Alzheimer’s, Neurodegeneration and Oxidative Stress
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
Alzheimer’s Disease
Alzheimer’s is perhaps the scariest word for many of those middle aged or older to hear. The word conjures up may questions: How do I prevent this from becoming an issue for me? How do I know if I am at risk? What should I do to prevent it? In this article, I hope to shed some light on Alzheimer’s by helping you understand the mechanisms of action that contribute to its development and how these mechanisms may apply to your situation. This article will focus on free radical scavenging, support of endogenous antioxidant systems, and inhibition of oxidative stress-inducing compounds (e.g. COX-2, Prostaglandins, NADPH Oxidase, etc), and metal chelation/binding. I will explore various herbal supplements and review published research on how they effect cognitive performance in both Alzheimer’s and mild cognitive impairment (MCI). I will also refer to Chris Exley’s work on aluminum and the role it may play in the development of cognitive decline. Much of Chris Exeley’s work [51], especially that which is highlighted in his book Imagine You Were An Aluminum Atom, Discussions With Mr. Aluminum, focuses on the deleterious effects of aluminum exposure. Chris also reports that he routinely finds two things in the brains of Alzheimer’s patients who have donated their brains for postmortem research: unbound iron and aluminum. Curiously, aluminum can cause displacement of iron off of its transporter, ceruplasmin. Unbound iron can react with the free radical hydrogen peroxide in the Fenton reaction to form hydroxyl radicals. Perhaps it is not so curious, after all.
Why Read This Article?
You may be interested in this article if you:
Want to learn about factors that contribute to the development of cognitive decline
Want to understand the relationship between oxidative stress, free radicals and brain health
Want to learn how to support your body’s inherent antioxidant pathways
Want to learn which supplements may protect against free radical damage and neurodegeneration.
Oxidative Stress
Free Radicals
Free radicals are known to contribute to the development of oxidative stress. But where do free radicals come from? The production of free radicals comes from normal bodily processes (e.g. energy production), responses to infections (e.g. immune activation), and other processes gone awry (e.g. allergic reactions, dysfunctional pathways, lack of cofactors for various processes). The most commonly referred to free radicals in the literature are hydrogen peroxide, superoxide, hydroxyl radicals, and peroxynitrite.
Discussions surrounding oxidative stress are generally made within the context of the damage caused when free radical levels exceed our body’s ability to neutralize them via physiological antioxidant pathways and dietary intake of antioxidant compounds.
Free radicals can be scavenged (bound to by scavenging compounds) and neutralized by our body’s endogenous antioxidant systems (namely catalase, glutathione, superoxide dismutase, thioredoxin, peroxidase, and vitamin B12), but in the face of an excessive amount of free radicals, these processes become ineffective and damage can occur.
Ferroptosis
Increased oxidative stress triggers ferroptosis, the process whereby unhealthy cells are killed off and disposed of (ferroptosis is also referred to as autophagy and apoptosis, or as mitophagy when performed within the mitochondria). This process functions to prevent the buildup of diseased and dysfunctional cells, and in addition to being triggered by excess oxidative stress, it can also be triggered by various supplements and pharmaceuticals, and by certain dietary methods like fasting and ketosis. Interestingly, there are many case reports of people who use fasting as a means to support their cancer treatment. When I look at family lines, I usually see a prevalence of either cancer or neurological conditions (excess oxidative stress), but not both, possibly because these processes are diametrically opposed. Excess oxidative stress is linked to neurodegenerative diseases, but it would appear to protect against cancer given that it triggers the cleaning out of dysfunctional and diseased cells. There are other factors related to the development of cancer, of course, specifically those related to the activation of tumor suppressor genes like P53, and the BRCCA line of genes, too.
Herbs and Other Compounds That Combat Free Radicals
Below, I will summarize a number of herbs and compounds that:
Scavenge free radicals (and thus lower oxidative stress)
Up-regulate antioxidant systems
Inhibit oxidative free radical-producing systems
Modulate other systems believed to be involved in neurodegeneration (i.e. the gut-brain axis).
For each of these compounds, I have referenced published literature that shows how each herb has been linked to cognitive improvement, in either Alzheimer’s or mild cognitive impairment (MCI), or both. Yes, I said each is linked to cognitive improvement. Is this a coincidence? Unlikely, given the fact that oxidative stress is somehow involved in neurodegenerative processes.
Catalase
Catalase [1,2,3,4] is a compound produced by the body via the CAT gene, its cofactors being heme and copper.
It is marketed and sold as a supplement that combats gray hair (Haven’t I heard people say gray hair is caused by a copper deficiency? Yes, I have).
It is perhaps one of the supplements I have seen the lowest adverse reactions to.
Catalase neutralizes hydrogen peroxide.
Glutathione [5]
Whether by endogenous production or by exogenous supplementation, glutathione has been shown through variety of research to improve cognitive performance in neurodegenrative diseases like Alzheimer’s and Parkinson’s.
Benfotiamine, Carnosine and Advanced Glycation End Products [6-24]
Thiamine has long been associated with energy production, glucose metabolism, and mitochondrial function. Forms like benfotiamine and TTFD have better absorption rates over other forms of thiamine. (Benfotiamine is a fat-soluble form of thiamine, and of course, the brain is made up of lots of fat).
High dose benfotiamine has been shown to benefit Alzheimer’s patients after sustained high dose therapy.
Carnosine can act as a natural antioxidant and inhibitor of advanced glycation end products along with Benfotiamine. Alzheimer’s has been associated with both impaired glucose metabolism in the brain and the presence of advanced glycation end products (AGEs). Benfotiamine and carnosine in combination are often marketed by various supplement companies as a means to lower AGEs.
Olive Leaf [25]
Olive leaf is a potent scavenger of hydroxyl, super oxide, and nitrogen based free radicals.
It stimulates NrF2, a master controller of antioxidant genes.
It chelates heavy metals, helping it lower hydroxyl radical reactions like the Fenton reaction from excess unbound iron and excess hydrogen peroxide.
Is associated with better cognitive function scores:
“Group 1 participants had statistically significantly higher MMSE scores compared to Group 2 with a p-value of 0.0135. Specifically, the mean MMSE difference in patients receiving OLE was close to 0, indicating no memory deterioration, whereas in controls it was −4.1, indicative of cognitive decline. The remaining neuropsychological assessments (FRSSD, FUCAS, ADAS-Cog, CDR, GDS, and NPI) revealed better results in the OLE group, except for GDS, which showed no change, but without statistically significant differences between the two groups.”
Rutin [26]
Rutin, found in mulberry, is one of the most potent scavengers of the free radical super oxide.
Chelates iron, helping it prevent fenton like reactions from excess unbound iron and hydrogen peroxide.
Rutin stimulates NrF2.
Rutin can recouple NOS after NOS uncoupling.
“Rutin pretreatment (25 mg/kg, orally, once daily for 3 weeks) significantly attenuated thiobarbituric acid reactive substances (TBARS), activity of poly ADP-ribosyl polymerase, and nitrite level and decreased level of reduced glutathione (GSH) and activities of its dependent enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and catalase in the hippocampus of ICV-STZ rats. ICV-STZ rats showed significant cognitive deficits, which was improved significantly by rutin supplementation. The results indicate that rutin attenuates STZ-induced inflammation by reducing the expression of cyclooxygenase-2 (COX-2), glial fibrillary acidic protein (GFAP), interleukin-8 (IL-8), inducible nitric oxide synthase (iNOS), nuclear factor-kB, and preventing the morphological changes in hippocampus. The study thereby suggests the effectiveness of rutin in preventing cognitive deficits and might be beneficial for the treatment of sporadic dementia of Alzheimer type (SDAT).”
Vitamin C (ascorbic acid)
Vitamin C is an effective reducing agent.
It is also an effective scavenging agent for peroxynitrite and superoxide, both of which are damaging free radicals produced in various bodily processes, (particularly those associated with nitric oxide uncoupling, iNOS/NOS2 upregulation, or NOS3 downregulation).
If you have '“nitric oxide issues” you can almost bank on the fact that you also have a superoxide issue and oxidative stress.
Those with “nitric oxide issues” often have too much nitric oxide, causing vasodilation and low blood pressure.
A word of caution - while free radical scavengers may help, they also often cause vasodilation and can make many feel worse.
If you have neurotransmitter issues read on - it may be slightly more complicated, but you will need BH4 regardless - and it is oxidized by peroxynitrite. [5,6,7,8,9].
PYCNOGENOL [27]
Pycnogenol, a branded and standardized form of French Maritime Pine Bark is a free radical scavenger of super oxide, hydroxyl radicals, and hydrogen peroxide.
It is associated with decrease in plaque formation in the brain. Plaque formation is thought to result from several things, one being as a response to inflammation and oxidative stress:
“Pycnogenol significantly decreased the number of plaques in both treatment paradigms but did not alter levels of soluble Aß or the gene expression of APP-processing enzymes. The morphological analyses revealed no changes in the number of neurons, astrocytes, microglia, the myelination pattern, or the morphology of axons. Behavioural testing revealed an improvement of the spatial memory in the pre-onset treatment paradigm only.”
ROSEMARY [28]
Rosemary is a super oxide scavenger
It upregulates the phase II glucuronidation pathway
It stimulates HMOX-1 and HMOX-2 via carnosic acid, offering protection from glutamate induced excito-toxicity
It inhibits NOS2 (iNOS)
It stimulates NrF2
It raises the neurotransmitter acetylcholine by inhibiting acetylcholinesterase (ACHe), the enzyme that breaks down acetylcholine.
It chelates various metals.
“Through these structural features, these compounds display a vast array of pharmacological effects ranging between antioxidant, metal chelation, and anti-inflammatory properties. These very mechanisms do also appear to be involved in the potential therapeutic effect of the compounds for AD. The further effect of rosemary diterpenes in A𝛽 formation, aggregation, and toxicity accounts for their additional benefit in tackling AD. Given that AD is a complex disease involving many pathological processes, treatment with multifunctional drugs like those demonstrated by rosemary diterpenes constitutes a viable therapeutic approach. The cascade of neurodegeneration process in AD has lots of similarities with other diseases like Parkinson’s disease. Interestingly, some of the rosemary diterpenes such as carnosic acid (7) have been shown to have beneficial effect in Parkinson’s disease model [178, 179]. It is also worth noting that only (7) and (8) have been extensively investigated for their possible therapeutic effect related toAD. Other interesting diterpenes including the glycosidic forms could have different bioavailability and therapeutic profile.”
GRAPE SEED EXTRACT [29]
Grape seed extract (GSE), offers similar benefits to Pycnogenol, essentially because they both contain high levels of procyanidins. Procyanidins are potent free radical scavengers, something that appears to be behind the aggregation of AB peptides and tau tangles.
“Recent in vitro studies demonstrate that GSPE interferes with the aggregation of Aβ peptides and tau into neurotoxic oligomeric Aβ aggregates and tau fibril conformers (Figure 1, panel A). Moreover, our evidence suggests that the GSPE may also destabilize preformed Aβ and tau aggregates (Figure 1, panel B). Thus, GSPE might modulate AD dementia by beneficially modulating both Aβ and taumediated neuropathologic mechanisms (Figure 1, panels A and B). More importantly, our in vivo preclinical studies support the efficacy of GSPE to mitigate Aβ- or mutant tau-mediated neuropathologic phenotypes. Thus, GSPE might benefit AD by simultaneously interfering with the two hallmark neuropathologies of the disease. These new observations of the effects of GSPE treatment on AD pathologic features, taken together with the demonstrated bioavailability as well as safety and tolerability, strongly support the continued development of GSPE for AD prevention and therapy.”
GINGER [30]
Ginger may offer beneficial cognitive effects in Alzheimer’s from modulation of the gut-brain axis:
“We assessed changes in short-chain fatty acids (SCFAs), learning and memory abilities, neuroinflammatory markers in plasma, and the hippocampus, as well as histological changes in the intestine and hippocampus in sham-operated, diseased, and treatment groups. Oral administration of ginger ethanolic extract improved gut microbiota activity, increased SCFA levels, and enhanced the expression of tight junction proteins. Additionally, ginger extract reduced the concentrations of TNF-α and IL-1β in both plasma and the hippocampus. Furthermore, it significantly reduced cell death and amyloid plaque deposition in the hippocampal tissue. These physiological changes resulted in improved performance in learning and memory tasks in rats treated with ginger compared with the disease group. These findings provide compelling evidence for the beneficial effects of ginger on the gut-brain axis, leading to improvements in learning and memory through the reduction of neuroinflammation.”
SCHISANDRA AND EVODIA [31]
Schisandra has well studied benefits that effect thioredoxin genes that lower the free radical hydrogen peroxide.
It has been shown to lower acetyl aldehydes by stimulation of the ALDH2 gene, a gene implicated in fatty liver and cognitive issues.
Evodin, has well studied effects on inflammatory pathways like COX-2, TNFA, iNOS, and on pain receptors like TRPV1.
“The treatment group exhibited significant neuroprotective effects, ameliorating learning and memory impairments in the Alzheimer’s disease rat model. The treatment regimen modulated the activity of the BDNF/TRKB/CREB and GSK-3β/Tau pathways by influencing the expression of relevant genes, thereby reducing the generation of Aβ1-42 and P-Tau proteins and inhibiting the deposition of senile plaques. Furthermore, among the three treatment groups, the combined treatment demonstrated notably superior therapeutic effects on Alzheimer’s disease compared to the single-drug treatment groups.”
MANGOSTEEN [32]
Mangosteen, derived from mangos, has well known free radical scavenging properties attributed to its compounds called xanthones, alpha-mangostin and gamma-magnostin.
It is a strong scavenger of superoxide, hydroxyl radicals, hydrogen peroxide, nitric oxide, and peroxynitrite. Coicidentally, one of the principal sources of oxidative stress is NADPH Oxidase upregulation, and mangosteen inhibits NADPH, while also inhibiting iNOS (NOS2) and COX-2.
“The proportion of participants who achieved the minimum clinically important difference for the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADASCog; –2.6 points) at 24 weeks was significantly higher in the low-dose group (and a trend in the high-dose group) than in the placebo group. WME appeared safe and well tolerated. At 24 weeks, the 4-hydroxynonenal level declined in both intervention groups. The participants with a 5% reduction in this level showed greater ADAS-Cog improvements. Conclusion: WME is a safe and well-tolerated cognitive enhancer in AD with varying benefits across individuals based on antioxidative response.”
CURCUMIN (TUMERIC) [33]
Curcumin has many well known anti-inflammatory and antioxidant effects.
Inhibits TNFA
Chelates iron
Upregulates NrF2
Supports IL-10
“A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer’s disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. This paper reviews the various mechanisms of actions of curcumin in AD and pathology.”
However, it also is a potent inhibitor of thioredoxin, an important antioxidant system.
ASTAXANTHIN [34,35]
Astaxanthin is a free radical scavenger that up regulates antioxidant systems.
Astaxanthin is a potent scavenger of superoxide, hydrogen peroxide, and hydroxyl radicals.
It stimulates PON1, which prevents the oxidation of LDL
Supports the phase 2 detoxification pathway, glucuronidation
Is a potent stimulator of NrF2.
“In vivo experiments showed that Aβ25–35 impaired cognitive function, promoted morphological changes in hippocampal neurons, decreased Bcl-2 expression, increased Bax expression, decreased superoxide dismutase and GSH-px levels, and increased reactive oxygen species and malondialdehyde levels. Conversely, AST alleviated the impact of Aβ25–35 in mice, with reversed outcomes. NAM administration reduced SIRT1 and PGC-1α expression in the hippocampus. This decrease was accompanied by cognitive dysfunction and hippocampal neuron atrophy, which were also evident in the mice. Additionally, in vitro experiments showed that Aβ25–35 could promote oxidative stress and induce the senescence and apoptosis of PC12 cells. Nonetheless, AST treatment counteracted this effect by inhibiting oxidative stress and altering the state of PC12 cells. Notably, the Aβ + NAM group exhibited the most significant rates of senescence and apoptosis in PC12 cells following NAM treatment.” “In this context, fucoxanthin and astaxanthin, natural carotenoids abundant in algae, has shown to possess neuroprotective properties through antioxidant, and anti-inflammatory characteristics in modulating the symptoms of AD. Fucoxanthin and astaxanthin exhibit anti-AD activities by inhibition of AChE, BuChE, BACE-1, and MAO, suppression of Aβ accumulation. Also, fucoxanthin and astaxanthin inhibit apoptosis induced by Aβ1–42 and H2O2-induced cytotoxicity, and modulate the antioxidant enzymes (SOD and CAT), through inhibition of the ERK pathway. Moreover, cellular and animal studies on the beneficial effects of fucoxanthin and astaxanthin against AD were also reviewed.”
BILBERRY [36]
Bilberry has well-known compounds that help inflammation and oxidative stress
Stimulates the PON1 gene, involved in preventing the oxidation of LDL.
Is a potent anti-inflammatory:
“Results: Compared to placebo the selected memory and motor test scores were un-affected by the bilberry/red grape intervention. However, the plasma levels of tissue damage biomarkers decreased significantly more in the bilberry/red grape group. In particular lactate dehydrogenase (LDH) decreased from 362 U/L (median, baseline) to 346 U/L (median, post intervention) in the bilberry/red grape group. Also, several biomarkers of inflammation (EGF, IL6, IL9, IL10 and TNFα) decreased significantly more in the bilberry/red grape group. Furthermore, several plasma polyphenols; p-coumaric acid, hippuric acid, protocatechuic acid, 3HPAA and vanillic acid, increased significantly more in the bilberry/red grape group compared to placebo with the largest increase in p-coumaric acid with 116%; from 2.2 [1.0,5.5] to 4.7 [2.8,8.1] μM/L (median [95% CL]). Conclusions: The results indicate that a nine-week bilberry/red grape juice intervention has no measurable effects on the selected memory scores in aged men experiencing memory problems but decreases the level of biomarkers of inflammation and tissue damage. Whether the dampening effects on inflammation and tissue damage biomarkers have relevance for neuroinflammatory brain pathology remains to be established.”
BERBERINE [37]
Sigificant research that shows that berberine upregulates a series of genes in the Peroxidase family (PXRD) as well as PPAR-Gamma which has wide effects on other antioxidant genes like PON1.
“Berberine improved cognitive dysfunction and decline of β-amyloid precursor protein in AD animals. Berberine showed significant memory-improving activity in several animal models of memory deficits by mechanisms including downregulation of APP-associated protein expression, modulation of Aβ, and effects on BACE1 and tau phosphorylation”
FUCOIDAN [38, 39]
Fucoidan has well-known effects on a variety of systems involving inflammation, immunity, gut issues, oxidative stress, and coagulation. (see other blog article, “The Magic Of Brown Seaweed”).
It effects a number of genes and systems (GPX4, HMOX, NrF2, SIRT1, NFKB, NRLP3).
In a recent publication by Harvard scientists, fucoidan was highlighted as a potential compound for preventing brain aging. This is because fucoidan has been shown to increase SIRT6, an enzyme associated with increasing mouse lifespan, by 14-fold. Fucoidan itself has been shown to increase the lifespan of flies while promoting neuroprotective effects like what was shown by Wang and colleagues in mice. From these findings, the Harvard authors said fucoidan — which can be purchased in supplement form — is a “promising anti-aging phytochemical.”
“Fucoidan boosts the memory of mice modeling inflammation-induced brain aging. An inflammatory protein associated with cognitive decline called IL-1β is reduced by fucoidan. Injection of fucoidan also promotes the production of neurons, suggesting it protects against brain damage.“
“Only fucoidans S, UE, and UF showed anti-aggregation effects against Aβ1–42, as determined using Thioflavin T (ThT) fluorometric fibrillisation kinetics and transmission electron microscopy (TEM) of fibril morphology. However, all five fucoidan samples reduced the cytotoxicity of both Aβ1–42 and hydrogen peroxide in neuronal PC-12 cells and demonstrated inhibition of apoptosis induced by Aβ1–42. Three fucoidan samples (FF, UE and UF) showed significant activity in enhancing neurite outgrowth. Fucoidan from different seaweed sources and with varying chemical compositions demonstrate a range of neuroprotective activities that may have potential to alter Aβ1–42 neurotoxicity in Alzheimer's disease.”
“Fucoidan isolated from Fucus vesiculosus demonstrated neuroprotective activity against Aβ, but did not inhibit its aggregation. Fucoidan isolated from Laminaria japonica can improve learning and memory in Aβ-treated rats by inhibiting the activity of acetylcholine esterase (AChE), reducing oxidative stress and promoting anti-apoptotic activity. Recently, fucoidan isolated from Undaria pinnatifida was investigated in PC-12 cells for neuroprotective activity against toxicity induced by d-galactose and Aβ25–35. Fucoidan from U. pinnatifida can increase cell viability by inhibiting the apoptosis induced by d-galactose and Aβ25–35, while also improving learning and memory in impaired mice.”
CAT’S CLAW [40]
Cat’s Claw has a variety of well-known antiviral, antimicrobial, anticandida properties.
Potent inhibitor of voltage gated channels
Inhibitor of voltage gated calcium channels like CACNA1c (similar to rosemary and Ginkgo).
It is one of two ingredients in the supplement Percepta, which has published research stating that it helps improve cognition in Alzheimer’s patients. Ion channel dysregulation (i.e. calcium, sodium, potassium, and chloride ion channels) is implicated in a variety of neurological disorders including Autism, Parkinson’s, Alzheimer’s, and various mood and learning disorders. Potassium ion channels are regulated strongly by ketones, and the ketogenic diet is often prescribed for those with epiliepsy, with a strong success rate (>50%) in significantly reducing seizures. Mycotoxins, heavy metals, infections, EMF, all have well-published research on how they causedysregulation of these various ion channels.
Impacts the formation of beta amyloid and tau protein:
“Cat’s claw, was identified as a potent inhibitor and reducer of both beta-amyloid fibrils and tau protein paired helical filaments/ fibrils (the main component of “tangles”). cat’s claw demonstrated both the ability to prevent formation/aggregation and disaggregate preformed Aβ fibrils (1–42 and 1–40) and tau protein tangles/filaments. The disaggregation/dissolution of Aβ fibrils occurred nearly instantly when cat’s claw and Aβ fibrils were mixed together as shown by a variety of methods including Thioflavin T fluorometry, Congo red staining, Thioflavin S fluorescence and electron microscopy. Specific proanthocyanidins (i.e. epicatechin dimers and variants thereof) are newly identified polyphenolic components within Uncaria tomentosa that possess both “plaque and tangle” reducing and inhibitory activity. One major identified specific polyphenol Cat’s claw was epicatechin-4β-8-epicatechin (i.e. an epicatechin dimer known as proanthocyanidin B2) that markedly reduced brain plaque load and improved short-term memory in younger and older APP “plaqueproducing” (TASD-41) transgenic mice. Proanthocyanidin B2 was also a potent inhibitor of brain inflammation as shown by reduction in astrocytosis and gliosis in TASD-41 transgenic mice. The discovery of a natural plant extract from the Amazon rain forest plant (i.e. Uncaria tomentosa or cat’s claw) as both a potent “plaque and tangle” inhibitor and disaggregator is postulated to represent a potential breakthrough for the natural treatment of both normal brain aging and Alzheimer’s disease.”
L-ERGOTHIONEINE [41]
L-Ergothioneine is a well-known and studied antioxidant that does not need to be recycle like glutathione.
It has specific properites that offer neuroprotection in the face of oxidative stress from heavy metals
Has iron and copper-chelating properties as well.
Ergothioneine is not synthesized by the body endogenously, and can only be obtained from the diet, principally from certain mushrooms like shiitake, oysters, and king trumpet.
The transporter for L-Ergothioneine just so happens to be related to the transporter for pyrodoxic acid, the toxic metabolite produced during the metabolism of the active form of B6 (P5P). This transporter is also inhibited by very specific gut metabolites that are often found elevated in those with ME/CFS, Long Haul, or Mold Illness. Curious, eh?
Low blood levels are associated with neurodegeneration:
“Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.”
PANAX GINSENG [42]
Panax ginseng is a well known antioxidant.
It has specific properties that upregulate the glutathione gene GPX1, the most ubiquitous glutathione peroxidase gene in the body, with mutations that are connected to increases in all cause mortality. Glutathione peroxidase genes are the principal genes used to neutralize the free radical hydrogen peroxide, the one that combines with excess unbound iron to form hydroxyl radicals.
Panax ginseng also inhibits both Acetylcholinesterase and NMDA receptors, offering protection from glutamate excitotoxicity and ion channel dysregulation. Noticing a pattern?
Ginseng is used as a traditional herbal medicine used for both prevention and treatment of various diseases:
“Ginseng is a traditional herbal medicine used for prevention and treatment of various diseases as a tonic. Recent scientific cohort studies on life prolongation with ginseng consumption support this record, as those who consumed ginseng for more than 5 years had reduced mortality and cognitive decline compared to those who did not. Clinical studies have also shown that acute or long-term intake of ginseng total extract improves acute working memory performance or cognitive function in healthy individuals and those with subjective memory impairment (SMI), mild cognitive impairment (MCI), or early Alzheimer’s disease (AD) dementia who are taking AD medication(s). Ginseng contains various components ranging from classical ginsenosides and polysaccharides to more recently described gintonin. However, it is unclear which ginseng component(s) might be the main candidate that contribute to memory or cognitive improvements or prevent cognitive decline in older individuals. This review describes recent clinical contributors to ginseng components in clinical tests and introduces emerging evidence that ginseng components could be novel candidates for cognitive improvement in older individuals, as ginseng components improve SMI cognition and exhibits add-on effects when co administered with early AD dementia drugs. The mechanism behind the beneficial effects of ginseng components and how it improves cognition are presented. Additionally, this review shows how ginseng components can contribute to SMI, MCI, or early AD dementia when used as a supplementary food and/or medicine, and proposes a novel combination therapy of current AD medicines with ginseng component(s).”
TART CHERRY [43]
Tart cherry is a well known free radical scavenger.
It can often be found in combination with Vitamin C supplements.
It contains high levels of anthocyanins, quercetin, and melatonin. Melatonin in particular has well studied benefits as a hydroxyl radical scavenger.
Tart cherry has been shown through research to downregulate NFKB, activate NrF2, activate PPAR Gamma/Alpha, and stimulate FOXO3a.
Research also supports that tart cherry inhibits inflammatory pathways like NOX2 (moderate inhibitor), COX-2 (strong inhibitor), and ALOX5 (mild to moderate) that produce free radicals.
“… the purpose of this study was to determine if tart cherry supplementation can improve cognitive and motor function of aged rats via modulation of inflammation and autophagy in the brain. Thirty 19-month-old male Fischer 344 rats were weight-matched and assigned to receive either a control diet or a diet supplemented with 2 % Montmorency tart cherry. After 6 weeks on the diet, rats were given a battery of behavioral tests to assess for strength, stamina, balance, and coordination, as well as learning and working memory. Although no significant effects were observed on tests of motor performance, tart cherry improved working memory of aged rats. Following behavioral testing, the hippocampus was collected for western/densitometric analysis of inflammatory (GFAP, NOX-2, and COX-2) and autophagy (phosphorylated mTOR, Beclin 1, and p62/SQSTM) markers. Tart cherry supplementation significantly reduced inflammatory markers and improved autophagy function. Daily consumption of tart cherry reduced age-associated inflammation and promoted protein/cellular homeostasis in the hippocampus, along with improvements in working memory.”
SULFORAPHANE [44]
Sulforaphane is a supplement that has received much study for its ability to inhibit Keap1 and thus enable NrF2 to performs its important antioxidant enzyme-stimulating functions (GPX, SOD, CAT, etc.).
Sulforaphane is known to stimulate AhR, which results in the stimulation of IL-10, UGT, and SULT enzyme systems.
It also inhibits NFKB, HDAC and DNMT.
“Taken together, in the present study, Sulforaphane (SFN) was observed to improve cognitive function and to protect against Ab deposition in AD model mice. Up-regulation of p75NTR, mediated at least in part by reduction of HDAC1 and HDAC3 expression, was implicated as a potential anti-Ab mechanism of SFN. SAHA has been documented to play a protective role in Huntington’s disease through decreasing HDAC 2 and 4 levels (Mielcarek et al., 2011). Thus, the effects of different HDAC inhibitors on various diseases may be mediated through regulating different HDAC types. In addition, other biological functions of SFN, such as anti-oxidation (Zhang et al., 2015), anti-inflammatory (Brandenburg et al., 2010), immunoregulation (Shih et al., 2016), ..”
MANGIFERIN [45, 46]
Mangiferin has well-studied free radical scavenging (super oxide, hydroxyl radicals, hydrogen peroxide), antioxidant stimulating (GPX), and aldehyde reducing properties by stimulating ALDH2.
May improve memory and cognitive impairment:
“After screening through articles identified from Scopus and PubMed based on the inclusion and exclusion criteria, a total of 11 articles between 2009 and 2019 were included. …The results of 11 articles showed that mangiferin effectively improved spatial recognition, episodic aversive events, short- and long-term memories primarily occurring via its antioxidant and anti-inflammatory effects. The outcomes of the review revealed that mangiferin improves memory and cognitive impairment in different animal models, indicating that it has potential preventive and therapeutic roles in Memory Impairment (MI).
May protect against formaldehyde-induced neurodegeneration:
“Formaldehyde (FA) has been found to induce major Alzheimer’s disease (AD)-like features including cognitive impairment, A Beta deposition, and Tau hyperphosphorylation, suggesting that it may play a significant role in the initiation and progression of AD. Therefore, elucidating the mechanism underlying FA-induced neurotoxicity is crucial for exploring more comprehensive approaches to delay or prevent the development of AD. Mangiferin (MGF) is a natural C-glucosyl-xanthone with promising neuroprotective effects, and is considered to have potential in the treatment of AD. The present study was designed to characterize the effects and mechanisms by which MGF protects against FA-induced neurotoxicity. The results in murine hippocampal cells (HT22) revealed that co-treatment with MGF significantly decreased FA-induced cytotoxicity and inhibited Tau hyper phosphorylation in a dose-dependent manner. In addition, MGF markedly inhibited FA-induced oxidative damage, including Ca2+ overload, ROS generation, and mitochondrial dysfunction, all of which are associated with endoplasmic reticulum stress (ERS). Further studies showed that the intragastric administration of 40 mg/kg/day MGF for 6 weeks significantly improved spatial learning ability and long-term memory in C57/BL6 mice with FA-induced cognitive impairment by reducing Tau hyperphosphorylation and the expression of GRP78, GSK-3 , and CaMKII in the brains. Taken together, these findings provide the first evidence that MGF exerts a significant neuroprotective effect against FA-induced damage and ameliorates mice cognitive impairment, the possible underlying mechanisms of which are expected to provide a novel basis for the treatment of AD and diseases caused by FA pollution.”
SAFFRON [47]
Saffron has a well-studied history related to improving sleep and mood.
Saffron helps inhibit : NLRP3, NFKB, CASP1, PYCARD, IL1B, TRPV1, TRPM2, CYSLTR1, P2RX7, PANX1, all of which are related to various inflammatory cascades.
Inhibits NMDA activation.
In relation to sleep, saffron effects GABA, GAD1, GAD2, TPH2 (tryptophan stimulation), MAOA inhibition, stimulation of AANAT, Circadian rhythm (CLOCK, BMAL1), Period genes (PER1, PER2), and the HPA AXIS (CRH, NR3C1).
“Seventeen in vitro and in vivo preclinical studies have described the efficacy of saffron on cognitive impairment in animal models of AD, highlighting that crocin appears to be able to regulate glutamate levels, reduce oxidative stress, and modulate Aβ and tau protein aggregation. Only four clinical studies have indicated that the effects of saffron on cognitive impairment were not different from those produced by donepezil and memantine and that it had a better safety profile.”
MAGNOLIA BARK [48]
Magnolia bark has a well-studied history of helping with NMDA receptor over-activation, conversion of glutamate to gaba, and as a cox-2 inhibitor.
It helps regulate blood glucose by stimulating GLUT4 and the antioxidant gene NrF2.
It also effects a wide variety of other genes: inhibits HIF1a, NFKB (RELA), NLRP3, CASP1, PYCARD, TXNIP, TRPM2, TRPV1 (pain), GABA, KCNQ (potassium channels for pain/seizures), GABA-activated chloride channels (promoting anxiolytic effects), and TRPM, all of which can stabilize neurosensitization and overwhelm.
“… we investigated memorial improving and anti-Alzheimer’s disease effects of extract products of Magnolia officinalis in a transgenic AD mice model. Oral pretreatment of two extract products of Magnolia officinalis (10 mg/kg/day in 0.05% ethanol) into drinking water for 3 months ameliorated memorial dysfunction and prevented Aβ accumulation in the brain of Tg2576 mice. In addition, extract products of Magnolia officinalis also decreased expression of β-site APP cleaving enzyme 1 (BACE1), amyloid precursor protein (APP) and its product, C99. Although both two extract products of Magnolia officinalis could show preventive effect of memorial dysfunction and Aβ accumulation, our ethanol extract of Magnolia officinalis (BioLand LTD, Korea) could be more effective than Magnolia ExtractTM (Health Freedom Nutrition LLC, USA). Therefore, our results showed that extract products of Magnolia officinalis were effective for prevention and treatment of AD through memorial improving and anti-amyloidogenic effects via down-regulating β-secretase activity…”
UROLITHIN A AND COQ-10 [49, 50]
Both urolithin A and CoQ10 have a long history of improving mitochondrial function, lowering oxidative stress, and helping improve energy production.
Urolithin A stimulates mitophagy and autophagy:
“Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer’s disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA’s long-term treatment of AD and mechanisms of action are unknown. We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aβ) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD. Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA.”
CoQ10 acts as a potent antioxidant:
“It is well known that coenzyme Q10 (CoQ10) has important antioxidant properties. Because one of the main mechanisms involved in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative diseases is oxidative stress, analysis of the concentrations of CoQ10 in different tissues of AD patients and with other dementia syndromes and the possible therapeutic role of CoQ10 in AD have been addressed in several studies. We performed a systematic review and a metaanalysis of these studies measuring tissue CoQ10 levels in patients with dementia and controls which showed that, compared with controls, AD patients had similar serum/plasma CoQ10 levels. We also revised the possible therapeutic effects of CoQ10 in experimental models of AD and other dementias (which showed important neuroprotective effects of coenzyme Q10) and in humans with AD, other dementias, and mild cognitive impairment (with inconclusive results). The potential role of CoQ10 treatment in AD and in improving memory in aged rodents shown in experimental models deserves future studies in patients with AD, other causes of dementia, and mild cognitive impairment.”
Low Dose Lithium [53, 54]
Lithium gets most of its popular press for treating bipolar disorder, but in low doses there are published benefits related to mood and cognitive performance.
It acts as an aluminum chelator. (!!!)
In low doses, it is also a B12 and serotonin transport nutrient (yes, both B12 and serotonin are involved in cognitive function).
“… Three clinical trials including 232 participants that met the study's inclusion criteria were identified. Lithium significantly decreased cognitive decline as compared to placebo (standardized mean difference = -0.41, 95% confidence interval = -0.81 to -0.02, p = 0.04, I2 = 47% , 3 studies, n = 199). There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups.”
Lithium may stabilize calcium homeostasis:
“Our recent study has revealed that lithium stabilizes disruptive calcium homeostasis, and subsequently, attenuates the downstream neuropathogenic processes of AD. Through these therapeutic actions, lithium produces therapeutic effects on AD with potential to modify the disease process. This review critically analyzed the preclinical and clinical studies for the therapeutic effects of lithium on AD. We suggest that disruptive calcium homeostasis is likely to be the early neuropathological mechanism of AD, and the stabilization of disruptive calcium homeostasis by lithium would be associated with its therapeutic effects on neuropathology and cognitive deficits in AD.”
What !!!??? Calcium channel dysregulation. Yep. So now you want my list of calcium channel blockers:).
Aluminum’s Impact On Voltage Gated Calcium Channels and Sodium and Potassium Ion Channels [55, 56]
Yes, aluminum impacts ion channels, and not just calcium channels, but sodium and potassium channels as well. Whoa!
Aluminum has been shown to have neurotoxic properties:
“Al3+ reduced intracellular calcium concentrations around 25% and decreased catecholamine secretion in a dose-dependent manner, with an IC50 of 89.1 μM. ..This blockade was irreversible, since it did not recover after wash-out. Moreover, Al3+ produced a bigger blockade on N-, P- and Q-type calcium channels subtypes (69.5%) than on L-type channels subtypes (50.5%). Sodium currents were also inhibited by Al3+ in a time- and concentration-dependent manner, 24.3% blockade at the closest concentration to the IC50 (419 μM). This inhibition was reversible. Voltage-dependent potassium currents were non-significantly affected by Al3+. Nonetheless, calcium/voltage-dependent potassium currents were inhibited in a concentration-dependent manner, with an IC50 of 447 μM. This inhibition was related to the depression of calcium influx through voltage-dependent calcium channels subtypes coupled to BK channels. In summary, the blockade of these ionic conductances altered cellular excitability that reduced the action potentials firing and so, the neurotransmitter release and the synaptic transmission. These findings prove that aluminum has neurotoxic properties because it alters neuronal excitability by inhibiting the sodium currents responsible for the generation and propagation of impulse nerve, the potassium current responsible for the termination of action potentials, and the calcium current responsible for the neurotransmitters release.”
SUMMARY
Hopefully this article intrigues you a bit and encourages you to explore what is going on in the field of neurodegenerative disease. The big takeaway is that there is such a wide variety of antioxidants available that have been shown to help improve symptoms. This makes sense considering that the development of Alzheimer’s is associated with high oxidative stress. Further, the source(s) of increased oxidative stress have consistently been associated with various metals that are either misplaced, unbound, or in excess.
Outside of the scope of this article is the heme pathway (see my other article on Porphyria). Heme is needed for iron to be bound and stored as ferritin. In my view, the heme pathway is by far the pathway most sensitive to heavy metals, environmental toxins (e.g. pesticides), and inappropriate (high or low) levels of various compounds (e.g. copper, cobalamin, manganese, etc.).
To be discussed in another blog article is something teased at in this article: dysregulation of calcium, sodium, and potassium ion channels and their prevalence in various neurodegenerative diseases. Heavy metals, mycotoxins, various food additives, EMF, and Clostridia sp. metabolites (pathogenic gut bacteria) can all dysregulate these ion channels. Coincidentally, genetic mutations in genes that clear heavy metals are implicated in Autism.
Where do I start, you ask? Do I just randomly pick from the antioxidant supplement list you provided above? No. A more methodical approach is most beneficial.
First, I would look at your antioxidant systems, ion channels (sodium, potassium, calcium) and for evidence of genetic compromise. Next, I look at the nutritional cofactors needed for these antioxidant systems. Then, I would look for potential contaminants that would inhibit specific genes needed for these antioxidant systems to function well (this would include very specific gut-based metabolites). And lastly, a good baseline would also include a comprehensive oxidative stress panel of eighteen biomarkers that look for excess free radical levels (hydrogen peroxide, superoxide, peroxynitrite, hydroxyl radicals, prostaglandin production, and nitration radicals). Assessing this way puts me in a fantastic position to be able to select supplements that will make a large impact and that are tailored to your specific needs.
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