Risk factors for Alzheimer’s disease (AD) affecting the rate of cognitive decline and brain shrinkage include nonmodifiable factors such as age, low education levels, and genetic factors, whereas modifiable risk factors have also been identified. One such modifiable risk factor is homocysteine (Hcy), an amino acid that is produced in the methylation cycle of protein metabolism. The association between elevated plasma Hcy and cognitive impairment has been well established (Budge et al., 2002, McCaddon et al., 2001 and Seshadri, 2006), although the underlying mechanisms to explain the association are still being researched.
The Hcy pathway
Hcy is produced via protein metabolism. The conversion of Hcy to useful metabolites, S-adenosyl methionine and glutathione, requires vitamins B9 (methyl folate), B12 (cobalamin), and B6 (pyridoxine) as cofactors ( Morris, 2012a and Refsum et al., 2006). Hence, if the B-vitamin supply through the diet is suboptimal, remethylation of Hcy via the enzyme methionine synthase is reduced, and plasma levels of Hcy rise. The importance of the remethylation process is the regeneration of the active form of folate, tetrahydrofolate, needed for thymidine synthesis, DNA replication, and neurogenesis. S-adenosyl methionine is a methyl donor for the central nervous system and important to neurotransmitter synthesis. Vitamin B12 is also important for fatty acid metabolism, acting as a cofactor for the enzyme methylmalonyl-CoA mutase and also promoting neural membrane formation. Buildup of methylmalonic acid (MMA) indicates the loss of this B12 function. Disruption of any of these pathways is likely to lead to loss of cognitive function and contribute to neuronal atrophy. Increased oxidative stress occurs in the brain when Hcy is elevated ( Birch et al., 2009) and may increase the permeability of blood brain barrier. It is well known that vitamin B12 deficiency is a cause of pernicious or megaloblastic anemia, peripheral neuropathy, lack of energy, and poor memory.
Hcy levels rise with age (Nygård et al., 1998), possibly because of poor absorption of B vitamins from the diet and other factors including male sex, smoking, high blood pressure, and other clinical conditions (Refsum et al., 2006). However, studies in AD patients showed that blood levels of total Hcy are higher than in healthy controls, whereas folate and B12 levels are lower (Clarke et al., 1998).
Brain shrinkage, Hcy, and cognitive decline
Brain shrinkage because of cortical atrophy occurs with normal aging (Fjell et al., 2009 and Thambisetty et al., 2010). The rate of brain atrophy has been shown to be a marker of cognitive decline (Fox et al., 1999) in domains such as memory, processing speed, and executive function (Fjell and Walhovd, 2010).
A 5-year study of people older than 60 years showed that percentage brain volume loss occurred at an average rate of 0.7% ± 0.3% per year (Vogiatzoglou et al., 2008). However, the decrease in brain volume was greater among those with lower vitamin B12 levels and markers of functional B12 including holo-transcobalamin at baseline. Brain volume loss was also associated with higher plasma total Hcy and MMA levels at baseline. For those with the lowest tertile of baseline vitamin B12 (<308 pmol/L), there was a 6-fold increase in the rate of brain volume loss. Elevated total Hcy is also associated with a smaller hippocampus in community-dwelling older adults (Williams et al., 2002). Minimal hippocampal width was shown to decline by 0.7 mm for each 10 micromolar increment in Hcy.
The rate of brain atrophy is known to be increased with neurodegenerative diseases such as AD. Atrophy in the medial temporal lobes becomes detectable by brain imaging at an early stage and is followed by increasing atrophy spreading to other regions of the brain in a sequential pathway (Smith, 2002). Rates of atrophy in those with AD can reach up to 12% per year and have been directly associated with cognitive decline starting in the domain of episodic memory and later involving domains of attention, executive function, processing speed, language, visuospatial skills, and orientation.
Hcy levels have also been associated with cognitive decline. For example, the Hordaland Homocysteine Study found that a rise in Hcy levels over time (6 years of follow-up) predicted cognitive decline (Nurk et al., 2005). This association has been confirmed in other studies (McCaddon et al., 2001) and reviews (Sachdev, 2005) and shown to be age dependent (Oulhaj et al., 2010). Controversies to these findings have been discussed by Morris (2012a).
Elevated Hcy is a risk factor for brain atrophy, cognitive decline, and AD. Hcy can be lowered with B vitamins that are important cofactors in the methylation cycle of Hcy. Together, these cofactors play a role in DNA repair and integrity of the neural membranes; thus, deficiencies will result in damage and brain atrophy.
Treatment with B vitamins can reduce the rate of brain shrinkage in older adults, especially in those with elevated Hcy. The treatment can also delay cognitive decline if taken long term (over 1 year) in those with high Hcy levels. Treatment is likely to be more beneficial in those whose brain shrinkage has not yet reached critical levels and in those who do not yet have dementia.