VITAL-DEP (VITamin D and OmegA 3 TriaL-Depression Endpoint Prevention)

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VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention; NCT01696435) began as a first- of-its-kind factorial randomized controlled trial of two plausible agents – vitamin D3 (cholecalciferol 2000 IU/d) and omega-3 fatty acids (EPA and DHA in 1:1 ratio, 1000 mg/d) – for the prevention of late-life depression (LLD) and promotion of long-term healthier mood among older adults. VITAL-DEP, an ancillary of the VITAL trial of cardiovascular disease and cancer prevention, enrolled over 18,000 men and women, aged 50+ years (mean age=67 years) and at risk for depression, who were followed for a median of 5.3 years of randomized treatment. Detailed phenotypic assessments were completed at baseline and follow-up in a subset of over 1,000 participants in the local Clinical and Translational Science Center for: psychiatric diagnostic interviews; neuropsychological testing; self-reports on dimensional measures of depression, anxiety, daily functioning, and social, health and behavioral risk factors. VITAL-DEP achieved substantial racial/ethnic diversity: 20% of participants are Black/African American adults and 30% are racial/ethnic minorities. This competing renewal leverages the rich resources of the assembled cohort and builds on the findings regarding randomized treatment effects in the prior funding period. We observed: 1) evidence that vitamin D3 significantly reduces decline in global cognition and executive function among Black adults; 2) modest differences in effects of omega-3 on LLD risk and sex differences in effects. Inflammatory, structural and functional MRI, and plasma and PET tau markers selected for this proposal show evidence in the literature and preliminary data for relevance to LLD and cognition. Also, given evidence of higher burden of LLD and cognitive decline for women, Black adults, APOE4 carriers and those with higher systemic inflammation, we will determine moderation in outcomes by these risk groups. Specific Aims: 1) We will test causal effects of long-term vitamin D3 on serial measures of plasma tau (NT1), which is associated with neuropsychiatric symptoms in preclinical dementia and has high long-term predictive validity for cognitive decline, independent of other preclinical cognitive markers. 2) We will measure associations of baseline plasma tau with long-term cognitive change, mood symptoms and differences in MRI and PET-tau markers at follow-up. Secondarily, we will examine biological mechanisms for observed sex differences for omega-3 and LLD risk and race differences for vitamin D3 and cognitive decline. In exploratory aims, we hypothesize: study associations will be moderated by baseline inflammation, vascular risk, age, hormone status (in women), and APOE4. Findings from prior funding periods already have implications for public health regarding use of both supplements for prevention in late-life mental health. This renewal proposal will similarly impact the field by clarifying mechanisms for treatment effects on LLD and cognition in key clinical groups and the direct effects of the agents on the brain and preclinical risk markers.