Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the major cause of dementia and no preventive or effective treatment has been established to date. The etiology of AD is poorly understood, but genetic and environmental factors seem to play a role in its onset and progression. In particular, factors affecting the one-carbon metabolism (OCM) are thought to be important and elevated homocysteine (Hcy) levels, indicating impaired OCM, have been associated with AD. We aimed at evaluating the role of polymorphisms of key OCM enzymes in the etiology of AD, particularly when intakes of relevant B-vitamins are inadequate. Our review indicates that a range of compensatory mechanisms exist to maintain a metabolic balance. However, these become overwhelmed if the activity of more than one enzyme is reduced due to genetic factors or insufficient folate, riboflavin, vitamin B6 and/or vitamin B12 levels. Consequences include increased Hcy levels and reduced capacity to synthetize, methylate and repair DNA, and/or modulated neurotransmission. This seems to favor the development of hallmarks of AD particularly when combined with increased oxidative stress e.g., in apolipoprotein E (ApoE) ε4 carriers. However, as these effects can be compensated at least partially by adequate intakes of B-vitamins, achieving optimal B-vitamin status for the general population should be a public health priority.

One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond

“…One-carbon metabolism disturbances may cripple DNA repair, methylation, and/or synthesis, as well as reduce the availability of neurotransmitters, phospholipids, and myelin [51]. Several of these mechanisms may be involved in cognitive dysfunction and underlying neurobiology.…”

What does your cell really do? Model-based assessment of mammalian cells metabolic functionalities using omics data

“…We further used these identified tasks to investigate their expression patterns (i.e., percentage of patient samples associated with an active task and related median score) across the groups of patients presenting or not a positive diagnosis for Alzheimer's disease. Very distinctive median score distribution depending on the Alzheimer's diagnosis are observed for 4 tasks previously highlighted in the literature as being implicated in the Alzheimer's disease ( Figure 6E-G): the synthesis of Tn antigen 40,41 (glycoprotein N-acetylgalactosamine), the synthesis of tetrahydrofolate 42 and the salvage of IMP and GMP 43 . While the other metabolic tasks identified do not present distinctive patterns at the level of the median score distribution, we can observe that healthy subjects often present a higher percentage of samples for which these tasks are active (Supplementary Figure 5).…”

Personalised Medicine for Dementia: Collaborative Research of Multimodal Non-pharmacological Treatment with the UK National Health Service (NHS)

“…and prescribes an intervention as a 'disease modifying therapy' (DMT) that targets change in the underlying disease process leading to cell death [52]. The mechanisms and determinants are many [53] and predominantly involve nutritional deficiency [54], inflammation [55], oxidative stress [56], mitochondrial dysfunction [57], impaired methylation pathways [58], impaired Aβ clearance [43], hormone imbalance [59], chronic stress [60], gut dysbiosis [61], insulin dysregulation [62], infections [40,[63][64][65][66], poor sleep [67], vascular disease [68], and toxicity [41,60,69,70], including heavy metals [71][72][73][74][75].…”