B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment

Background: Metals, silicon, and homocysteine are linked to Alzheimer's disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI). Objective: Examine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vitamins affect these relationships. Methods: MCI participants (n = 266, 77.6-year-old, 60.7% female) in VITACOG trial were randomized to receive daily folic acid (0.8 mg)/vitamin B12 (0.5 mg)/vitamin B6 (20 mg) (n = 133) or placebo for two years. At baseline and end-of-study, cranial MRIs were obtained from 168 participants, cognition was analyzed by neuropsychological tests, and serum iron, copper, arsenic, aluminum, and silicon quantified by inductively-coupled plasma mass spectrometry in 196 participants. Data were analyzed by bivariate and multiple regression. Results: Baseline iron, cysteine, and homocysteine were significantly associated with brain atrophy rate. Homocysteine effects on brain atrophy rate were modified by iron and cysteine. At baseline, iron, copper, aluminum, and silicon were significantly associated with one or more domains of cognition: semantic memory, verbal episodic memory, attention/processing speed, and executive function. At end-of-study, baseline iron, copper, aluminum, and silicon predicted cognition in at least one domain: semantic memory, verbal episodic memory, visuospatial episodic memory, attention/processing speed, and global cognition in the placebo but not the B vitamin group. Conclusion: Disparate effects of serum iron, copper, aluminum, silicon, and homocysteine on cognition and brain atrophy in MCI suggest that cognitive impairment is independent of brain atrophy. These factors showed domain-specific associations with cognition, which were abrogated by B vitamin therapy.