The potential impact of L-leucine on the cognitive function of patients with Alzheimer's disease

As one of the essential branched-chain amino acids (BCAAs) for the human body, L-leucine is predominantly metabolized in skeletal muscle and can also cross the blood-brain barrier to participate in the physiological regulation of the central nervous system. Recent studies have indicated that the potential effects of L-leucine on cognitive function in patients with Alzheimer’s disease (AD) are primarily achieved through multiple pathways, including regulating the balance of neurotransmitters in the brain, improving energy metabolism, inhibiting neuroinflammation, and reducing β-amyloid (Aβ) deposition. However, its efficacy exhibits dose dependence and individual variability. The specific mechanisms and clinical potential are elaborated as follows:

I. Core Mechanisms of Action: Multi-pathway Regulation of the AD Pathological Process

The core pathological features of AD include abnormal aggregation of Aβ to form senile plaques, hyperphosphorylation of tau protein to form neurofibrillary tangles, neuroinflammation, and disrupted energy metabolism in the brain. These pathological changes directly lead to neuronal damage and cognitive decline. L-leucine exerts potential neuroprotective effects by targeting and intervening in the aforementioned pathological processes.

Improving Cerebral Energy Metabolism to Maintain Neuronal Function

The normal activity of brain neurons relies on adequate energy supply. However, the cerebral glucose metabolism rate is significantly reduced in AD patients, particularly in memory-related brain regions such as the hippocampus and temporal lobe. L-leucine can enhance cerebral energy levels through two pathways:

As a ketogenic amino acid, L-leucine can be metabolized in the liver and brain to produce ketone bodies (β-hydroxybutyrate), which can replace glucose as an energy substrate for neurons and provide efficient energy for metabolically impaired neurons.

L-leucine can activate the intracellular mammalian target of rapamycin (mTOR) signaling pathway, which is involved in regulating mitochondrial biogenesis and functional repair. This enhances the energy production efficiency of neuronal mitochondria, alleviates the energy deficit in the AD brain, thereby protecting the survival and synaptic plasticity of hippocampal neurons and delaying memory decline.

Inhibiting Neuroinflammation to Reduce Neuronal Damage

Chronic neuroinflammation is a key driver of AD progression. Activated microglia release large amounts of pro-inflammatory factors (e.g., TNF-α, IL-6), exacerbating neuronal apoptosis and synaptic loss. The anti-neuroinflammatory effects of L-leucine are mainly reflected in two aspects:

Regulating the polarization direction of microglia, promoting their transformation from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, reducing the secretion of pro-inflammatory factors, and increasing the release of anti-inflammatory factors (e.g., IL-10) to alleviate the inflammatory microenvironment in the brain.

Inhibiting the activation of the nuclear factor κB (NF-κB) signaling pathway, a core regulatory pathway of inflammatory responses. L-leucine can reduce the transcription and expression of inflammatory factors by decreasing NF-κB activity, thus mitigating inflammatory damage to neurons.

Regulating Aβ Metabolism and Tau Protein Phosphorylation to Delay Pathological Deposition

Abnormal Aβ aggregation and tau protein hyperphosphorylation are hallmark pathological changes of AD. L-leucine can intervene in these two processes through indirect pathways:

Promoting Aβ clearance: The mTOR pathway activated by L-leucine can upregulate the expression of insulin-degrading enzyme (IDE) in the brain. IDE is a key enzyme for Aβ degradation, which can accelerate the breakdown of cerebral Aβ and reduce the formation of senile plaques.

Inhibiting tau protein hyperphosphorylation: The activity of glycogen synthase kinase 3β (GSK-3β) is abnormally elevated in the AD brain, which is the core kinase leading to tau protein hyperphosphorylation. L-leucine can inhibit GSK-3β activity by regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, reducing the phosphorylation level of tau protein and delaying the formation of neurofibrillary tangles.

Modulating Neurotransmitter Balance to Improve Cognition-Related Signal Transduction

Acetylcholine (Ach) is a neurotransmitter closely associated with learning and memory. In AD patients, cholinergic neurons are lost in large numbers, resulting in a significant decrease in Ach levels. Studies have found that L-leucine can enhance the activity of choline acetyltransferase (ChAT) in the brain, a key enzyme for Ach synthesis, thereby increasing cerebral Ach concentrations, strengthening signal transduction in cholinergic neural pathways, and improving patients’ learning and memory abilities. Meanwhile, L-leucine can regulate the metabolic balance of glutamate, reducing the excessive accumulation of excitatory amino acids and avoiding excitotoxic damage to neurons.

II. Clinical Research Evidence and Limitations

1. Positive Findings from Basic and Clinical Studies

Animal experiments have shown that supplementing AD model mice with L-leucine (or a BCAA mixture) leads to a significant reduction in Aβ deposition in the hippocampus, a decrease in tau protein phosphorylation levels, and a marked improvement in the mice’s spatial learning and memory abilities (e.g., performance in the Morris water maze test). Small-sample clinical studies have indicated that short-term supplementation with BCAAs (containing L-leucine) in AD patients results in decreased serum levels of pro-inflammatory factors and a slight improvement in Mini-Mental State Examination (MMSE) scores, with no obvious adverse reactions observed. These findings suggest that L-leucine has potential value in improving cognitive function in patients with mild to moderate AD.

2. Research Limitations and Controversies

Dose dependence and individual variability: Excessive supplementation of L-leucine may lead to excessively high blood BCAA concentrations, inhibiting the entry of aromatic amino acids (e.g., tryptophan, tyrosine) into the brain, interfering with the synthesis of neurotransmitters such as serotonin and dopamine, and potentially exacerbating cognitive impairment. In addition, AD patients exhibit differential responses to L-leucine depending on factors such as disease stage and genotype (e.g., APOE ε4 carriers).

Lack of large-sample long-term clinical data: Currently, there is a paucity of large-sample, double-blind, placebo-controlled clinical trials investigating the effects of L-leucine monotherapy on cognitive function in AD. Its long-term safety and efficacy have not been fully verified.

Complexity of action targets: The mTOR pathway activated by L-leucine has a dual effect: moderate activation can promote neuronal repair, while excessive activation may exacerbate Aβ production. Therefore, precise dosage control is required to balance its effects.

III. Application Prospects and Precautions

Potential of Combined Intervention

The effect of L-leucine alone on improving cognitive function in AD is limited, and it is more suitable as an adjuvant component in combined interventions. For example, combining it with cholinesterase inhibitors (e.g., donepezil), NMDA receptor antagonists (e.g., memantine), or synergizing it with nutrients such as Omega-3 fatty acids and vitamin D can enhance intervention efficacy through multi-target regulation.

Principles of Individualized Application

Supplementation for AD patients should follow the principle of individualization: patients with mild AD can appropriately increase the intake of L-leucine-rich foods (e.g., lean meat, eggs, milk, legumes) under the guidance of a dietitian; patients with moderate to severe AD need to undergo serum amino acid profile testing and use low-dose BCAA preparations under the guidance of a physician, avoiding large-scale self-supplementation.

Safety Considerations

At normal dosages, L-leucine has good tolerability in AD patients and does not cause severe adverse reactions. However, for AD patients with comorbid renal insufficiency, the dosage must be strictly controlled to avoid increasing the metabolic burden on the kidneys; for patients with comorbid diabetes, blood glucose changes need to be monitored, as L-leucine may affect insulin sensitivity.

L-leucine exerts potential protective effects on cognitive function in AD patients through pathways such as improving cerebral energy metabolism, inhibiting neuroinflammation, and regulating the pathological processes of Aβ and tau protein. However, current research is still in the exploratory stage, and its efficacy is affected by factors such as dosage, disease course, and individual variability, meaning it has not yet become a routine treatment for AD. Future research needs to clarify its optimal dosage and applicable population through larger-scale clinical trials, providing a reliable basis for the application of L-leucine in the adjuvant treatment of AD.