Alzheimer's disease and nutrition: Focus on the impact of hyperhomocysteinemia

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. Despite advances in the understanding of the genetics of AD, environmental risk factors are still under investigation, and the etiology is still not completely understood. The environmental component of AD, which we explore in the first part of this review, takes on greater importance with more advanced disease onset. Moreover, genetics does not explain all of AD. Environmental risk factors are divided into modifiable and nonmodifiable risk factors. Among the modifiable risk factors, nutrition seems to play a predominant role. One-carbon metabolism (OCM) is involved in this food-related component, notably through B vitamins. Homocysteine, a sulfur-containing amino acid, is at the crossroads of OCM. Abnormal increases in homocysteine levels (hyperhomocysteinemia) are associated with deleterious effects on cognition. Various mechanisms can lead to hyperhomocysteinemia, including genetic factors associated with different polymorphisms, dietary deficiencies targeting vitamins B9 and B12, and renal insufficiency. The second part of the review details OCM and the role of homocysteine. Finally, part 3 highlights the numerous studies in the literature describing the association between hyperhomocysteinemia and cognitive decline. However, the mechanistic links between hyperhomocysteinemia and cognitive decline in AD are poorly understood. Several hypotheses have been proposed in the literature. The toxic effects of homocysteine could be mediated by N-homocysteinylation, a nonenzymatic reaction leading to the irreversible accumulation of N-homocysteinylated proteins. Finally, we detail some therapeutic trials targeting one-carbon metabolism in AD, notably vitamin B9 and B12 supplementation.