Clinical Nutrition ESPEN · Sep 3, 2025

Association between serum vitamin D metabolite levels and cognitive function in community-dwelling older adults: A cross-sectional study

By Yu C, Ide M, Sugimoto T et al.

BACKGROUND & AIMS: Vitamin D deficiency has been associated with cognitive decline and Alzheimer's disease (AD); however, findings remain inconsistent. Assessing vitamin D status based solely on total 25-hydroxyvitamin D [25(OH)D] may be insufficient, and other metabolites, such as 24,25-dihydroxyvitamin D₃ [24,25(OH)₂D₃] and 3-epimer-25-hydroxyvitamin D₃ [3-epi-25(OH)D₃], may provide additional insights. This study aimed to examine the association between serum vitamin D metabolite concentrations and cognitive function in older adults. METHODS: A cross-sectional study was conducted involving 289 community-dwelling participants aged 65-85 years clinically diagnosed with AD, mild cognitive impairment (MCI), or were cognitively normal (CN). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Serum concentrations of 25-hydroxyvitamin D₃ [25(OH)D₃], 25-hydroxyvitamin D₂ [25(OH)D₂], 24,25(OH)₂D₃, 3-epi-25(OH)D₃, and 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The Vitamin D metabolite ratio (VMR) was calculated as 24,25(OH)₂D₃/25(OH)D₃ × 100 (%). Associations among metabolite concentrations, MMSE scores, and AD prevalence were analyzed. RESULTS: Participants had relatively high serum total 25(OH)D levels (median: 23.5 ng/mL), with males showing higher vitamin D metabolite concentrations. Total 25(OH)D correlated with 24,25(OH)₂D₃, 3-epi-25(OH)D₃, and VMR. In males, 3-epi-25(OH)D₃ and 24,25(OH)₂D₃ were associated with lower MMSE scores (p < 0.01) and higher AD risk (OR = 2.78, p = 0.03). In females, VMR was associated with higher MMSE scores (p = 0.01) and lower AD risk (OR = 0.64, p < 0.01), while 1,25(OH)₂D₃ was linked to higher AD risk (OR = 1.04, p = 0.01) and quartile 2 with lower MCI risk (p < 0.05). CONCLUSIONS: Sex-based differences in vitamin D-cognition associations may reflect disparities in vitamin D levels and hormonal effects, such as estrogen-enhancing and testosterone-suppressing metabolism. 1,25(OH)₂D₃, VMR, and 3-epi-25(OH)D₃ may be more sensitive than total 25(OH)D.

doi.org/10.1016/j.clnesp.2025.08.032Open accessPubMed 40912362Biomarkers