Homocysteine, Cognitive Functions, and Degenerative Dementias: State of the Art

Abstract

There is strong evidence that homocysteine is a risk factor not only for cerebrovascular diseases but also for degenerative dementias. A recent consensus statement renewed the importance and the role of high levels of homocysteine in cognitive decline in several forms of degenerative dementia, such as Alzheimer’s disease. Although the molecular mechanisms by which homocysteine causes cell dysfunction are known, both the impact of homocysteine on specific cognitive functions and the relationship between homocysteine level and non-Alzheimer dementias have been poorly investigated. Most of the studies addressing the impact of hyperhomocysteinemia on dementias have not examined the profile of performance across different cognitive domains, and have only relied on screening tests, which provide a very general and coarse-grained picture of the cognitive status of the patients. Yet, trying to understand whether hyperhomocysteinemia is associated with the impairment of specific cognitive functions would be crucial, as it would be, in parallel, learning whether some brain circuits are particularly susceptible to the damage caused by hyperhomocysteinemia. These steps would allow one to (i) understand the actual role of homocysteine in the pathogenesis of cognitive decline and (ii) improve the diagnostic accuracy, differential diagnosis and prognostic implications. This review is aimed at exploring and revising the state of the art of these two strictly related domains. Suggestions for future research are provided.

Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging

“…Homocysteine in cells is also removed through the remethylation or transsulfuration pathways. Hyperhomocysteinemia due to the inherited deficiency of cystathionine β-synthase, decreased renal excretion due to impaired renal function, or imbalance of one-carbon metabolism has been well demonstrated to be associated with an increased risk of cardiovascular diseases [ 99 ] and neurocognitive disorders [ 100 ]. In fact, blood homocysteine levels tend to increase with age, which may be associated with an age-dependent decline in global DNA methylation [ 18 ].…”

The effects of the interplay between vitamins, antibiotics, and gut microbiota on the pathogenesis and progression of dementia: A systematic review and meta‐analysis

“…The mechanism of homocysteine‐induced dementia is complicated 40 . The link between cognitive deterioration and high homocysteine levels has been explained by many mechanisms 41,42 . Neurotoxicity is also associated with homocysteine.…”

“… 40 The link between cognitive deterioration and high homocysteine levels has been explained by many mechanisms. 41 , 42 Neurotoxicity is also associated with homocysteine. Oxidative stress, inflammation, and brain cell loss can result from high homocysteine levels.…”

Bioinorganic Chemistry of Micronutrients Related to Alzheimer’s and Parkinson’s Diseases

“…Vitamin B 6 is also required for the conversion of homocysteine (Hcy) to cysteine and, together with vitamin B 12 and folate (vitamin B 9 ), plays a key role in maintaining physiological plasma levels of Hcy (10–20 mol/L) [ 52 ]. Interestingly, higher Hcy concentrations in the blood are considered a major risk factor for AD, PD, and vascular dementia [ 53 , 54 , 55 ].…”

“…Clinical studies on AD patients have indicated that lower concentrations of vitamins B 9 and B 12 correlate with high serum Hcy levels [ 88 , 89 ]. As previously mentioned, hyperhomocysteinemia is commonly observed in PD, AD, and MCI cases [ 53 , 54 , 55 ]. The correlation between elevated Hcy concentrations and vitamins B 9 and B 12 deficiency might be explained by taking into account that both vitamins are involved in the methionine/homocysteine cycle [ 90 ].…”