Exploring the role of depression in the association between APOE ε4 and cognitive function: Evidence from the Brain...

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD) and associated with increased risk of depression. We examined whether depression modifies the association between APOE ε4 and cognition.

Using the Brain Health Registry (BHR), APOE ε4 status was determined by saliva-based genotyping. Depression and depression severity were self-reported as history of depression (yes/no), the Geriatric Depression Scale (GDS; range 0-14), and Patient Health Questionnaire (PHQ-9 range: 0-27). Cognitive function was measured via the Paired Associates Learning (PAL) test, including First Attempt Memory Score (FAMS) and Total Errors Adjusted (TEA). Linear regression estimated associations between APOE ε4, depression, and PAL (FAMS and TEA, separately) adjusted for age, gender, and education. An APOE ε4*depression interaction was tested. Inverse probability weights (IPW) were applied to address missingness.

Among 422 eligible participants, 25% were APOE ε4 carriers. Carriers were slightly younger than non-carriers (65 vs. 67 years, p = 0.025) with no other significant sociodemographic differences. GDS and PHQ-9 scores were right-skewed, and carriers had slightly lower medians (GDS: 1 vs. 2, p = 0.055; PHQ-9: 1 vs. 2, p < 0.001) but higher self-reported depression (18% vs. 14%, p = 0.3). APOE ε4 was associated with lower FAMS and higher TEA, but results were not statistically significant. Depression measures also showed non-significant associations with FAMS and TEA. No interactions were detected.

APOE ε4 and depression were non-significantly associated with cognition, and depression did not modify the association between APOE ε4 and cognitive function.