Effects of long‐term daily supplementation with vitamin D3 and marine omega‐3 fatty acids on change in ADRD biomarkers: A secondary analysis of a randomized clinical trial

Abstract INTRODUCTION Vitamin D3 and omega‐3 supplementation may slow outcomes related to Alzheimer's disease and related dementias (ADRD), with variation by sex or race, but their effects on ADRD‐associated biomarkers are unknown.

Methods

In this secondary analysis of a randomized clinical trial (RCT), we included 929 participants from the in‐clinic subcohort of the VITamin D and OmegA‐3 TriaL – a completed, placebo‐controlled, 2×2 factorial trial testing vitamin D3 (2000 IU/day) and omega‐3s (1 g/day) for cardiovascular disease and cancer prevention. Plasma ADRD biomarkers were assayed at baseline and 2‐ and/or 4‐year follow‐up. Study outcomes were longitudinal change in four ADRD biomarkers: N‐terminal tau fragment (NT1), amyloid beta (Aβ)40:42, neurofilament‐light (NfL), and glial fibrillary acidic protein (GFAP). Repeated‐measures models were used, with sex and race were pre‐specified effect modifiers.

Results

The sample mean (SD) age was 65.0 (6.6) years; 49.2% were female, and 8.2% were Black adults. Neither vitamin D3 nor omega‐3s, compared to placebo, significantly reduced ADRD biomarkers over 4 years. Pre‐specified subgroup analyses suggested potential interactions by sex and race. Vitamin D3 supplementation resulted in a reduction in NT1 among males (−2.7%) but not females (p‐interaction = 0.08). Among Black participants, vitamin D3 supplementation resulted in a 16.2% reduction in NfL levels [95% CI: −30.5% to 1.1%; p‐interaction = 0.06], while omega‐3 supplementation showed a 12.4% reduction in GFAP levels [95% CI: −21.5% to −2.2%; p‐interaction = 0.049].

Discussion

In this secondary analysis of a RCT, neither vitamin D3 nor omega‐3s significantly reduced selected plasma ADRD biomarkers over 4 years. Potential differences were observed by sex and race in reductions of ADRD biomarkers in response to these supplements; however, these analyses were uncorrected for multiple hypothesis testing and should be interpreted cautiously as hypothesis‐generating signals requiring replication. TRIAL REGISTRATION ClinicalTrials.gov identifiers: c (VITAL); NCT01696435 (VITAL‐DEP).