Neuropsychiatric symptoms, APOE ε4, and the risk of incident dementia A population-based study

Objective:To investigate the population-based interaction between a biological variable (APOE epsilon 4), neuropsychiatric symptoms, and the risk of incident dementia among subjects with prevalent mild cognitive impairment (MCI).Methods:We prospectively followed 332 participants with prevalent MCI (aged 70 years and older) enrolled in the Mayo Clinic Study of Aging for a median of 3 years. The diagnoses of MCI and dementia were made by an expert consensus panel based on published criteria, after reviewing neurologic, cognitive, and other pertinent data. Neuropsychiatric symptoms were determined at baseline using the Neuropsychiatric Inventory Questionnaire. We used Cox proportional hazards models, with age as a time scale, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were adjusted for sex, education, and medical comorbidity.Results:Baseline agitation, nighttime behaviors, depression, and apathy significantly increased the risk of incident dementia. We observed additive interactions between APOE epsilon 4 and depression (joint effect HR = 2.21; 95% CI = 1.24-3.91; test for additive interaction, p < 0.001); and between APOE epsilon 4 and apathy (joint effect HR = 1.93; 95% CI = 0.93-3.98; test for additive interaction, p = 0.031). Anxiety, irritability, and appetite/eating were not associated with increased risk of incident dementia.Conclusions:Among prevalent MCI cases, baseline agitation, nighttime behaviors, depression, and apathy elevated the risk of incident dementia. There was a synergistic interaction between depression or apathy and APOE epsilon 4 in further elevating the risk of incident dementia.