Alzheimer's Disease (AD) is the most common form of dementia. An estimated 26.6 million people worldwide had Alzheimer's in 2006; this number may quadruple by 2050.
In the early stages, the most commonly recognized symptom is memory loss, such as difficulty in remembering recently learned facts. As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. The mean life expectancy following diagnosis is approximately seven years.
The cause and progression of AD are not well understood. Research indicates that the disease is associated with plaques and tangles in the nerve cell bodies of the brain. Currently-used pharmaceutical treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available.
At present, there appears to be no definitive evidence to support the belief that any particular measure is effective in preventing AD. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD.
The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Several vitamins such as B12, B3, C, and folic acid have been found in some studies to be related to a reduced risk of AD but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects. Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models.
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.
Intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction may also delay the onset or reduce the severity of Alzheimer's disease. Bilingualism is also related to a later onset of Alzheimer's. Some studies have shown an increased risk of developing AD with occupational exposure to magnetic fields, intake of metals, particularly aluminum, or exposure to solvents.
We have made very little progress in the treatment of Alzheimer’s Disease. Standard treatments, such as donepezil (Aricept) and memantine (Namenda), accomplish very little with regards to improving quality of life in these unfortunate individuals. Similarly, research and development by the pharmaceutical industry has not yielded any “home runs.” We have spent many years and many dollars developing drugs to target amyloid beta plaques with little success.
Recently, the FDA approved lecanemab (Leqembi) for the treatment of Alzheimer’s disease. The results showed that lecanemab successfully removed amyloid and tau proteins from the brains of people living with early Alzheimer’s disease. For the people taking lecanemab, this meant that the decline in their thinking and memory skills was slowed down by 27%. It also slowed down the decline in quality of life by up to 56%.
Donanemab is the most recent of the immunotherapy drugs targeting amyloid beta, as it successfully leads to the removal of amyloid from the brain. In May 2023, the company reported its Phase III study showed the drug could slow the pace of Alzheimer's disease by 35%. In July 2023, results from 1,736 people treated with donanemab showed slowing of Alzheimer's progression at 76 weeks, with 24% of the people, however, displaying cerebral edema.
Yet, the best we have been able to do is to slow down the rate of cognitive decline; not stop the decline nor reverse it. There are a growing number of scientists that are challenging the buildup of insoluble plaques of beta-amyloid as the cause of Alzheimer’s disease. Many people with amyloid plaques have no symptoms of dementia, and treatments aimed at slowing the buildup of plaques have shown no effect on reversal of the disease process.
So, what is the solution to this problem called Alzheimer’s Disease? What if I substituted Alzheimer's Disease for the word “Cancer;” or substituted any other chronic disease? With chronic diseases, there is typically not a single drug or a single modality that will successfully treat or manage the disorder. The disorder must be treated with multiple modalities.
Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Increasing evidence also suggests that oxygen therapy may improve many of the aforementioned pathological aspects of AD.
Patients with Alzheimer’s Disease (AD) or mild cognitive impairment (MCI) were treated with Hyperbaric Oxygen Therapy (99.9% O2, 0.4 to 0.7 MPa) for 40 minutes, once per day, for 20 days. Cognitive function and daily living activities were evaluated before HBOT and at 1, 3, and 6 month follow-ups. HBOT ameliorated cognitive impairment in patients with AD patients or amnestic MCI (Chen et al., 2020).
Another study also showed that HBOT (60 daily HBOT sessions within 3 months) increased cerebral blood flow and improved cognitive performance in older adult patients with significant memory loss at baseline (Shapira et al., 2021). Furthermore, HBOT also promoted good cognitive function healthy individuals (Yu et al., 2015).
A study from researchers at Tel Aviv University and Shamir Medical Center showed that HBOT halted the growth of small amyloid beta plaques and reduced the volumes of medium-sized and large plaques, as well as prevented the formation of new ones.
Alzheimer's Management by Albumin Replacement (AMBAR) study: At 14 months, participants in the TPE-treated group vs the placebo group experienced significantly less decline. Importantly, there was a statistically significant improvement in quality of life (QoL) measured by a self-reported questionnaire among patients with mild-AD from baseline to 14 months among the TPE-treated groups compared with the control group. A self-reported improvement was not seen among patients with moderate-AD, although an improvement in QoL was reported by caregivers among this population, perhaps suggesting diminished awareness of cognitive and functional impairments in the moderate-AD group.
Oxidative stress is believed to be an important player in AD pathology. Glutathione (GSH) is a major antioxidant, and it is already known that GSH is depleted significantly in the hippocampal regions in mild cognitive impairment (MCI) and AD patients compared to healthy old subjects. A recent study has shown that the depletion of GSH level in MCI and AD patients in the hippocampal regions is directly correlated with executive function. There is currently an ongoing trial at Baylor College of Medicine using oral glycine and n-acetylcysteine (which are two of the 3 substances necessary for the production of glutathione) for the treatment of patients with AD.
Australian researchers have shown that a dietary supplement that increases the levels of a powerful antioxidant in the brain may represent a novel strategy for the treatment and/or prevention of cognitive impairment and debilitating neurodegenerative diseases such as Alzheimer’s disease. A team of researchers from UNSW Sydney’s Centre for Healthy Brain Ageing (CHeBA), and the School of Biotechnology and Biomolecular Sciences (BABS), has shown that dietary supplementation with glutathione precursor γ-glutamylcysteine (γ-GC), marketed as GlyteineTM, reduced oxidative stress, neuroinflammation and amyloid pathology in the brains of transgenic mice, a murine model to study Alzheimer’s disease. The study also found significant cognitive improvements in the mice as determined using the Morris water maze, a test often used to test memory in mice.
Researchers at RUSH University Medical Center recently discovered that a muscle-building supplement called beta-hydroxy beta-methylbutyrate, also called HMB, may help protect memory, reduce plaques and ultimately help prevent the progression of Alzheimer's disease. Studies in mice with Alzheimer's disease have shown that HMB successfully reduces plaques and increases factors for neuronal growth to protect learning and memory. Previous studies indicate that a family of proteins known as neurotrophic factors are drastically decreased in the brains of people with Alzheimer's disease and have been found to help in survival and function of neurons, which are cells that receive and send messages from the body to the brain and vice versa.
"Our study found that after oral consumption, HMB enters into the brain to increase these beneficial proteins, restore neuronal connections and improve memory and learning in mice with Alzheimer's-like pathology, such as plaques and tangles," Pahan said.
Galantamine-memantine combination superior to donepezil-memantine combination in Alzheimer’s disease; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457262/
Donepezil (Aricept) and memantine (Namenda) are commonly used as the first line drugs to treat mild-moderate Alzheimer’s. Galantamine is superior to donepezil because it is a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor.
In several preclinical studies, cognitive impairments significantly improved with the galantamine-memantine combination compared to either medication alone. Synergistic benefits were also seen with the combination. In a randomized controlled trial (RCT) in prodrome AD, cognition significantly improved with the galantamine-memantine combination compared to galantamine alone; cognition declined after galantamine was discontinued.
In a retrospective study in AD, the galantamine-memantine combination significantly improved cognition compared to the donepezil-memantine combination.
Although galantamine and memantine are both FDA approved for the treatment of AD, the combination is still underutilized in clinical practice.
Interleukin-1 beta (IL-1) is a pro-inflammatory cytokine which has been found to play a pathogenic role in Alzheimer’s. In animal models, blocking IL-1 significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β. Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3β, and p38–MAPK, and also reduces phosphorylated tau levels.Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.
Anakinra is an IL-1 antagonist that is approved by the FDA for the treatment of rheumatoid arthritis. Studies are ongoing regarding using this drug off-label for Alzheimer’s, cancer, and even aging.
Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. An open label pilot study on H2 treatment was conducted. Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus.
Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (−4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly).
Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects.
The authors investigated the effects of 4 weeks of H2 gas inhalation on community-dwelling adults of various ages. Fifty-four participants, including those who dropped out (5%), were screened and enrolled. The selected participants were treated as a single group without randomization. We evaluated the association between total and differential white blood cell (WBC) counts and AD risk at individual levels after 4 weeks of H2 gas inhalation treatment. The total and differential WBC counts were not adversely affected after H2 gas inhalation, indicating that it was safe and well tolerated. Investigation of oxidative stress markers such as reactive oxygen species and nitric oxide showed that their levels decreased post-treatment. Furthermore, evaluation of dementia-related biomarkers, such as beta-site APP cleaving enzyme 1 (BACE-1), amyloid beta (Aβ), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor A (VEGF-A), T-tau, monocyte chemotactic protein-1 (MCP-1), and inflammatory cytokines (interleukin-6), showed that their cognitive condition significantly improved after treatment, in most cases. Collectively, our results indicate that H2 gas inhalation may be a good candidate for improving AD with cognitive dysfunction in community-dwelling adults of different ages.
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At Advanced Medical Therapeutics, we combine multiple modalities to treat AD, including a cocktail of supplements to complement the aforementioned treatments.
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