Abstract
BACKGROUND: Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process. METHODS: Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms. RESULTS: Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10(-5)), amygdala (β = -0.07; p = 8.44 × 10(-4)), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10(-6)). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 × 10(-5)) and 3.97 % (95 % CI: -0.007 to -2.94 × 10(-4)) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet. CONCLUSIONS: These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.