An Additional Chance against Alzheimer’s Disease – Green Walnuts

• Sorin Godeanu M.D. in ICU and pharmacognosy at Carol Davila University of Medicine and Pharmacy

    Academic Professor Doctor Ionescu-Târgoviște

Alzheimer’s disease is characterized by progressive cognitive decline, as well as by a memorization deficit. At the moment (July 2023), there are around 47 million pacients suffering from this disease, and the prognosis is about 130 million pacients until 2050. This disease’s pathogenesis – it’s about extracellular beta amyloid aggregates and intracellular hyperphosphorylated τ protein neurofibrillar clusters situated in the limbic cortical areas inside the human brain. The disease is characterized by memory loss and progressive neurocognitive dysfunction.

Multiple mechanisms are responsible: the amyloid cascade, τ protein hyperphosphorylation and oxidative stress. The beta amyloid was discovered by Paul Block and George Mannesco in 1892 in the circular accumulations found in the brains of older patients.

In 1991, John Hardy sends out the following hypothesis: beta amyloid is a transmembrane protein produced through hydrolysis of APP (beta Amyloid Precursor Protein), through the amyloidogenic pathway. Studies have shown that APP produces C-terminal fragments through hydrolysis with alpha, beta, gamma secretases.

Beta-42 amyloids are more predisposed to aggregation and plaque formation than beta-40 amyloids; they also have higher neurotoxicity. Beta-amyloids deposited as neurotoxic amyloid plaques in the hippocampus and the basal segment recruit more beta-amyloids in order to form insoluble aggregates and induce mitochondrial destruction, unstable homeostasis, and synaptic dysfunction. Microglia and astrocytes are activated, creating the inflammatory response as well as oxidative stress, therefore leading to neuronal dysfunction and apoptosis – Alzheimer’s disease.

Pathogenic modifications are initiated by the soluble beta-amyloid oligomers; they slowly accumulate in a period of 10 to 30 years before symptoms start appearing, such as synaptic dysfunction and learning or memorization deficit. Beta-42 amyloid oligomers lead to oxidative destruction of synaptic membranes and induce τ protein hyperphosphorylation. 

In 1988, Claude Wischek isolated the τ protein in the brain plaques of patients with Alzheimer’s disease. Phosphorylated τ proteins in Alzheimer’s disease undergo conformational changes and lose their ability to polymerize with tubulin, resulting in dysfunctional microtubules. Experiments have shown that τ protein phosphorylation is correlated with the degree of τ protein aggregation and the severity of pathology in Alzheimer’s disease. τ protein, like amyloid beta, influences cognitive status. Acetylation of τ protein inhibits its ability to bind microtubules and promotes τ protein aggregation, leading to mitochondrial dysfunction and synaptic deficits. Walnut extract inhibits and defibrillates fibrillar beta-amyloid, the main component of amyloid plaques in the brains of Alzheimer’s patients.

The polyphenolic components present in walnuts are believed to be responsible for their anti-amyloidogenic activities. Two major components, gallic acid and ellagic acid, have been described as dual inhibitors of the enzyme acetylcholinesterase, which is responsible for acetylcholine inactivation. It has been observed that the administration of 8-13 walnuts over a minimum period of 4 weeks improves endothelium-dependent vasodilation.

Alzheimer’s disease is a neurodegenerative disease triggered by oxidative stress with cholinergic impairment. Oxidative stress and neuroinflammation play an important role in aging, cognitive deterioration, and Alzheimer’s disease. Amyloid beta protein, the main component of amyloid plaques found in the brains of Alzheimer’s patients, generates free radicals in neurons, leading to oxidative damage and cell death. Amyloid beta induces neuroinflammation through the increase of pro-inflammatory cytokines and enzymes. Walnuts contain several components with antioxidant and anti-inflammatory effects. Studies conducted on humans and animals suggest that walnut consumption improves cognition and reduces the progression of Alzheimer’s disease. Walnuts enhance antioxidant defense, reduce levels of free radicals, decrease lipid peroxidation, and inhibit protein oxidation.

Clinical studies have associated walnut consumption with improved cognitive performance and memory enhancement. Walnuts inhibit fibrillization and solubilize beta-amyloid fibrils, which is an anti-amyloidogenic property of walnuts.

Early and long-term treatment with walnut extracts helps maintain cognitive function and reduces the risk of developing Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative condition that gradually leads to memory loss and cognitive decline over a period of 5-20 years. It is the most common form of dementia in elderly individuals and accounts for 60% of dementia cases. In Alzheimer’s disease, the loss of neuronal mass occurs concurrently with progressive accumulation of fibrillar beta-amyloid, triggering the disease’s onset. Beta-amyloid is a protein composed of 40-42 amino acids that exists in both soluble and fibrillar forms. Neuropathological changes evolve slowly before clinical signs of dementia are diagnosed.

Oxidative stress refers to an imbalance between free radicals and antioxidants. When the level of free radicals becomes toxic due to accumulation, they react with lipids, proteins, and nucleic acids in cells, leading to cell death.

As a result, oxidative stress affects the cellular membrane, fluidity, enzymatic activities, and ion transport. The brain is vulnerable to oxidative stress because it consumes 20% of the total oxygen and has limited antioxidant capacity, with a high content of unsaturated lipids. Oxidative stress, along with neuroinflammation, contributes to brain aging.

Neuroinflammation, mediated by activated microglial cells and astrocytes, releases pro-inflammatory cytokines such as IL6, IL1 beta, and TNF-alpha, which have been associated with aging brains and Alzheimer’s disease. Amyloid beta activates microglia, leading to increased production of the aforementioned pro-inflammatory cytokines and stimulates pro-inflammatory enzymes like inducible nitric oxide synthase (iNOS), resulting in elevated nitric oxide production. In Alzheimer’s disease, COX2 (cyclooxygenase-2) levels increase, induced by pro-inflammatory mediators, leading to increased production of inflammatory prostaglandins, particularly PGE2 in the brain.

Prostaglandin synthesis is a source of ROS (reactive oxygen species) in the brain, contributing to increased oxidative stress in elderly individuals and those with Alzheimer’s disease.

Walnuts play a significant antioxidant role due to their content of flavonoids, phenolic acids (such as ellagic acid), melatonin, folates, gamma-tocopherol (vitamin E), selenium, juglone, and proanthocyanidins. Walnuts also contain a substantial amount of alpha-linolenic acid, which has anti-inflammatory effects.

Indeed, studies have shown that alpha-linolenic acid inhibits inflammation by reducing inducible nitric oxide synthase (iNOS), inhibiting cyclooxygenase, and pro-inflammatory cytokines.

The anti-amyloidogenic properties of walnuts inhibit beta-amyloid, fibrillization, and solubilization of beta-amyloid fibrils. As a result, walnuts reduce oxidative stress caused by beta-amyloid and inhibit ROS production.

In conclusion, walnuts deactivate free radicals, limit oxidative stress, and prevent neuronal cell death induced by beta-amyloid, the characteristic protein of Alzheimer’s disease. Walnuts contain active compounds that enhance endogenous antioxidant capacity and can modulate the cellular redox status.

Administration of walnut extracts, both in laboratory and medical clinical settings, leads to improved cognitive performance in assimilating environmental information and enhances motor skills for exploring a labyrinth in experiments. Animals subjected to walnut extracts have demonstrated reduced stress and anxiety, resulting in fewer errors. Alpha-linolenic acid is a precursor to vital fatty acids important for regulating serotonin and dopamine levels, as well as modulating motor responses.

Elidor developed walnut green tablets with a focus on their active substance content, involved in both neuronal processes and synaptic levels, as well as blocking neurodegenerative processes. Statistics have shown a threatening evolution of neurodegenerative diseases, and such interventions hold promise in counteracting their progression.

It’s important to mention that depression can be considered a risk factor for dementia, given that over 20% of dementia patients have been diagnosed with depressive disorder.

In a study conducted over 28 years, depressive symptoms were observed to be more prominent about 10 years before the diagnosis of dementia was formulated. However, among those who consumed walnuts, the symptoms were less frequent and less intense. These patients showed interest in participating in activities, and there was an improvement in cognitive function, including faster learning of protocols and more efficient motor coordination. Additionally, there was a reduction in anxious behavior and an improvement in oxidative stress by balancing the ratio of free radicals to antioxidants.

Based on these findings, it is recommended to take green walnut (Nuca Verde) tablets at a dosage of 4-6 tablets per day for at least 3-4 months, with regular evaluations of neurological status. This intervention may help in managing depressive symptoms and potentially mitigate the risk of developing dementia. As always, it’s essential to consult with a healthcare professional before starting any supplement regimen or treatment plan.