HY-FOLIC® VASCULAR COGNITIVE IMPAIRMENT
Introduction
Stroke patients experience a vulnerable phase in which the brain is highly susceptible to damage due to disrupted blood flow and neuronal injury. During this recovery period, multiple factors influence the rate and quality of neurological restoration. One important yet often overlooked biochemical factor is hyperhomocysteinemia, defined as elevated levels of homocysteine in the blood and brain tissue.
Homocysteine is an intermediate metabolite derived from methionine metabolism. Methionine, an essential amino acid obtained from protein-rich foods such as meat, eggs, and dairy, undergoes conversion into S-adenosylmethionine (SAMe), a key compound in methylation processes that regulate neurotransmitter synthesis and neuroprotection. After donating its methyl group, SAMe is converted into homocysteine.
Under normal physiological conditions, homocysteine does not accumulate because it is either remethylated to methionine or converted into cysteine through transsulfuration pathways. These processes require essential cofactors such as 5-MTHF (active folate), vitamin B6, and vitamin B12. However, micronutrient deficiencies, aging, renal dysfunction, or genetic polymorphisms such as MTHFR mutations impair these pathways, leading to homocysteine accumulation, particularly in the nervous system.
Elevated homocysteine is known to induce neurotoxicity, exacerbating post-stroke brain injury. One mechanism involves reduced production of SAMe, a critical methyl donor required for the synthesis of neurotransmitters such as dopamine, serotonin, and norepinephrine. Imbalance of these neurotransmitters negatively affects mood regulation, cognition, and neural recovery capacity.
Moreover, excess homocysteine promotes oxidative stress and inflammation, accelerates neuronal damage, and excessively activates NMDA receptors, resulting in excitotoxicity. These combined effects impair brain tissue regeneration, worsen learning and memory functions, and contribute to neurological complications such as post-stroke depression, seizures, and vascular dementia.
Several studies have demonstrated a negative correlation between homocysteine levels and cognitive recovery scores after stroke, indicating that higher homocysteine is associated with poorer outcomes in attention, memory, and emotional regulation.
Managing homocysteine levels is essential for stroke rehabilitation. Supplementation with 5-MTHF (active folate), together with vitamins B6 and B12, has been scientifically proven to reduce homocysteine, restore methylation pathways, and enhance neuroplasticity — the brain’s ability to form new neural networks after injury [2,11].
Hyperhomocysteinemia may result from deficiencies of folate (B9), vitamin B12, and B6, as well as MTHFR C677T polymorphism, which impairs the body’s ability to convert folate into its active form, 5-MTHF (active folate) [12]. In such cases, conventional folic acid supplementation may be less effective since it requires enzymatic activation. Conversely, 5-MTHF (active folate) is directly bioactive, enabling efficient remethylation of homocysteine into methionine via methionine synthase and vitamin B12, especially in individuals with MTHFR polymorphisms [13].
Clinical trials have demonstrated that 5-MTHF (active folate) supplementation significantly reduces homocysteine levels, improves vascular endothelial function, and enhances neurovascular repair. Additionally, 5-MTHF (active folate) exhibits superior central nervous system penetration compared to folic acid, making it a more effective option for supporting neurological recovery in post-stroke patients [14]. Through its role in methylation and neurotransmitter synthesis (serotonin and dopamine), 5-MTHF (active folate) may also improve mood and cognitive outcomes for neurological recovery in post-stroke patients [15].
5-Methyltetrahydrofolate (5-MTHF) (Active Folate) in Cognitive Disorders
5-MTHF (active folate), the biologically active form of folate, plays a fundamental role in neurological and cognitive processes. Folate deficiency has long been associated with depression, dementia, and Alzheimer’s disease. As a bioactive molecule, 5-MTHF (active folate) readily crosses the blood–brain barrier and participates in critical biochemical reactions within the central nervous system [5][8][9].
5-MTHF functions as a primary methyl donor in the remethylation of homocysteine to methionine, leading to the production of SAMe, a central molecule in methylation reactions. These reactions regulate gene expression, neurotransmitter synthesis (serotonin, dopamine, norepinephrine), and neuronal integrity. Furthermore, 5-MTHF supports the production of tetrahydrobiopterin (BH4), a vital cofactor for neurotransmitter synthesis, thereby promoting mood stability and cognitive resilience [1].
Consequences of 5-MTHF Deficiency in Cognitive Impairment
5-MTHF (active folate) functions as a primary methyl donor in the remethylation of homocysteine to methionine, leading to the production of SAMe, a central molecule in methylation reactions. These reactions regulate gene expression, neurotransmitter synthesis (serotonin, dopamine, norepinephrine), and neuronal integrity. Furthermore, 5-MTHF (active folate) supports the production of tetrahydrobiopterin (BH4), a vital cofactor for neurotransmitter synthesis, thereby promoting mood stability and cognitive resilience [1].
Consequences of 5-MTHF (active folate) Deficiency in Cognitive Impairment
5-MTHF (active folate) deficiency leads to homocysteine accumulation, which is neurotoxic and strongly associated with increased risk of dementia and brain atrophy. Individuals with MTHFR genetic variants (particularly C677T) show impaired folate conversion and are at greater risk of neurocognitive decline. Additionally, certain medical conditions such as Helicobacter pylori infection can further reduce 5-MTHF (active folate) levels and worsen cognitive deterioration [2][3].
Hyperhomocysteinemia contributes to Alzheimer’s disease, dementia, and mood disorders through multiple mechanisms:
Hyperhomocysteinemia has been recognized as an independent risk factor for both vascular and mixed dementia, through mechanisms such as:
Effectiveness of 5-MTHF (active folate) in Cognitive Preservation
A meta-analysis of 23 randomized controlled trials demonstrated that supplementation, including 5-MTHF (active folate), significantly improves cognitive performance, particularly in countries without folic acid food fortification. This highlights baseline folate status as a determinant of treatment efficacy [6][10].
Systematic reviews also confirm that 5-MTHF (active folate) supplementation in older adults lowers homocysteine and improves working memory. In Alzheimer’s disease, 5-MTHF (active folate) reduces β-amyloid deposition, enhances memory function, and decreases oxidative stress in the brain [4][5].
Advantages of 5-MTHF (active folate) Over Folic Acid
Unlike folic acid, 5-MTHF (active folate) does not require enzymatic activation and is immediately bioavailable. This is especially important for individuals with MTHFR polymorphisms. Furthermore, 5-MTHF (active folate) avoids the accumulation of unmetabolized folic acid (UMFA) in circulation, which may negatively affect immune and neurological function. Evidence also shows that 5-MTHF (active folate) supplementation is more effective in increasing brain folate concentrations than folic acid [1][7].
Conclusion
5-MTHF (active folate) is an essential nutrient for neurological health, supporting DNA methylation, neurotransmitter synthesis, and homocysteine regulation. Its deficiency is strongly associated with cognitive decline, mood disorders, and dementia, particularly in individuals with impaired folate metabolism. With higher bioavailability and greater efficacy than folic acid, 5-MTHF (active folate) represents a superior form of folate supplementation for promoting vascular repair and cognitive recovery.
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