The VITAL (VITamin D and OmegA-3 TriaL) study was recently funded (recruitment starts January 2010) to investigate the effects of vitamin D and marine omega-3 fatty acid supplements on the primary prevention of cardiovascular disease and cancer. We propose to initiate a substudy of cognitive decline (VITAL-Cog) among 3000 participants aged 65+years, including 1000 African-Americans. This is an exciting opportunity to conduct a large and highly cost-effective randomized double-blind placebo-controlled 2x2 factorial trial of vitamin D (vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (docosahexaenoic acid + eicosapentaenoic acid, 1000 mg/day) supplements for slowing cognitive decline. Data from laboratory studies, epidemiologic research, small primary prevention trials, and/or large secondary prevention trials suggest that these nutritional agents may reduce cognitive decline, but large trials among a generally healthy aging population are lacking. Growing public enthusiasm for supplemental vitamin D as well as fish oil underscores the urgent need for a timely initiation of such a trial, before their use becomes sufficiently prevalent (through supplements and food fortification). VITAL participants will be recruited from the general population by mail among health and other professionals, members of AARP, subscribers to Essence magazine, and others; African-Americans will be oversampled, as they have a higher prevalence of vitamin D deficiency. Respondents will be enrolled in a 3-month placebo run-in phase to test participation. We propose to administer baseline telephone cognitive testing during the run-in period, permitting a pre-randomization assessment. The telephone cognitive battery will include 7 tests of general cognition, verbal memory, and executive function (we have extensive experience with telephone cognitive testing, and the battery will be validated in 300 VITAL-Cog participants with in-person cognitive tests). At the end of the run-in, those who remain willing and eligible and who report having taken at least two-thirds of the pills, will be randomly assigned to one of four treatment groups for 4.5 years. Blood samples will be collected to allow assessment of effect modification by baseline 25-hydroxyvitamin D, omega-3 fatty acid levels, as well as by apolipoprotein E4 status. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects and medical history. At 1.5 to 2-year intervals, VITAL-cog participants will receive follow-up cognitive function assessments, for a total of 3 assessments over the 4.5 years; participants in the 10th percentile of worst decline will also receive telephone informant interviews using the Dementia Questionnaire. Given our success with prior telephone based cognitive function assessments in multiple trial settings, we believe VITAL-cog will be able to provide definitive results regarding the study hypotheses. To complete pre-randomization assessment of cognitive function, it is critical that VITAL-Cog be undertaken in parallel to the placebo run-in period for the parent trial (1 U01 CA138962), which is scheduled to begin in April 2010.