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

Abstract

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 B 12 (0.5 mg)/vitamin B 6 (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.

Associations between plasma metal elements and risk of cognitive impairment among Chinese older adults

“…This present study showed that compared to participants in the normal cognition group, the CI group participants had lower plasma Fe levels, which is consistent with previous studies ( Gong et al, 2021 ). In addition, in a 2-year follow-up study, Jakubowski et al (2021) found that serum Fe levels significantly decreased in mild CI as the disease progressed. Thus, we inferred that Fe dysfunction may be relevant to AD pathogenesis and progress.…”

“… Shen et al (2019) found that mice with Fe-supplemented drinking water had a dramatic decrease in the levels of Aβ 42 , phosphorylated tau, and neuronal apoptosis. However, one study reported that cortical Fe levels are increased in patients with AD and co-localized with Aβ plaques ( Jakubowski et al, 2021 ). This may be due to peripheral Fe deficiency, leading to Fe transporters in the BBB taking up more Fe2+ and releasing it in the brain, ultimately resulting in Fe overload, neuroinflammation, and Aβ deposition ( Dong et al, 2015 ).…”

Exploring the complexities of 1C metabolism: implications in aging and neurodegenerative diseases

“…These findings are echoed through the literature, where another study evaluating the effects of baseline iron, cysteine, and Hcy on brain atrophy rate, showed that Hcy was associated with accelerated brain atrophy and predicted worse cognition. The same study demonstrated that the brain atrophy rate was abrogated by treatment with B vitamins ( Jakubowski et al, 2021 ). Regardless of the severity of the dementia in AD, there is approximately a one-third increase in the level of Hcy in the blood of these patients.…”

Association Between Blood Biochemical Factors Contributing to Cognitive Decline and B Vitamins in Patients With Alzheimer's Disease

“…Independently, B vitamins deficiency also induced cerebrovascular dysfunction, activation of tau kinases and enhanced Aβ metabolism contributed to AD development ( 16 – 18 ). David Smith and colleagues' studies also indicated a possible pathogenetic role of B vitamins (B12, Folate) in mild cognitive impairment, as B vitamins therapy could abrogate effects of iron-associated brain atrophy rate ( 19 ). Thiamine diphosphate (TDP) is the bioactive form of thiamine, which acts in the production of energy from carbohydrates in the cells and is essential in the proper functioning of the nervous system ( 20 ).…”