Mid- and Late-Life Depression Increases Risk of Alzheimer’s Disease and Related Dementias (ADRD) in Veterans

Abstract Objective: Little is known about the association of mid-life depression and future ADRD in Veterans and how traumatic brain injuries (TBI) modulate this risk. We used 20-year longitudinal data from the Veterans Health Administration’s electronic health record to understand this association. Method/Data Selection: Participants included Veterans with a depression diagnosis (n=272,739) and a matched control group without depression (n=435,965), excluding those with ADRD diagnosis prior to index date. We performed a time-to-event analysis between depression and ADRD using the Fine-Gray model with death as a competing event, with separate models stratified by age at index (< 60 versus ≥60 years) and TBI status relative to index date. Results/Data Synthesis: Depression was associated with risk of future ADRD (Hazard ratio (HR)=1.36; 95% CI=1.35-1.38). This association was stronger for mid-life depression (i.e., age at index < 60: HR=2.56; 95% CI=2.44-2.69) compared to late-life depression (i.e., age ≥60: HR=1.70; 95% CI=1.67-1.72). TBI diagnosis prior to index conferred higher risk (HR=1.80; 95% CI=1.62-2.00) compared to no TBI (HR=1.38; 95% CI=1.36-1.40) or TBI after index (HR=1.15; 95% CI=1.08-1.23). Conclusions: Our findings add support to consider cognitive screening in older patients who have had a prior diagnosis of depression, especially mid-life depression, as they are at higher risk of ADRD, with attention to potential aggravating factors such as TBI history and its timing relative to depression symptoms. Future studies will incorporate depression treatment history and depression severity to understand how these modulate risk.