at risk for Alzheimer's disease and related disorders (ADRD), may underlie both the pathogenesis and consequences of depression. Investigating the relationship between white-matter integrity and depressive symptoms in middle-aged individuals at high risk for ADRD can provide insights into early markers of neurodegeneration. METHOD: We examined 301 cognitively normal offspring (mean age 54.6±6.9 years; 59.8% female) of ADRD patients from the Israel Registry for Alzheimer's Prevention (IRAP) study. Diffusion tensor imaging (DTI) was used to assess white matter integrity through fractional anisotropy (FA) and mean diffusivity (MD). Depressive symptoms were evaluated using the Center for Epidemiological Studies-Depression (CESD) scale. Linear and logistic regression models, adjusting for age, sex, education, and the time between depression assessment and MRI acquisition, were used to analyze associations between white matter integrity and depressive symptoms. RESULT: The mean CESD score was 10.9±7.8 representing sub- syndromal depression. Higher FA in the genu and cingulum adjacent to the corpus callosum was associated with lower CESD scores (β=-46.8; SE=16.5; p = 0.005 and β=-68.2; SE=21.5; p = 0.002, respectively) and decreased odds of clinical depression (OR [95% CI]=0.89 [0.80-0.99] and OR[95% CI]=0.86 [0.75-0.98], respectively). No significant associations were found between FA in other white matter tracts or MD measures and depressive symptoms. CONCLUSION: In cognitively normal individuals at increased ADRD risk, disrupted white matter integrity in specific tracts is associated with more depressive symptoms already in midlife. These findings highlight the potential of white matter alterations as early biomarkers of neurodegeneration, creating opportunities for timely intervention and prevention.