The Alzheimer’s Solution Revolution Podcast

Summary   Hello and welcome to episode #19!   This is Ralph Sanchez and today I'll be talking the outcomes of two recent studies that investigated the potential use of Viagra and Cialis in the risk reduction for late-onset Alzheimer's disease (LOAD).   I was in part inspired to provide an overview on these two recent studies as they are cautionary tales on how many studies do not include the interrelated factors that are essential in arriving to an integrated assessment and analysis that serves their very premise— which is, does this or that work in a potential solution to something else?   Does Viagra or Cialis offer any proposed solution to the risk for LOAD and dementia?   Well today, I'll be adding a great deal of information—the missing pieces to the puzzle as it were—with regard the pathways by which Viagra and Cialis may or may not work, and many other complimentary or natural alternatives that play a similar role in maintaining and optimizing a healthy cardiovascular and cerebrovascular system.   First, let me provide a little insight as to the molecular pathways in which drugs like Viagra and Cialis function, and why they may be considered as repurposed drug candidates for the treatment or in the risk reduction for LOAD.   Viagra (sildenafil) and Cialis (tadalafil) are Phosphodiesterase-5 inhibitors (PDE5is) which fall into a class of drugs that are normally prescribed to men to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).   PDE5is can have a profound effect on cardiovascular health and PDE5is mediate their benefits by inhibiting the breakdown of a molecule, cyclic GMP (cyclic 3′,5′ guanosine monophosphate).   Cyclic GMP (cGMP) is an intracellular and second messenger molecule that modulates many downstream pathways, including significant effects in vasorelaxation—the ability of your blood vessels to dilate and expand as needed.   The vascular effect that is enabled by PDE5i-induced vasodilation is a pivotal pathway in vascular homeostasis and a healthy heart-brain axis.   And that vasodilation effect is how PDE5is improve and treat ED.   There is a lot more to that vasodilation benefit mediated by PDE5i therapy  which I'll get to here soon.   So on to a brief description of the two recent studies on Viagra and Cialis, and so much more that was not included in those studies that will provide a crucial insight into how you can improve your vascular health and reduce your risk for LOAD.   NIH Studies First, a recent (2021)National Institutes of Health (NIH) funded study reported a risk reduction benefit of 69% for Alzheimer's disease (AD) in users of Viagra (Sildenafil).   The analysis simply compared Viagra users to those who did not take it, and the study was focused on a screen of drugs that could potentially be repurposed in the risk reduction for AD in aging individuals.   In a similar and second NIH funded study published this year (2022) titled— Drug Repurposing for Effective Alzheimer's Medicines—(DREAM), the NIH analyzed data from Medicare beneficiaries that were treated with Viagra and Cialis.   The NIH team compared people with pulmonary arterial hypertension (PAH) treated with Viagra and Cialis over those with PAH on another class of drugs (endothelin receptor antagonists) used to treat pulmonary hypertension.   And note that PAH is a term that refers to high blood pressure in the blood vessels leading from the heart to the lungs   Yes, PDE5is are also prescribed to patients to reduce blood pressure in PAH, and off-label use of PDE5 inhibitors (PDE5is) is used to treat cardiovascular diseases, Raynaud's disease and women with female sexual arousal disorder.   The average age of patients included in the DREAM study “was 74 years (range 65–96 years), and 69% were women.”   Notably, studies have shown that in women, "PDE5 inhibitor efficacy is estrogen dependent in female heart disease."   The DREAM PDE5i study rationale for focusing on patients with PAH and treated with PDE5is, Viagra or Cialis, for the new study analysis over those individuals on another class of antihypertensive drugs was attributed to the odds that the two groups were  "more likely to have people with similar characteristics".   In comparing those two pulmonary hypertension groups in the DREAM study the research team concluded that they "observed no evidence for a reduced risk of Alzheimer's disease and related dementia with phosphodiesterase-5 inhibitors"—Viagra or Cialis.   Bottom line, two differences in the design and outcomes as the Viagra study was favorable while the DREAM study was not. Fair enough.   However, there is much more to this story that was not included in the two studies, which includes an important benefit for heart and brain health that is only in part mediated by PDE5i therapy.   And we begin with nitric oxide— a vital molecule produced in your body and brain that not only impacts many potential benefits to your health, it can also be a component in deleterious oxidative stress reactions that are very damaging to your body and brain.   Nitric Oxide Nitric oxide (NO) was first discovered in 1772 but it was not until 1987 that it was identified as an important signaling molecule that played a vital role in endothelium-dependent vasodilation in mammals.   A few years later, in 1992, the journal Science nominated nitric oxide as the “Molecule of the Year” due to its role as a fundamental signaling agent in cardiovascular health and function.   In the body and brain, NO can be synthesized by two distinct pathways.   First, endogenous nitric oxide (NO) can be synthesized from the amino acid L. arginine (L-arginine-NO-synthase pathway) which is the initial upstream driver of cGMP activation in vasodilation.   Remember that we started this overview by emphasizing the role of PDEis in blocking the degradation of cGMP.   However, NO signaling is where cGMP activation begins.   Additionally, another amino acid—L. citrulline—is metabolized from arginine and can be utilized in regeneration of arginine.   Both amino acids are at the center of many studies which showcases their metabolism in vasodilation pathways.   Nitric oxide may be also be derived from the intake and metabolism of foods rich in nitrate (nitrate–nitrite–nitric oxide pathway).   Vegetables such as beets, celery, arugula and spinach, and fruits (e.g., strawberries) supply approximately 80%—85% of dietary nitrates in individuals that consume such foods regularly.   Indeed, those foods are not only a terrific source of nitrate, they also are rich in many types of polyphenols which are key nutrients in protecting against oxidative stress pathways associated with nitric oxide metabolism.   Many of you listening in or reading the transcript have likely become familiar with supplements using beets, or arginine and citrulline and other synergistic ingredients that have been heavily marketed to athletes as performance enhancers.   In a clinical setting, these NO enhancing products are often used for ED and cardiovascular health support.   Drugs (organic nitrates) are also well-known NO donors (e.g., nitroglycerin, amyl nitrite).   Thus, NO can be produced from the precursors L. arginine and L. citrulline, or nitrates and nitrites that are either derived from foods, supplements and drugs.   Another important understanding in all of this is that oral and gut bacteria convert dietary nitrate (NO3) to nitrite (NO2), and in the acidic stomach nitrite is further reduced to nitric oxide.   NB, antiseptic mouthwashes inhibit nitrate to nitrite metabolism by eradicating oral bacteria, and proton pump inhibitors (PPIs) and antacids suppress stomach acid and nitrite to NO metabolism.   To recap NO is an essential signaling and vasodilatory molecule secreted by vascular endothelial cells, which stimulates the production of cGMP (NO/cGMP Pathway) via activation of the receptor for cGMP— soluble guanylate (guanylyl) cyclase (sGC).   Another important point about NO in women is that estrogen (E2) increases NO synthesis.   Thus, the estrogen-NO dynamic is vital in vascular relaxation and endothelial-dependent vasodilation in women and should be included in any risk assessment for cardiometabolic and dementia risk in perimenopause or the earliest stage of menopause.   In contrast, cardiovascular disease (CVD) risk factors such as excess belly fat, high blood pressure, insulin resistance and type 2 diabetes, glycation and chronic inflammation (inflammageing) disrupts endothelial function, promotes arterial stiffness, and blunts the synthesis of NO.   Studies have shown that ED occurs in approximatelym35% to 75% of men with type 2 diabetes, and related studies have concluded that ED predicts future cardiovascular events.   Additionally, CVD risk factors upregulate the formation of an arginine metabolite—ADMA (asymmetric dimethylarginine)—that inhibits vascular NO production (eNOS uncoupling).   ADMA impairs vascular endothelial function and increases vascular oxidative stress (NO-ONOO cycle), and elevated ADMA has been linked to CVD in many studies. See image below.   A useful assessment in analyzing the underlying factors associated with cardiometabolic disease such as atherosclerosis is the serum arginine/ADMA ratio which provides information on arginine bioavailability for production of NO.   So, to summarize, the integrity of NO-sGC-cGMP Pathway is critical to signaling and vasodilation mechanisms that are essential to blood flow and vascular/endothelial homeostasis.   Healthy endothelial function and NO levels is critical in the normal function of many vital organ systems including the cardiovascular and cerebrovascular system (neurovascular system), and the respiratory and renal systems.   Indeed, a healthy endothelium is a fundamental cornerstone to living younger, longer.   For a more thorough overview of the neurovascular system, please listen in to episode #16 titled: “Brain Detoxification-Part 1-The Role of the Blood Brain Barrier and The Glymphatic System” here on this channel.   NO-PDE5i Brain Benefits But what about the role of PDE5is in all of this?   Is there a role for PDE5i therapy in preventing cognitive decline?   Would the PDE5i—sildenafil, or other PDE5 inhibitors, impart the same benefits on brain and cognitive health as healthy levels of NO does?   Previous studies have shown that low dose sildenafil activates signaling pathways which suppresses the processing and generation of beta-amyloid and tau protein aggregates.   Additionally, PDE5 inhibition mediated benefits include: induces cellular antioxidant levels, blunts neuroinflammation, and stimulates the production of new mitochondria (mitochondrial biogenesis) Now, is there a world where the combined therapy of NO and PDE5i therapy exists?   Only a handful of recent studies have shown that supplemental citrulline or arginine therapy in combination with a PDE5 inhibitors could be a synergistic and therapeutic alternative to PDE5i monotherapy for severe ED and pulmonary hypertension.   Overall, combination therapy was superior to monotherapies.   No such combination studies that investigated PDE5 inhibitors with citrulline or arginine therapy in the risk for late-onset Alzheimer's disease (LOAD) have been undertaken.   Bottom line, given the lack of research that includes the multiple pathways of NO metabolism and its role in endothelial function, the investigation into Viagra or any other PDE5i in the risk reduction for LOAD is grossly incomplete.   And that answers the unfinished Viagra and Cialis story as a viable treatment for cognitive impairment or Alzheimer's as the NIH studies on Viagra and Cialis just did not go deep enough into interrelated mechanisms that intersect with the PDE5 enzyme.   However, key nutrients, nutraceuticals and herbs are well-known NO precursors and PDE5 inhibitors, and they also protect against the upregulation of NO and the pro-inflammatory pathways and oxidative stress cascades associated with excess NO production.   Without a doubt, dietary, nutrient and botanical/herbal extracts are vital interventions in an optimal heart-brain health protocol.   More on that below after this brief overview on the glycocalyx.   The Glycocalyx (preview) I must add that any overview on NO in vascular and endothelial health is incomplete without an overview on the glycocalyx—a gel-like thin protective layer covering present on endothelial cells which maintains the endothelial barrier.   In fact, almost every cell in the human body, including bacteria, are covered by a glycocalyx layer.   And yes, the role of a glycocalyx layer in bacteria is another story.   The degradation of the endothelial glycocalyx layer in aging and cardiovascular disease significantly reduces endothelial cell production of NO, and collectively these interactions are a major and underlying factor in cardiovascular AND neurovascular disease.   I have been closely following the emerging research with regard to the glycocalyx over the past 5 years, and the evidence that you cannot have a healthy-heart-brain axis without a vibrant endothelial glycocalyx is compelling.   Case in point, the recent studies that have demonstrated the importance of the glycocalyx in vascular/endothelial health have established a new and critical insight into the treatment and potential reversal of atherosclerosis.   Nutrition-Diet (preview) A host of nutrients, nutraceuticals and herbs are well-known NO precursors and PDE5 inhibitors.   First, apart from arginine and citrulline, vitamin C, E and D are core nutrients in NO-mediated endothelium-dependent relaxation.   Recently, vitamin K2-MK-7 studies have also been linked to enhanced NO-dependent endothelial function.   Glutathione has been shown to be an essential and protective antioxidant in modulating NO reactivity and protecting against the damaging NO-ONOO cycle.   Glutathione and glutathione-based enzymes detoxifies peroxynitrite (ONOO)—a reactive nitrogen species, and improves nitric oxide bioavailability and endothelial function.   And, tetrahydrobiopterin (BH4) is a key enzymatic cofactor required for the synthesis of several neurochemicals—serotonin, dopamine and NO.   Additionally, polyphenols and in particular flavonoids, are the most the most frequently reviewed and studied phenolic NO precursors and PDE5 inhibitors, and they support the integrity of the glycocalyx structure and function.   So many nutrients  to make a case for including the phytoestrogenic benefits of many flavanoids, but here is an abbreviated list of the most cited plant/herbal derivatives and nutrients: Resveratrol Quercetin Catechins, epicatechin (e.g.,green tea) Pine bark (Pycnogenol®) and grape seed extracts (GPSE) Isoflavones (e.g. genistein) Hawthorne (Crataegus species) Icariin (Epimedium brevicornum) Aged garlic extracts Pomegranate extracts Gingko biloba Black ginger (kaempferia parviflora) Xanthones (Anaxagorea luzonensis) And, all the nitrate/flavanoid-rich foods including beets, spinach/leafy greens, and celery, pomegranate, berries, cherries, citrus, garlic, dark chocolate and many others.   Of course, a low-carbohydrate Mediterranean diet or Mind Diet lifestyle is rich in polyphenols and other heart and brain health nutrients.   In addition, exercise training and caloric restriction promotes NO activity and endothelium-dependent vasodilation through activation of eNOS.   Additional points covered in this episode's audio file…   NO Synthesis (preview) Now, I'll briefly describe how NO is synthesized as there are principal pathways that illustrate key and elemental features of NO metabolism—good and bad.   The NO-cGMP pathway is in part regulated by the activity of a family of enzymes—nitric oxide synthases that regulate nitric oxide (NO) synthesis.   There are three NOS enzyme synthases—neuronal (nNOS), endothelial (eNOS), and inducible (iNOS).   iNOS driven NO production is associated with immune system responses to various stimuli such as infections, and NO can either function as a regulator of such responses, or excessive production of NO by iNOS can upregulate those pathways in a destructive manner.   Nitric Oxide-S-nitrosylation (preview) I want to add another important feature of NO metabolism with regard to the risk for LOAD.   And that is the physiological and pathophysiological role of another NO reaction that takes place in the body and brain which is termed S-nitrosation, or S-nitrosylation.   I was not planning on adding this to this episode, but a recent research study just published reported that a S-nitrosylation pathway was a risk factor in Alzheimer's disease in women.   S- nitrosylation is the bonding of NO to sulfur compounds on amino acids such as cysteine.   In a recent study finding reported on just a few days ago—December 14, 2022, the elevated S-nitrosylation modification of an immune system protein known as complement component C3 (SNO C3) was present at much higher (six-fold) levels in the brains of women who had died of Alzheimer's, compared to men who had died with the disease.   The postmortem brain research that was conducted at Scripps Research and Massachusetts Institute of Technology (MIT) also reported that declines in estrogen, which normally serves as a neuroprotective hormone, was likely a strong factor in the generation of the SNO-C3 form of complement C3.   Cured Meats (preview) Another key factor to weigh into this overview with regard to diet, nitrates, nitrites and NO, are cured meats.   In fact, some of you may be anticipating this section of the  overview by now as there is considerable concern and media dissemination of the potentially deleterious role of nitrates and nitrites used in various types of processed meat products such as bacon, sausages and other “deli meats”.   In fact, many studies have explored the risk of nitrate and nitrite added to various foods as their metabolism under certain conditions can potentially convert into a toxic nitrosamines (N-nitroso compounds)   That's it for this summary and as always, thank you for listening in or taking the time to read the summary . Please do listen in to hear the rest of the story. God bless and goodbye.   BrainDefend® Ralph Sanchez, MTCM, CNS, D.Hom. https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez        

Welcome!   This is Ralph Sanchez and today I'll be expanding on the last two episodes—#16 & #17—in this special brain detoxification series. This is the third or part three in that series.   In our last two brain detoxification episodes I described the pathways of beta-amyloid and tau protein transport and clearance from the brain, and in their degradation in the liver in what I describe as the liver-brain axis in Alzheimer's disease.   Today I'll provide an overview on two related and crucial mechanisms of clearing debris, eliminating pathogens and neurotoxic proteins within the neuron and brain—namely autophagy and a complimentary proteasome degradation pathway.   Autophagy We'll begin with autophagy which falters in aging and is significantly impaired in many age-related diseases such as cancer, cardiovascular disease, diabetes and neurodegenerative diseases such as Alzheimer's.   These age-related diseases directly impact cellular protein turnover and disposal which is largely dependent on autophagy and a proteasomal degradation pathway, termed the ubiquitin-proteasome pathway.   To keep this overview as simple as possible in light of the fact that all three forms of the autophagic machinery (macroautophagy, microautophagy, and chaperone-mediated autophagy ) and related pathways are very complex, I will for the most part only be describing here the role of macroautophagy with regard to the autophagy-lysosome pathway in waste recycling, removal and clearance.   Macroautophagy is the most studied and described type of autophagy and it is the very same one that most educators speak of when describing the role of dysfunctional autophagy in the risk for AD.   Now an important focus of today's overview on autophagy is that it serves as an intracellular clearance mechanism of potentially toxic proteins such as beta-amyloid and tau protein that disrupt neuronal function and the integrity of our cognitive function in aging IF they are not appropriately turned over and degraded as needed.   Autophagy also mediates the degradation of pathogens (e.g., viruses, bacteria), the removal of damaged cellular organelles like the mitochondria, and the cellular removal and recycling of proteins derived from the degradation of these targets for a nutrient and energy supply.   The recycling of proteins and cellular organelles is a component in the regeneration of new proteins that serve as functional and structural substrates—e.g., cellular membranes and new organelles.   Indeed, autophagy is a vital mechanism in cellular homeostasis throughout our healthspan.   If your brain detoxification pathways are at their best, your odds of preventing dementia and living younger, longer are vastly improved.   Now much of the public awareness with regard to the role of beta-amyloid in the brain revolves around the notion that beta-amyloid protein eventually forms plaque—outside the neuron—in the extracellular environment.   And to that point, in the first episode (#16) of this brain detoxification series that focused on the transport and removal of beta-amyloid and tau protein from the brain, I gave an overview on the presence of beta-amyloid and tau protein in the extracellular fluid—the interstitial fluid—that is then funneled into the glymphatic system or transported across the blood brain barrier for removal from the brain.   Additionally, the amyloid precursor protein (APP) that traverses the membranes of the neuron and generates the very beta-amyloid peptides that can eventually aggregate into deposits in the extracellular environment is also present on membranes within the neuron.   APP is also present on mitochondrial membranes and the membranes of other intracellular organelles (e.g./ endoplasmic reticulum), and it is also cleaved (by beta- gamma-secretase) to generate intracellular beta-amyloid peptides that are potentially toxic if not degraded and cleared away.   Now apart from APP and beta-amyloid, I want to highlight as well that tau protein associated with neurofibrillary tangles NFTs in AD is normally a constituent and very important protein that is incorporated into microtubules—the cytoskeletal and conveyance network of the neuron and its axon.   And there are toxic tau proteins derived from pathological processing of the neuronal microtubule proteins like tau that form the characteristic tangles (NFTs) associated with Alzheimer's disease (AD).   Therefore, a very intricate waste and recycling disposal system—the autophagy-lysosome pathway—has evolved for the requisite removal and degradation of toxic intracellular debris from the brain.   Lastly, there is a mechanism by which beta-amyloid and tau protein in the interstitial fluid is taken up into the neurons in what is termed the endocytic pathway.   The endocytic pathway is essentially a process of cellular ingestion (endocytosis) by which the plasma membrane forms a vesicle that engulfs substances—good (nutrients) and bad—and takes it up into the cell.   The uptake of debris destined for disposal and degradation in autophagy via the endocytic pathway is first carried forth to its destiny by way of carriers termed endosomes.   The endosome pathway includes early and late endosomes, (endosomal trafficking) that ultimately transport their cargo to lysosomes in what is known as the endosomal-lysosomal pathway that is a component of the autophagy-lysosomal system.   Bottom line, the autophagy-lysosomal system is vital to the degradation and clearance of toxic debris that is essential for the maintenance of central nervous system homeostasis.   Now, as in all risk factors associated with the increased risk for late-onset Alzheimer's disease (LOAD), functional impairments in the autophagy-lysosome pathway are linked to many genes and genetic variants such as the ApoE4 variant, which is again the strongest risk factor linked to LOAD.   For example, recent studies have showed that ApoE4 modifies early endosome function by "clumping" of their internal compartment and cargo which ultimately resulted in the dysfunctional transport and recycling of beta-amyloid protein.   However, many other genes (e.g., BIN1, CD2AP, PICALM, SORL1and TREM2) and genetic variants play a key role in all of this as well.   Now, that is a snapshot on the autophagy-lysosome pathway, and its intricate beta-amyloid and tau protein clearance mechanisms and pathways.   Now I'll describe the other important protein degradation, clearance and recycling system that works in concert with autophagy— the ubiquitin–proteasome system.   The Brain Proteosome The second and major protein degradation pathway degrade in all cells of the body and brain is the ubiquitin–proteasome system (UPS).   The UPS, is composed of proteasomes—a protein degrading complex, and ubiquitin which is another protein that essentially tags other proteins destined for proteasomal degradation.   All in all, the ubiquitin–proteasome system is a protein degradation pathway, AND it assists in the eventual recycling of proteins back to the cell or plasma membrane where they are reused.   I'll hereinafter refer to the ubiquitin–proteasome system (UPS) as the proteasome or proteasome pathway.   The proteasome pathway is distinguished from autophagy in that autophagy is more specific to processing “long-lived proteins”, while the proteasome pathway is in charge of processing “short-lived proteins”.   So, let me explain that important terminology with regard to short-lived proteins and long-lived proteins which will further explain why there are two intraneuronal degradation pathways—the autophagy-lysosome and proteasome pathways.   Short-lived proteins are soluble and early stage protein derivatives of APP or microtubules such as beta-amyloid and tau proteins respectively, that are termed monomers and oligomers.   BTW, I describe the role of oligomers in the disruption of synaptic function and brain insulin resistance in my book—The Diabetic Brain in Alzheimer's Disease, so please read that when you have a chance.   Now examples of long-lived proteins are the insoluble and more significant aggregate stages of those proteins such as amyloid fibrils and plaque, and neurofibrillary tangles (NFTs) which are associated with tau protein.   And again, the proteosome pathway processes short-lived proteins, and the autophagy-lysosome pathway processes long-lived proteins such as more significant misfolded aggregates of tau and beta-amyloid proteins that are potentially neurotoxic.   And I must add that the processing of long-lived protein aggregates is also referred to as aggrephagy—a third pathway process by which aggresomes—much like endosomes—sequester protein aggregates which are chaperoned toward the autophagy-lysosome degrading complex.   Regardless, of the short-lived or long-lived processing pathways in the proteasome or autophagy-lysosome pathways, the cellular quality control mechanisms directed at protein degradation and recycling are crucial in living younger, longer.   And, I'll emphasize here once more that failure of the autophagic-lysosomal machinery in the degradation and clearance of long-lived proteins such as beta-amyloid and tau protein aggregates is a core pathological feature in the progression of late-onset Alzheimer's disease (LOAD).   Additionally, there exists a synchronous crosstalk between these two protein degradation systems—the proteosome pathway and autophagy— which are an inherent and vital aspect in the maintenance of cellular protein proteostasis (protein homeostasis), and in the protection against LOAD.   Now there is an additional and set of detoxification pathways that I've yet to provide an overview on that are also vitally important in protecting your body and brain—the phase I, II and phase III detoxification pathways and mechanisms.   Phase I, II III Detoxification Pathways In episode #17, or part two of this brain detoxification series I gave an overview on advanced glycation end-products (AGEs) and the receptor for AGEs—RAGE (receptor advanced glycation end-products).   Please listen in to episode #8 and #17 for a more comprehensive description of glycation cascades in the formation of AGEs and ALEs as it is integral in the understanding of the brain-damaging effects that advanced glycation and lipoxidation end-products (AGEs and ALEs) pose to the body and brain.   In episode #8, I provide a summary of the primary takeaways from my book, The Diabetic Brain in Alzheimer's Disease, including the role of glycation reaction compounds such as AGEs and ALEs in risk for LOAD.   And, here is why phase I and phase II detoxification pathways are relevant to this discussion with regard to glycation reaction compounds that include AGEs, ALEs.   To begin with, the elimination of both exogenous (xenobiotics) and endogenous toxins is dependent on a set of metabolic detoxification pathways that are well-known and commonly referred to as phase 1 & 2 detoxification pathways.   Phase I & II are commonly associated with the liver's critical role in metabolism and elimination of both environmental toxins (e.g., pesticides, chemicals) and endogenous toxins.   The human organism is a significant source of endogenous toxins that are either derived by energy metabolism (reactive oxygen/nitrogen species), gut microbes that generate endotoxins (which I covered in the last episode), and the very toxic glycation associated compounds I am in part describing in this overview today.   These exogenous and endogenous toxins are a significant threat to your physiological and neurological wellbeing as you age, and the risk for numerous health disorders including dementia and LOAD.   With regard to phase I and phase II, the metabolism and biotransformation of environmental and endogenous compounds/toxins proceeds through phase I and phase II pathways.   In phase I, compounds/toxin that are mostly lipid soluble are transformed into water-soluble compounds that form intermediate compounds that are further metabolized for phase II processing.   In phase II, the phase I intermediates are packaged (conjugated) for elimination via bile and urine.   Note, that phase I intermediates are highly reactive and damaging compounds. Thus, the metabolic flow between phase I biotransformation to phase II conjugation is very important.   So, here is the point of this very limited phase I and phase II overview.   There is evidence that phase I & II detoxification pathways also metabolize the intermediate glycation stage compounds termed carbonyls, which are also referred to as glycotoxins.   Please listen in to the podcast for a more thorough overview on glycation cascades that lead to carbonyl formation that result from chronic glycation reactions (e.g., hemoglobin A1c) linked to hyperglycemia and diabetes.   Reactive carbonyl and dicarbonyl compounds (two carbonyls) are a component of intermediate glycation reactions that precedes the formation of AGEs and ALEs.   Bottom line, phase I & II metabolism of carbonyls and ultimately carbonyl reduction, blunts the eventual formation of AGEs and ALEs and that is a very important understanding.   I must add that add that toxic AGEs and ALEs are also in part metabolized and degraded by the proteasome which highlights yet another critical factor in the degradation of AGEs by the proteasome and in autophagy.   Now a little on phase III.   In the previous to last episode—#16, I described the function of the P-Glycoprotein (P-gp) transporter in the clearance of beta-amyloid at the blood brain barrier (BBB).   The P-gp efflux transporter at the blood brain barrier (BBB) is vital in the clearance of beta-amyloid from the brain, and it also functions to protect against in the reentry of peripheral beta-amyloid into the brain.   The P-gp transporter is also a component of a phase III efflux transporter system, which actively protects against and removes drugs and environmental toxins (xenobiotics) from the capillary wall of the BBB and therefore functions as a vital functional barrier mechanism in the BBB.   So apart from P-gp efflux of drugs and xenobiotics at the BBB as a phase III mechanism, it mediates the same benefit in the efflux of beta-amyloid at the BBB.   I'll leave the phase III detoxification description to that very brief overview, but I'll add that the phase I, II and III detoxification mechanisms and systems, and the content of the past two brain detoxification episodes will all in my book that that will focus on the critical role of brain detoxification in living younger, longer in the coming new year.   So that brings us to the solution.   Of course, prevention of type 2 diabetes and cardiovascular disease (cardiometabolic disease) is essential in mitigating the degeneration of these vital body-brain detoxification pathways as we age.   And apart from a risk reduction and prevention focus, there are prime lifestyle and nutrition interventions that augment a preventive approach.   Now much of the science is dedicated to drug solutions to resolve the decline of the UPS and autophagy-lysosomal pathway in aging and a host of health disorders.   No doubt, the drug-centered research is illuminating, and certainly, with regard to treatment approaches to cancer (e.g. proteasome inhibition), all is an extremely important body of research.   However, there is a significant body of evidence with regard to basic interventions that augment and activate the proteasomal and the autophagy-lysosome pathway.   So how do we nourish and enhance these vital protective brain detoxification pathways as we age, and which to the point of this episode are linked to the detoxification of pathogens and toxins that includes beta-amyloid and tau protein degradation and clearance?   As I delineated in the previous two brain detoxification episodes, nutrients, dietary therapies and lifestyle are crucial and effective interventions in modulating these brain-saving pathways linked to the protection and enhancement of cognitive health in aging.   And, predictably, recent studies have demonstrated that a family of phytochemicals—polyphenols and carotenoids, uniquely regulate the proteasomal and autophagy-lysosomal pathways, and thus they protect against the noxious AGEs and ALEs that are potent risk factors in LOAD.   I will emphasize as well that regulation—the activation or inhibition of the proteasomal and autophagy-lysosomal pathways—are both mechanisms that are important in the potential benefit of polyphenolic compounds that include curcumin (curcuminoids) and resveratrol (stilbenes) which are the most widely studied, followed by catechins such as EGCG found in green tea and other foods and beverages, and isoflavone derivatives (genistein) from soy, and other foods and herbs.   While supplementation with these phytochemical compounds may be useful for augmenting the proteasome and autophagy, it should be based on a prudent and personalized evaluation of need and goals.   Without such guidance, a plant-based Mediterranean or MIND diet that are rich in polyphenolics and carotenoids is likely the best option for most individuals.   As such, these protective diet-derived phytochemicals are critical buffers against the early oxidized and lipid peroxidation compounds upstream before they form more toxic AGEs and ALEs downstream.   The same holds true for many nutrients including B6, B1 as benfotiamine (a fat-soluble form of vitamin B1), lipoic acid, carnosine and glutathione.   Plus dietary therapies such as fasting, caloric restriction and ketogenesis preserves and optimizes the proteasome pathway and the autophagy-lysosome pathway.   Lastly, lifestyle habits such resistance and aerobic exercise are associated with benefiting the proteasome and the autophagy, and it is important to note that in caloric restriction therapy, exercise will buffer the loss of muscle mass that may result from such dietary therapies.   That's it for today, and as always, grateful that you took the time to listen in to this or any of my other episodes here.   God bless and goodbye.   BrainDefend®   Ralph Sanchez, MTCM, CNS, D.Hom. https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez

Summary   Hello and welcome to episode #17! This is Ralph Sanchez and today I'll be expanding on the first episode's overview with regard to beta-amyloid and tau protein clearance and detoxification. If you did not catch that episode (#16), I provided an in-depth overview on the role of the blood brain barrier (BBB) and the glymphatic system in clearing and transporting toxic beta-amyloid and tau protein from the brain. In today's episode, I'll review the emerging science and research with regard to the brain-liver axis in beta-amyloid clearance and metabolism, and how the gut fits into that, and a little on tau protein too. Now, the peripheral metabolism of beta-amyloid in the body is a very complex overview, however, I will cover two important organs that are associated with the origin and degradation of beta-amyloid in the body—the gut and liver. And, I will provide key features about that to illustrate what I term—the gut-brain-liver axis in late-onset Alzheimer's disease (LOAD). First, there are three points I will make here with regard to the gut-brain axis, and its potential role for a healthy brain, or for neurological disease such as Alzheimer's and Parkinson's disease. First, the gut is potentially a powerful vector for proinflammatory cascades that induce neuroinflammation responses.   Secondly, alteration of the gut barrier integrity leads to similar loss of the blood brain barrier integrity,   And lastly, the generation of beta-amyloid proteins produced by bacteria in the gut. Yes, certain gut bacteria have been identified as specific beta-amyloid peptide producers linked to a beta-amyloid burden in the brain. Now note the latter point I just made about gut-derived beta-amyloid-like peptides (proteins) generated by gut microbiota which I will elaborate on more here soon. Nevertheless, the role gut-derived beta-amyloid-like proteins has in recent years been identified as drivers of neuroinflammation, AND amyloid and tau protein aggregation and deposition in the brain. Of course, pro-inflammatory pathways are driven by a host of physiological and pathological mediators that includes the gut, and numerous chronic diseases such heart disease and diabetes (cardiometabolic disease) which is well-described in the research literature.   Gut-Brain Axis in Neuroinflammation   The role of the gut-brain axis is a significant factor in the risk for numerous health disorders throughout life, and it can have substantial implications on your body-brain health as you age. Numerous studies that have examined the role of gut health disorders such as small intestine bacterial overgrowth or dybiosis to the detriment of brain health and the risk for cognitive decline and dementia have been accruing now for many years. BTW, for those of you who have not run into the reference to gut dysbiosis, it simply refers to the altered gut ecosystem that is reflected by unhealthy imbalances of the gut microbiota. And, as before, one significant driver of gut inflammation is the disordered ecological balance of the gut microbiota (dysbiosis). Additionally, bacterial overgrowth patterns of dysbiotic bacteria are highly associated with elevations of a potent gut-brain toxin— lipopolysaccharides. Lipopolysaccharides are bacterial surface molecules that are a major component of the outer membrane of Gram-negative bacteria. Lipopolysaccharides are normally shed by gut bacteria, but in the case of microbiome imbalances associated with bacterial overgrowth patterns (dysbiosis), a proliferation of dysbyotic bacteria—the bad guys, too much pro-inflammatory lipopolysaccharide matter is shed into the gut and peripheral circulation which can lead to powerful systemic toxic and inflammation reactions. With regard to the central nervous system and individuals at risk for dementia and Alzheimer's disease, dysbiosis and the excessive generation of pro-inflammatory lipopolysaccharides alter the integrity of the BBB, and can induce beta-amyloid and tau protein aggregation and accumulation in the brain—plaques and tangles. Both gut bacteria and lipopolysaccharides can migrate into the brain and upregulate neuroinflammatory and neurodegenerative mechanisms there that include damage to the myelin. Apart from the pro-inflammatory cascades associated with dysbiosis and intestinal permeability or leaky gut, the gut microbiota are producers of amyloid proteins that contribute to the progression of late-onset Alzheimer's disease (LOAD).   Gut-Derived Amyloid Protein   Now that you hopefully have an understanding of dysbiosis and the overgrowth patterns of potentially toxic bacteria in the gut-brain axis, there is an additional risk for neurotoxicity that dysbiotic bacteria generate. They are also a source of beta-amyloid like proteins as I mentioned a little earlier here. Yes, species of gut bacteria are known sources of amyloid-like proteins (similar but not duplicate structure), and these gut-derived amyloid proteins also are known to cross a leaky gut barrier and a leaky BBB. Plus, gut-derived amyloid-like proteins can function through a phenomenon known as “molecular mimicry”, as prion proteins (infectious pathogens made of protein) that cross-seed and stimulate aggregation of beta-amyloid in the brain. BTW, if the term molecular mimicry is new to you, it describes the molecular likeness or similarity of a foreign antigen or protein to self-proteins that can elicit immunological reactions as evident in several autoimmune disorders. Examples of amyloid secreting gut microbiota are E.coli and Clostridium that are singled out in a few recent studies. However, there are many species of E.coli and Clostridium that are not toxic. In fact, they are beneficial bacteria of the gut terrain too . Dysbiosis, Metabolic Disease and the BBB   Now, one more important point with regard to dysbiosis, gut-derive beta-amyloid proteins, the BBB and metabolic health. Over the years, microbiome studies have become an intense and significant component of the gut-brain axis and its role in Alzheimer's and dementia. And, what these studies do ultimately signify as a body of evidence is that imbalances in ratios of the major phyla of bacteria in the gut—Firmicutes and Bacteriodetes—and dysbiosis are associated with a greater risk for cognitive impairment and dementia. The Firmicutes/Bacteroidetes ratio is significantly higher in obesity and T2D and thus serves as a valuable biomarker for metabolic diseases, which underscores the importance of dysbiosis and gut microbiome assessments and a personalized evaluation of those results for individuals at risk or for those already diagnosed with metabolic disease and cognitive impairment. Of course, I elaborate on the role of obesity, T2D, metabolic syndrome, hypertension and cardiovascular disease in my book—The Diabetic Brain in Alzheimer's Disease. One critical aspect of metabolic disease that I cover in my book is the deleterious consequences of glycation in the body that leads to the metabolism of advanced glycation-end products (AGEs) that results from persistent elevations of blood glucose or hyperglycemia. Glycation is the process—a chemical reaction—that occurs when certain types of sugars such as glucose or fructose attach to proteins, fats (lipids), and DNA. Glycation that is not inhibited by a healthy diet and lifestyle causes severe damage to protein and fat structures in our body and brain, and to the DNA structure. Unrestrained and prolonged glycation reactions are associated with aging, diabetes, neurodegenerative disorders, cardiovascular and renal disease, and many other disorders. Additionally, an unrestrained glycation process leads to the upregulation of AGEs and the progression of the same diseases. Advanced glycation-end products or AGEs bind to the receptor for AGEs or RAGE, which is acts at the BBB as a conduit for beta-amyloid entry or reentry into the brain. Plus, AGE-RAGE interactions amplify pro-inflammatory pathways and oxidative stress cascades in the brain that is a significant factor in the risk for Alzheimer's disease and its progression in aging. So, to summarize what I've covered so far, there is an intersection between gut dysbiosis, inflammation pathways and the microbiota, and with metabolic disease such as type 2 diabetes, that damages the BBB and facilitates beta-amyloid entry into the brain. Last week I briefly covered the role of diabetes in disruption of the BBB and the inhibition of beta-amyloid clearance out of the brain, and now you have a more robust review of the gut-brain axis and the metabolic factors that damages the efflux mechanism of beta-amyloid clearance from the brain and which also facilitates the influx of beta-amyloid into the brain. And, I must add one more feature of the shared pathophysiology between type 2 diabetes and Alzheimer's disease—amyloid deposition. Amyloid deposition is also a pathogenic feature of type 2 diabetes (T2D). Amyloid deposition in T2D transpires in the Islet of Langerhans beta cells of the pancreas—the insulin producing cells. I share that pancreatic amyloid protein deposition aspect of diabetes to point out that there are several tissues in the body that harbor the amyloid precursor protein (APP) which generates amyloid proteins associated with amyloid lesions. And, these peripheral amyloid proteins are often associated with the increased risk and in the progression of Alzheimer's disease. There is more to this pancreas-diabetes-Alzheimer's link that will be the subject of another podcast here in the future. And in episode #8 (The Role of Cardiometabolic Disease and Insulin Resistance in Vascular Dementia, Type 3 Diabetes and Alzheimer's disease) I provide a synopsis of my book in which I provide the links between obesity, cardiometabolic disease, insulin resistance, and its role in T3D—a type of insulin resistance pattern in the brain associated with AD Now onto the liver as it also plays major role in the metabolism and detoxification of beta-amyloid in the periphery, and how that influences the risk for Alzheimer's.   Liver Metabolism and Clearance of  Beta-amyloid Protein   Now last week, I promised to review the all-important aspect of beta-amyloid detoxification in the body by the liver. And, I ‘ll start by making two crucial points about the liver-brain axis in Alzheimer's disease. The liver is both a source of circulating beta-amyloid that can cross the blood brain barrier (BBB), and it is the PRIMARY site of beta-amyloid disposal or detoxification once it is cleared out of the brain. Please refer to the previous episode here for an overview on clearance mechanisms of beta-amyloid across the blood brain barrier. Now, here is an excerpt from a very recent study (02/2020) on the role of the liver in the metabolism beta-amyloid: "the liver is the origin of brain beta-amyloid deposits and that it is involved in peripheral clearance of circulating beta-amyloid in the blood. Hence the liver could be targeted to decrease beta-amyloid production or increase peripheral clearance." The title of that study—"Is Alzheimer's Disease a Liver Disease of the Brain?"—was published in 2020. However, that 2020 study was actually preceded by studies in 2011 and earlier, that the described a “blood to brain” pathway of amyloid protein derived from their processing in the liver that crossed the BBB. Now, if you were able to listen in to the previous episode on role of the BBB and glymphatic system in brain detoxification of beta-amyloid and tau protein, the clearance of beta-amyloid from the brain and across a healthy blood brain barrier is essential in the detoxification of beta-amyloid in the liver. But once it is transported into the blood, what happens next? Well, therein lies to rest of the story and one whereby the low-density lipoprotein receptor-related protein (LRP1) plays a major role again. Yes, the role of LRP1 and LRP2 at the BBB in the brain clearance of beta-amyloid was an important mechanism in that process that I covered in Part 1 of this three-part “brain detoxification” series. Now, the type of LRP1 in peripheral circulation is another form of LRP1 referred to as soluble LRP1 (sLRP1), which I will herein after reference as sLRP. sLRP is a major plasma transport protein of beta-amyloid once it is cleared from the brain, and it is theorized that sLRP binds to 70–90% of the beta-amyloid that circulates in peripheral blood. This peripheral pool or “sink”—as it is often referred to in the research—of beta-amyloid is now considered to be a critical component of a “peripheral sink hypothesis” in which the increase in the peripheral clearance of beta-amyloid could reduce the brain burden of beta-amyloid protein. Indeed, while the clearance and removal of beta-amyloid from the brain is an essential first step in its detoxification in the body, the next crucial step is its clearance from the body and sLRP is pivotal in that regard. Next step? Once it is transported to the liver, the liver LRP1 receptor takes up beta-amyloid to liver cells (hepatocytes) where it is degraded and/or excreted through the biliary system (bile). Without going into the details, the kidneys also clear circulating beta-amyloid in the urine. And lastly, in last week's episode I also described the clearance pathway for tau protein. There is evidence in a mouse model that the peripheral tau protein pool is cleared by the liver and kidney too. Tau protein may also be cleared through immune system cells such as macrophages that ingest (phagocytize) and break it down (catabolize). And that brings to the end here today. This podcast episode— Brain Detoxification—Part 2—The Gut-liver-Brain Axis—has the rest of the details not included in this summary. Please listen in if you want the rest of the story! Thank you for reading or listening in!   Ralph Sanchez, MTCM, CNS, D.Hom BrainDefend® https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez  

Summary   Hello and welcome to episode #16!   Today I'll be describing an elemental aspect in maintaining a healthy brain as you age and preventing the cognitive decline that is associated with unhealthy aging and the risk for Alzheimer's disease as you age—brain detoxification.   Because brain detoxification mechanisms are a very complex review, I will provide it in three parts–this episode and the next two.   Now, most people that are oriented toward health and wellness strategies know that a good detox for their body is one of the more healthful things one can do for their wellbeing.   But what about your brain?   Well, there are also several key brain detoxification mechanisms that are often overlooked or not emphasized enough.   And while detoxification programs and kits are extremely popular, the majority of detox programs I know of barely mention or address the challenge of brain detoxification.   Now because brain detoxification mechanisms are a very detailed review, I will provide it in three parts–this episode and the next two.   This episode will focus on the importance of a system of brain detoxification pathways and mechanisms that are vital to brain health and in risk reduction for late-onset Alzheimer's disease (LOAD)—the blood brain barrier (BBB) and the glymphatic system.   The glymphatic system is now considered to contribute to approximately 60% of the brain's beta-amyloid drainage to the cervical lymph nodes and further downstream.   Both the glymphatic system and BBB are interconnected AND interdependent systems in the clearance of metabolic waste and neurotoxic proteins that are associated with Alzheimer's disease (AD)—beta-amyloid and tau protein—the two proteins that can accumulate and form the hallmark plaque and tangle lesions associated with AD in the brain.   The glymphatic system was first described in a paper published 2012 by Dr. Maiken Nedergaard and his team at the University of Rochester Medical Center.   Since then, many studies have investigated how it works and all the moving parts associated with the workings of the glymphatic system.   So, let's go over what the glymphatic system is...it is often described as a lymph like network as it was though that there were not any conventional lymphatic vessels in the brain as there is in the body.   However, there is a lymphatic system that is integrated within the glymphatic system—the meningeal lymphatics which I describe in this episode.   In short, the glymphatic system is composed of several essential parts that include the meningeal lymphatics to make it a functional apparatus that is essential in brain detoxification.   To paint a picture in your mind of these related systems, the glymphatic system is where toxic protein and other waste material is collected and eventually drained into the blood stream, AND that waste is also exported into the meningeal lymphatic system and to the cervical lymphatic vessels and nodes which lie deep in the neck area.   So, there are two exit routs for the glymphatic waste fluid—the blood and the meningeal lymphatics.   Next week, I'll describe what happens next to this metabolic waste once it is exported from the brain and into peripheral circulation.   The Blood Brain Barrier and the Neurovascular Unit   The glymphatic system is a glial or astrocyte-dependent waste clearance pathway in the brain, which also has a dynamic relationship with the both neurons and the cerebral vasculature.   In fact, astrocytes fall into a family of brain cells termed the glia or neuroglia. Thus, the g in glymphatic or glia-lymphatic.   Because there is a strong symbiosis between neurons and astrocytes, neurons are considered a component of the neuron-astrocyte-blood vessel and blood brain barrier BBB relationship that is referred to as the neurovascular unit.   Indeed, the glymphatic network is a core pathway that is vital to brain detoxification, and the flow of that pathway it is closely aligned with astrocytes and the blood vessels that course through the brain.   This dynamic working relationship between astrocytes and blood vessels of the brain highlights the importance of vascular health in brain health as the health and structure of the vasculature and unimpeded blood flow is critical in how it facilitates the flow of the glymphatic system.   Another key factor in waste removal and detoxification of neurotoxic proteins such as beta-amyloid is the blood brain barrier (BBB), and the integrity of its structure and the receptors and transporters built into that structure.   Now, the blood brain barrier (BBB) normally functions as a vital barrier that controls the flow of nutrients, oxygen, and toxins in and out of the brain.   Now with regard to toxins, the integrity of the BBB and its transporters and receptors that regulate the influx of nutrients and toxic substances into the brain, and the efflux of toxic factors such as beta-amyloid protein out of the brain, is a pivotal factor in the risk for late-onset Alzheimer's disease.   A leaky and dysfunctional BBB is associated with aging and systemic inflammation, and it is a component in cerebral small vessel disease (cSVD).   And what does cSVD have to do with brain detoxification?   Cardiovascular and cerebrovascular health is crucial in a healthy brain and the functional integrity of glymphatic system.   The HEALTH of the vascular system and the unobstructed pulsation of arteries is essential in supporting fluid and cerebrospinal fluid (CSF) flow into drainage systems to adequately remove waste and toxins out of the brain via the glymphatic-lymphatic systems.   The transport of oxygen and nutrients into the brain is also dependent on a healthy vascular system and of course, that flow is severely impaired in cSVD.   And again, vascular health and the integrity of BBB is thus critical to the transport of fluids and waste across the BBB and into the blood stream.   Now remember, the glymphatic system is in part reliant on a healthy vascular system.   Therefore, preventing cardiovascular and cerebrovascular disease in aging is fundamental to a healthy neurovacular unit and maintaining a healthy BBB and glymph system.   Bottom line…a leaky and dysfunctional BBB is associated with aging, and systemic inflammation and oxidative stress, and it often is a component in cerebral small vessel disease (cSVD) in aging individuals.   And not surprisingly, studies also demonstrate that the neuroinflammation associated with beta-amyloid and tau protein aggregation and accumulation induces BBB permeability and dysfunction.   BBB Transporters/Receptors   The importance of receptors and transporters in BBB mediated removal of beta-amyloid is of paramount importance in preventing their accumulation in the brain.   One such transporter is the P-Glycoprotein efflux transporter (P-Glycoprotein/ABCB1) which is a member of a large family of ABC transporters.   The P-Glycoprotein (P-gp) transporter actively protects against and removes drugs and environmental toxins (xenobiotics) from the capillary wall of the BBB and therefore functions as a vital functional barrier mechanism in the BBB.   Next week, I'll talk more about this versatile transporter that is very important in BBB protection from noxious compounds from possibly entering the brain including beta-amyloid.   Plus, it is an important transporter on the removal of beta-amyloid from the brain and its dysfunction is considered as a critical factor in the accumulation of beta-amyloid in the brain.   Another major protein that is vital to the efflux of beta-amyloid from the brain, is the low-density lipoprotein receptor-related protein (LRP1)—a multifunctional protein.   LRP1 is the deemed the main cell surface receptor that mediates brain beta-amyloid clearance at the BBB and is often referred as a scavenger receptor.   LRP1 interacts with the P-gp transpoter, and P-gp deficiency contributes to LRP1 dysfunction which leads to increases beta-amyloid burden in the brain.   Plus, LRP1 protects against neuroinflammation by inhibiting cyclophilin A, a pro-inflammatory protein which I expand on in this episode.   Last an important aspect of LRP1:   Sustained elevations of blood glucose (hyperglycemia) in diabetes suppresses LRP1 expression in the brain.   Plus, another low-density lipoprotein receptor-related protein (LRP2), binds to clusterin or apolipoprotein J (ApoJ), which binds beta-amyloid 42 peptide, for efflux out of the brain.   The clusterin gene is considered by many researchers to be the third most predominant genetic risk factor associated with late-onset Alzheimer'.   I include the role of clusterin in in my overview of genetic variants in episode #7 “Primary Genetic Variants in the Risk for Late-onset Alzheimer's Disease—ApoE4 and Beyond”.   The integrity of the BBB and its transporters and receptors that regulate the influx of nutrients and toxic substances into the brain, and the efflux of toxic factors such as beta-amyloid protein out of the brain, is a pivotal factor in the risk for late-onset Alzheimer's disease.   In the case of tau protein clearance from the BBB, P-gp transporter and the LRP1 receptor do not mediate such clearance and there is only a very small amount of evidence that there may be a BBB clearance mechanism of tau protein, although not enough to warrant an overview here.   Nevertheless, I cover the role of glymphatic system drainage and clearance of tau protein from the brain in this episode.   Nutrition and Lifestyle   Of course, we all know that. diet and nutrition are vital components in nourishing and protecting the heart and brain throughout life, and it is particularly important as the years roll on into later life.   So, I'll briefly go over a host of nutrients that are associated with repairing and maintaining the integrity of the BBB and the glymphatic system.   First up, polyphenols such as resveratrol (pterostilbene), curcuminoids such as curcumin, carotenoids and sulphoraphane.   These phytochemicals are powerful anti-inflammatory and antioxidant compounds that activates the Nrf2-ARE (Antioxidant Response Element) signaling pathway which I talked about extensively in episodes #14 and #15.   For those of you that have not tuned into those episodes,  the Nrf2-ARE (Antioxidant Response Element) signaling pathway signaling induces the expression of over 300 genes that exert a powerful detoxification, antioxidant and anti-inflammatory protection for your body and brain.   And of course, that antioxidant and anti-inflammatory protection is central to mitigating and repairing the damage to the BBB associated with diabetes, cardiovascular and cerebrovascular disease, hypertension and TIAs or mini-strokes.   The same holds true for other nutrients I talked about in episode #15—namely choline, omega-3s, vitamin D AND B vitamins such as B12, folate and B1.   Please listen in to hear more on how these nutrients and many other key nutrients  function in supporting the glympahatic system and BBB in brain detoxification.   Lastly, many studies have demonstrated repeatedly that exercise and deep sleep increases glymphatic clearance of brain debris that includes beta-amyloid protein and tau protein.   The glymphatic system is essentially “turned on” during non-REM (NREM) sleep and after exercise.   Stage 3 or the delta stage of NREM (non-rapid eye movement) sleep is considered deep sleep.   Conversely, the link between poor sleep and the buildup of beta-amyloid in the brain is well-studied, and stress and stress hormones are a significant factor in sleep disruptions.   Now a major cause of disrupted sleep patterns is stress.   Excessive activation of the stress response pathways and the stress hormone, cortisol, is associated with the breakdown of the BBB and of course cortisol damages the vascular system and the very center of crucial memory and learning mechanisms—the hippocampus.   Therefore, stress modification interventions are also a factor in protecting the BBB and in the optimal flow of the glymphatic system.   We all know that too much stress over time is very deleterious to the health of our body and brain, so uninterrupted sleep, yoga, tai chi, qi gong and meditation are proven stress modification interventions that protect our body and brain as we age.   God bless and I'll be back for part two of this special overview on brain detoxification next week   Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez        

Summary   Today, I'll review the formulations and research that illustrates the role of medical foods which are a unique classification of formulations that are approved by the FDA.   Additionally, I will speak to the potential value of nutraceuticals and supplemental food-derived products in supporting cognitive health in aging individuals at risk for late-onset Alzheimer's disease (LOAD).   And what are medical foods?   Medical foods are defined products and nutrient formulations that are specifically designed for the dietary management of a disease. Medical food products are regulated by the FDA.   Plus, medical foods contain nutrients or food-based therapeutic ingredients that provide a medical or health benefit, and thus the use of "medical" in the term.   Three medical foods will be highlighted in today's episode that address three essential aspect of maintaining and optimizing cognitive function as you age—brain rejuvenation, brain protection (neuroprotection) and brain energetics (energy metabolism).   With regard to brain rejuvenation, the formulation—Souvenaid® (Fortasyn Connect), which is available in Australia where it is designated as a "Food for Special Medical Purpose", and it is also available in Singapore and parts of Europe.   Souvenaid® is a medical nutrition drink that contains a unique blend of ingredients known as Fortasyn® Connect, which is “formulated to support the growth of brain connections”, which means that it supports the synthesis of neuronal and synaptic membranes that are vital in synaptic function.   And that is an important point that I cover in The Diabetic Brain in Alzheimer's Disease.   The Souvenaid formulation includes omega 3 fatty acids (EPA, DHA), phospholipids, choline, selenium, vitamin E, vitamin C, B12 B6, folic acid and uridine.   Several studies and trials have evaluated the benefits of Souvenaid® and in a consensus opinion of those studies published in 2019 it was determined that there was improvement in memory and cognitive performance in patients with MCI and early Alzheimer's disease.   Nevertheless, it was also stated that “currently, there is not enough evidence to conclude that Souvenaid® decreases the rate of progression from MCI to dementia.”   However, you will often see if you do a search for that product that it is described by a few sources, including the Souvenaid website, that the formulation is suitable “for the early stages of Alzheimer's disease” which is often associated with MCI.   And here is why:   Several analyses and clinical trials have shown benefits in memory and cognitive performance in patients with MCI and early Alzheimer's disease as the 2019 consensus opinion analyses reported.   In the longest randomized clinical trial—3 years— in prodromal Alzheimer's or MCI due to Alzheimer's pathology—the LiPiDiDiet study, patients who were taking Souvenaid once daily for 3 years showed the following outcomes:   Slowed the progression of memory and cognitive decline by 60% Reduced brain shrinkage by 33% Reduced the loss of everyday task performance by 45%   The LiPiDiDiet study conclusions were:   “This multi-nutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long‐term use.”   Those findings were published in January of 2021.   The ingredient profile Souvenaid® formulation is designed for the rejuvenation of the critical membranes that surround the neuron which are particularly beneficial in the function of the synapse.   Neuronal cellular membrane integrity is vital for the myriad of synaptic signaling trafficking mechanisms that underlie synaptic plasticity.   And that is what Souvenaid® is designed to do—to enhance the formation and function of synapses that are a critical juncture in the communication and transmission between neurons that are central to learning and memory formation.   I decided to talk about this formula to emphasize the ingredients and what their combined benefits can do for nourishing and rejuvenation critical brain synapses.   Please listen into this episode to hear a my overview on the benefits associated with the Souvenaid ® ingredients.   the second formulation— CerefolinNAC®, which like Souvenaid, is composed of two key ingredients L-methylfolate—a bioactive folate, and N-acetyl cysteine.   The formula caplet contains L-methylfolate (Metafolin®), Algae-S Powder (Schizochytrium), 2 mg of Methylcobalamin and 600 mg of N-Acetyl-L-Cysteine. (N-acetylcysteine)   CerefolinNAC® is a prescription medical food “ formulated to meet the distinctive nutritional requirements of patients with a type of memory loss called mild cognitive impairment (MCI).”   CerefolinNAC® is “formulated to meet the distinctive nutritional requirements of patients with a type of memory loss called mild cognitive impairment (MCI).”   MCI is considered to be a prodromal stage that may convert to LOAD. Not all individuals with MCI progress to LOAD.   CerefolinNAC® provides a bioactive form of folate—methylfolate and methylcobalamin which is a form of B12 that also functions as a methyl donor and is a like folate, a critical nutrient for supporting healthy methylation pathways that includes an efficient metabolism of homocysteine.   How important are these B vitamins in cognitive health in aging individuals?   Several studies have shown that elevated homocysteine levels are associated with increased brain atrophy, and B vitamin therapy lowers aberrant levels homocysteine—a potentially toxic molecule that is linked to a decrease in brain grey matter which is referred to as brain shrinkage or atrophy.   The CerefolinNAC® ingredients are also beneficial for aging individuals at risk, or who have been diagnosed with cardiovascular disease which makes CerefolinNAC®  cardio-and neuroprotective.   Listen in to hear the rest of the CerefolinNAC® ingredients story.   The last medical food overview I cover in this episode is Axona.   Axona is a prescription medical food containing a proprietary formulation of medium chain triglycerides (MCTs).   MCTs are derived from coconut and palm kernel oils and there are four that are commonly designated in the family of MCTs— caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12).   Axona is primarily composed of caprylic acid or C8, which is also referred to as octanoic acid.   Research shows the MCTs and particularly C8 and C10 can fulfill a critical need for an energy substrate for the aging brain.   MCTs are metabolized to a ketone body—beta-hydroxybutyrate (BHB) in the liver, which provides cells and neurons with an alternative energy source to glucose.   I cover this in depth in my book, The Diabetic Brain in Alzheimer's Disease, along with the importance of ketogenic, intermittent fasting and caloric restriction diet therapy that supports and protects mitochondrial energy metabolism in the brain.   In today's episode I also briefly share about my favorite nutrients and extracts supplements that are based on a considerable amount of research with regard to benefiting heart and brain health.   Remember, anything that is good for your cardiovascular health is also very good for brain.   The importance of a healthy heart-brain axis cannot be overemphasized. The same holds true for the gut-brain axis.   Here is an overview of my favorite polyphenol, carotenoid and sulforaphane supplements.   First, my highly recommended polyphenol extracts available in many supplemental products include many resveratrol extracts, fisetin, grape seed extract, curcumin, genistein, EGCg (Epigallocatechin gallate), luteolin, found in celery and other vegetables, and quercetin.   Carotenoid supplements include astaxanthin—found in krill oil products, and lycopene, zeaxanthin and lutein.   A study published in May of this year (2022) found that people with the highest levels of the antioxidants—lutein and zeaxanthin and beta-cryptoxanthin (a carotenoid found in oranges, tangerines, mangoes, papaya, and peaches) in their blood were less likely to develop dementia decades later than people with lower levels of these antioxidants.   Another recent study (June 2022) determined while men and women eat about the same amount of carotenoids, that the requirements for carotenoids such as lutein and zeaxanthin in women are much higher, due to their increased vulnerability to macular degeneration and LOAD.   Another aspect of that vulnerability in women and increased need to more carotenoid intake is they store of these fat-soluble carotenoids in their body fat which makes them less available to the brain.   Lastly, sulforaphane which in supplemental form is usually derived from broccoli seed or sprouts is one of the most powerful phytochemicals available in a supplement.   Sulforaphane-rich foods include cruciferous vegetables such as kale, spinach and chard, and in broccoli, brussels sprouts, cabbage and other vegetables.   Please listen in to my last episode #14 for a more comprehensive overview on food-derived polyphenols, carotenoids and sulforaphane that are abundant in the Mediterranean, MIND and Improved MIND Diet.   The polyphenols, carotenoids and sulforaphane found in foods and available as supplements that not only provide antioxidant and anti-inflammatory cardio- and neuroprotection, they also stimulate:   neurogenesis, supports synaptic plasticity, improves cerebral blood flow, decreases beta-amyloid aggregation and their neurotoxic effects and supports their degradation (autophagy) and clearance, support metabolic health, selectively function as phytoestrogens and promotes longevity.   Ant the same benefits are associated with many vitamins and other nutrients such as B vitamins, glutathione and NAC that I covered here today, and vitamin D, C and E, CoQ10, alpha-lipoic acid and many others.   Now, for the most part I've covered in the ingredient-associated benefits of the medical foods and supplements which are an essential component of the cornerstones which I incorporate into my BrainDefend® body-brain health and renewal program—Protect, Rejuvenate and Energize.   A reminder to make sure your supplement is a product that's made by a good manufacturer, and one that features proprietary extracts which often includes a delivery system technology to facilitate their absorption.   Several studies and analyses over the past years have demonstrated that supplements bought on Amazon have been found to have labels that don't match contents, meaning that the ingredient levels are either non-existent of far below what the label states.   Please visit TheAlzheimer'sSolution.com or www.BrainDefend.com if you have a chance to learn more about my book and programs.   Sincerely, Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez

Summary In today's episode (#14), I'll be providing an in depth overview one of the most powerful factors that underlies healthy body and brain aging—DIET! Indeed, healthy foods provide key nutrients and phytochemicals work to optimize cognitive function, and protect against dementia and Alzheimer's in aging. However, since dietary therapies and specific foods in those diets that are linked to healthy aging is such a huge field of research, I'll be focusing on a particular diet that has become a meaningful food template for the preservation and enhancement of brain health—The MIND Diet. Similarly, other studies have examined the benefits of other diets such as Japanese diet and the DASH diet in the reduction of risk for dementia and Alzheimer's. In today's review of these diets, I'll also be referencing my version of The MIND Diet—The Improved MIND Diet, and of course, what distinguishes The Improved MIND Diet from all the other brain health and brain-saving diets. Now, what is so compelling about the research that underlies why these diets are so effective in many promoting a health body and brain in aging? After all, generations of moms and dads since Hippocrates espoused that “Food is Medicine”, have doggedly sought ways to get children into the habit of eating your vegetables for a healthy body and brain. Yes, we hopefully have all been coached to stick as many vegetables and fruits into out diets to optimize health and prevent common age-related diseases such as such as cardiovascular disease (CVD) and type 2 diabetes (T2D). However, the general public has little awareness of the marvelous body of evidence that points to a host of phytochemicals in fruits, vegetables and other foods that function as powerful activators of longevity wellness and a well-nourished brain that it takes for us to enjoy that ride. The research on the phytochemicals and particularly polyphenols and carotenoids abundant in those foods has become one of the most intense areas of study with regard to epigenetics, longevity medicine and in the prevention of many age-related diseases. Now a brief description of the MIND Diet In 2015 I ran across a report on the MIND Diet that incorporated two well recognized dietary models in their studies—the Mediterranean diet (MeDi) and the DASH diet, and the remarkable outcome in lowering the risk for Alzheimer's disease. Dr. Martha Clare Morris-a nutritional epidemiologist at the Rush University Medical Center, and colleagues, were the authors of two studies that examined The MIND Diet food template compared to the foods specific to the MeDi and the DASH diet. The MIND Diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) concept was derived from the research that had demonstrated a protective benefit from both the Mediterranean diet and the DASH diet against dementia and Alzheimer's disease. Thus, two MIND diet studies were initiated to determine if a hybrid MIND dietary pattern could be proven to ward of cognitive decline and Alzheimer's disease. What separated the MIND Diet from their Mediterranean and DASH diet models was a modification of the MIND Diet foods that were used in the studies. The MIND diet modifications included an emphasis on leafy greens and berries to “highlight the foods and nutrients shown through the scientific literature to be associated with dementia prevention.” Why leafy greens? The choice of leafy greens was based on previous studies that revealed a lower rate of cognitive decline in study participants that consumed greater amounts of leafy greens over a variety of vegetables. In addition, the study authors remarked that: “Green leafy vegetables are sources of folate, vitamin E, carotenoids and flavonoids—a sub-class of polyphenols—critical nutrients that have been related to lower risk of dementia and cognitive decline.” Main takeaways from The MIND Diet research. The first MIND Diet study showed that it “substantially slows cognitive decline with age.” More importantly, the second study concluded with two major outcomes: First, of the three diets—MeDi, DASH and MIND, The MIND Diet was shown to be the most beneficial for preventing cognitive decline and Alzheimer's. A greater adherence to The MIND Diet resulted in a 53% risk reduction of risk for Alzheimer's which was only slightly better than the MeDi. (12). However, there was also a 54% reduction of risk with a high adherence to the Mediterranean diet. Secondly, a moderate adherence to the Mind Diet also produced a significant risk reduction—35%, for AD, whereas moderate adherence to the Mediterranean and DASH diets did not have statistically significant risk reduction benefits. Lastly, The Improved MIND Diet emphasizes a personalized diet and nutrition analysis, and a tailored diet that best fits a personalized approach to your specific metabolic, genomic, and biochemical individuality. And as promised in this episode, here is how you can request a copy of chapter 1 of The Improved MIND Diet which includes some mindful recipes. Please go to TheAlzheimersSolution.com/improved-mind-diet-bonus and enter your contact information. You'll receive an email confirmation and instructions on how to download your bonus copy of chapter. Note, that you can learn about my BrainDefend® Body-Brain Renewal Program at BrainDefend.com and TheAlzheimersSolution.com. Thanks for reading and listening in if you have a chance! Sincerely, Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez  

Summary Today I am very much looking forward to pod-talking about one of the most important components associated with accelerated aging processes, and in the risk for Alzheimer's disease— the decline and inhibition of critical energy metabolism systems of the body and brain.   Many studies have shown that alterations in mitochondrial energy metabolism, or bioenergetics, have been linked to numerous disorders that disrupt normal metabolism, and it is a factor in brain aging and a number of neurodegenerative diseases such as Alzheimer's.   Aging is associated with progressive mitochondrial dysfunction and deficits of ATP, which underlies “The Mitochondrial Basis of Aging” hypothesis.   Now the role of mitochondrial function in biological aging and brain health is indeed vast, so I'll keep the focus in this podcast on two key components of brain energy metabolism, or neuroenergetics—dysfunctional glucose metabolism and insulin resistance, and a few key risk factors that can increase the risk for both.   Now, in brain energy metabolism, glucose is the most readily available fuel for youthful energy metabolism is glucose.   However, in the aging brain there is often a progressive decline in glucose utilization and brain energy metabolism, or glucose hypometabolism, which is a known risk factor for cognitive decline and impairment.   “The decline in brain energy metabolism distinguished by glucose hypometabolism and mitochondrial dysfunction are a significant set of related risk factors that are now viewed as early metabolic antecedents that set the stage for the development of late-onset Alzheimer's disease (LOAD).”   And, “Without the capacity to burn fuel for energy metabolism, an energy crisis is set forth in the neuron that gradually erodes our cognitive performance and sets the stage for the onset of late-onset Alzheimer's disease (LOAD).” Many studies have demonstrated that impairments in cerebral glucose metabolism and glucose hypometabolism to be a specific correlate to the cognitive dysfunction in the early stages of mild cognitive impairment (MCI), and to the eventual development of LOAD.   Plus, studies have surmised that evaluations that show a reduction in cerebral glucose utilization can accurately predict future cognitive decline in normal individuals as well as the conversion to mild cognitive impairment.   Now, a set of risk factors associated with aging are particularly notable in the risk for impaired glucose metabolism in the brain and the risk for cognitive impairment and dementia.   Atherosclerosis, Brain insulin resistance, The ApoE4 genetic variant, and Estrogen deficits in women   Lastly, I want to emphasize the role oxidative stress (OS)  with regard to mitochondrial function.   In the body and brain, OS is the result of environmental exposures and endogenous production of free radicals from mitochondrial energy metabolism.   Oxygen is required for mitochondrial ATP production and it is a major source of reactive chemicals that are potentially very damaging molecules.   And, an environment of OS is created when there is not an adequate reserve or supply of antioxidants such as glutathione that neutralize damaging oxygen based free radicals that are termed—reactive oxygen species (ROS).   An excess of  ROS and the induction of oxidative stress damages cells and their DNA and can lead to cell death.   Case in point, in brain glucose hypometabolism and the mitochondrial dysfunction associated with it, excessive oxygen radicals are generated which overwhelm the normal antioxidant resources of the mitochondria and brain cells.   Not to be overlooked in all of this is the fact that there are a host of laboratory-based biomarker assessments that are easily accessed, and those assessments can guide an early intervention and risk reduction strategy.   Please listen in to the full story on the role of “Glucose Hypometabolism, Impairments in Mitochondrial Function, and Oxidative Stress as Major Risk Factors for Alzheimer's Disease”.   Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez

Summary This episode (#12) continues the overview of neurosteroids and their critical function in the protection and enhancement of cognitive function. In episode #11, I reviewed the role of “Testosterone, Progesterone and Allopregnanolone—Critical and Timely Neurosteroid Interventions in the Risk Reduction of Alzheimer's Disease.”, and this podcast will add DHEA and pregnenolone to that overview. The focus today will center around the pressing fact that the declines of steroid hormones such as DHEA and pregnenolone have pronounced effects on brain and longevity wellness. DHEA, pregnenolone, estrogen and progesterone and other hormones in anti-aging therapies has long been sought after by people striving for an increased quality of life and the enhancement of a more youthful vitality. Additionally, age-related decline of DHEA, and abnormal cortisol levels, have long been associated with and increased risk for numerous health disorders including insulin resistance and type 2 diabetes, obesity, osteoporosis, cardiovascular disease, hypertension, depression, and cognitive decline and dementia. Plus, in the brain chronic stress and excess cortisol patterns is linked to the demise of newly formed brain cells and the inhibition of a critical phenomenon associated with it—neurogenesis, in a key learning and memory center—the hippocampus. The inhibition of neurogenesis (the generation of new brain cells) by excess cortisol is a significant risk associated with brain and hippocampal shrinkage, and the depression and dementia associated with prolonged stress patterns. On the other hand, low cortisol in aging individuals is linked to memory problems and depression as normal cortisol function in the brain is in fact required for cortisol activation of glucocorticoid receptors and memory acquisition and consolidation. Optimizing pathways that promote neurogenesis and neuroplasticity as we age is vital to longevity wellness and healthy cognitive function. The generation and development of new nerve cells such as neurons in the brain, or neurogenesis, occurs throughout one's lifetime and is perhaps the most critical phenomenon associated with modifying the risk for cognitive decline and dementia in aging. Many studies have shown that higher levels of neurosteroids such as DHEA, and allopregnanolone that is metabolized from progesterone and pregenenolone, induce neurogenesis and are protective against memory decline associated with normal aging and Alzheimer's disease. In this episode I also describe the role of DHEA and pregnenolone in modulating key synaptic receptors—NMDA, AMPA and GABA, which is a key dynamic in modulating calcium-related excitotoxicity. Excitotoxicity is a hallmark pathological insult linked to the progression of Alzheimer's disease. DHEA, pregnenolone and their sulfated forms—DHEAS and Pregnenolone sulfate (PREGS), are protective factors against excitotoxic events. Both DHEA and pregnenolone and their derivatives also provide anti-inflammatory and antioxidant protection and counter beta-amyloid induced neurotoxicity. There is more so please listen in to get the rest of this essential overview on neuroteroids in longevity wellness and the protection against cognitive decline and the risk for dementia. God bless! Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez  

In women, how important of a role does progesterone play in cognitive function? While a number of studies have shown that estrogen replacement therapy in women is protective against the risk for late-onset Alzheimer's disease (LOAD), only a few studies have demonstrated that progesterone also benefits cognitive function. Indeed, progesterone could be important in preserving cognitive function in women as they age—particularly in the menopausal transition when there is a precipitous drop in progesterone. Studies that investigated the protective role of hormone replacement therapy (HRT) in the potential prevention of LOAD have theorized that there is a "critical window" of opportunity for HRT in women. Research has demonstrated that early in menopause estrogen replacement therapy (ERT) may have a brain protective benefit, whereas ERT after 60 may increase the risk for LOAD. The same may hold true for progesterone replacement therapy. In 2021, a "University of Arizona Health Sciences study found women on hormone therapy were up to 58% less likely to develop neurodegenerative diseases including Alzheimer's disease, and reduction of risk varied by type and route of hormone therapy and duration of use." The study included estrogens and progestins and combination therapies on neurodegenerative diseases. Note that progestins are synthetically derived forms of progesterone. In fact, the study "found that using the natural steroids estradiol or progesterone resulted in greater risk reduction than the use of synthetic hormones." Not often included in the studies centered around the potential role of HRT in the risk reduction of LOAD, is the role of estrogen and progesterone metabolites. A key progesterone metabolite—allopregnanolone, is linked to the generation of new brain cells—neurogenesis. In a study published in 2020, allopregnanolone was determined to be  "a first in class regenerative therapeutic for early AD that targets endogenous neural stem cells and disease-modifying mechanisms." In adult neurogenesis, neural stem cells and progenitor cells are the neural precursor cells that give rise to new brain cells, including astrocytes, microglia, oligodendrocytes and neurons. The phenomenon of adult neurogenesis is a critical component to a healthy aging brain and the potential prevention of cognitive decline and impairment that marks the development of LOAD. Please listen in to today's episode and the continuing story on the role of hormones that are potentially a vital therapeutic intervention in both women and men at midlife.  

In the U.S., two-thirds of diagnosed cases of dementia and Alzheimer's disease are women. A number of studies have shown that lower estrogen levels "before, during, and after menopause" is a risk for late-onset Alzheimer's disease. However, the risk factors associated with declining estrogen levels and late-onset Alzheimer's disease in women as they age is not widely known. Estrogen is a regulator of glucose metabolism in women and brain estrogen deficiency sets in motion a brain energy metabolism crisis in women—particularly after menopause. A decline in estrogen in menopause is commensurate with a decline in cerebral glucose metabolism. Thus, the inability to efficiently metabolize glucose in the aging brain (glucose hypometabolism) predicates the need for an alternate fuel to sustain the brain's high demands for energy . The demand for an alternate mitochondrial fuel in low estrogen states results in a compensatory shift to ketone metabolism that is enabled by the metabolism of fats derived from myelin-a nerve sheath substance that wraps around the axon extension of nerves. That catabolism of myelin (grey matter demyelination) is a signature hallmark of grey matter atrophy and the loss of brain volume, which in turn is a pathological feature in the progression of Alzheimer's disease in the aging brain. Plus, female ApoE4 carriers may be at higher risk for glucose hypometabolism and an earlier onset of myelin breakdown. Additionally, ApoE4-related mitochondrial dysfunction is also linked to the development of late-onset Alzheimer's disease. Since "mitochondrial DNA is maternally inherited and mitochondrial defects that contribute to the risk for brain metabolic deficits that include glucose hypometabolism and oxidative stress is seen in adult offspring of mothers with a history of Alzheimer's.", optimizing mitochondrial function in the aging brain is of critical importance—particularly in ApoE4 carriers. Please listen in to episode # 10 for more on this vital association between estrogen deficiency and the increased risk for of late-onset Alzheimer's disease in women.   Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution  https://www.linkedin.com/in/ralph-sanchez  https://www.instagram.com/alzheimers_solution  https://twitter.com/RalphSanchez   

The Gut-Brain Axis—what does that connection represent? Well, the gut-brain connection is often described as a bidirectional highway that is linked to many cause and effect health consequences, and many studies have explored the impact of the gut environment and microbiome on brain health in that gut-brain dynamic. Indeed, the role of the gut-brain axis is a significant factor in the risk for numerous health disorders throughout life, and it can have substantial implications on your body-brain health as you age. For example, numerous studies have examined the role of gut health and disorders such as small intestine bacterial overgrowth (SIBO) and inflammatory bowel disease (IBD), and their consequences on brain health that includes mood and mental health disorders. Additionally, significant research that links SIBO and pro-inflammatory disorders such IBD in the risk for cognitive decline and dementia has been accruing now for well over two decades and I have been following that science since the 1990s and to this very day. In today's podcast, I'll be sharing about the findings of a few studies that investigated aspects of the gut-brain axis with regard to the risk for cognitive decline and dementia in aging. On such study, a substudy of CARDIA titled Association of the Gut Microbiota With Cognitive Function in Midlife, it was determined that " gut microbial community composition, was significantly associated with cognitive scores in an analysis of middle-age CARDIA participants," The parent CARDIA study (Coronary Artery Risk Development in Young Adults), was initiated in 1985-86 for the purpose of “examining the development and determinants of clinical and subclinical cardiovascular disease and their risk factors.”, from young adulthood into middle age. Since its inception, the CARDIA study has investigated the role of several risk factors that affect cognition and brain health in aging including cardiometabolic disease (diabetes, heart disease, obesity) which is highly associated with an increased risk for dementia and Alzheimer's disease in aging. There are two main findings that I focus on in this podcast with regard to the CARDIA substudy (Association of the Gut Microbiota With Cognitive Function in Midlife) that were significant modifiers of the gut-brain axis and cognitive performance... a gut bacteria associated with SIBO and cognitive performance and, short chain fatty acids (SCFAs) which are beneficial metabolites produced by healthy fermentation of resistant starches—a fiber that functions as a prebiotic. I also briefly review the findings of a few studies on the neuroprotective benefit of several probiotic strains and probiotic therapy in modifying the risk for type 2 diabetes and late-onset Alzheimer's disease. Please listen in to hear the rest of the gut-brain axis story! Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

Today in episode # 8 I'll be reviewing the role of hypertension, obesity, type 2 diabetes and heart disease (cardiometabolic disease), and insulin resistance in your risk for late onset Alzheimer's disease. The metabolic and biochemical pathways by which cardiometabolic disease increases the risk for dementia and Alzheimer's later life is the central theme in my book: The Diabetic Brain in Alzheimer's Disease. The book thoroughly describes how and why the most prevalent age-related disorders of our time, put your brain and you at great risk for either vascular dementia, type 3 diabetes and Alzheimer's disease in later life. The podcast provides an audio summary on how obesity and cardiometabolic disease drive pro-inflammatory pathways and insulin resistance in the body and brain. and subsequently increase the risk for late-onset Alzheimer's disease. Plus, I'll also provide an overview about a couple of very important biomarkers risk factors—hemoglobin A1c and advanced glycation end-products (AGEs)— that are prime risk factors for not only diabetes and heart disease, but also for cognitive decline, dementia and Alzheimer's disease. Hemoglobin A1c and fasting glucose are biomarkers that are easily and widely available on blood tests and these biomarkers and many others should be carefully tracked as one ages—particularly if there is a family history of cardiometabolic disease, dementia or late-onset Alzheimer's disease. Please listen in! Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

How does you unique genome increase the risk for Alzheimer's disease as you age? In todays episode—#7, I'll be giving a comprehensive overview on the APOE gene, the ApoE4 genetic variant, and other genes and their genetic variants linked to the risk for late-onset Alzheimer's Disease (LOAD), and how, when, and why Alzheimer's takes root in certain individuals that are carriers of these genes and the variants associated with them. While the ApoE4 genetic risk variant is widely recognized as a risk factor for LOAD, how ApoE4 contributes to the risk for Alzheimer's is not as so well recognized by most individuals. Indeed, the ApoE4 genetic variant is often highlighted as the most significant risk factor for LOAD, but how often have you run across the reasons why ApoE4 raises your risk for LOAD, and how other genetic variants may similarly and synergistically increase the risk for LOAD? Yes, many other risk variants add to the polygenic (more than one gene) disease profile of LOAD. The known functional and structural vulnerabilities linked to the ApoE4 variant are multifaceted, and I describe these functional and structural abnormalities that are linked to ApoE4 in my book, "The Diabetic Brain in Alzheimer's Disease". However, since the mechanisms that underly the link between ApoE4 in LOAD are a vast topic, I focus on two key points—cholesterol and fat binding and transport, and beta-amyloid deposition and clearance from the brain. ApoE4, APOJ, ABCA1 and ABCA7, and TREM2 variants greatly determine how these two key mechanisms—cholesterol and beta-amyloid metabolism are factored into the risk for LOAD. Additionally, I briefly describe another very common variant—MTHFR 677T, that is a critical risk variant in methylation and homocysteine metabolism—yet another pathway that links the importance of the heart-brain axis in the risk for Alzheimer's disease. Please listen in and get ready for about 35 minutes of a revealing overview on the genes and their variants that are widely available in genetic profiling tests, and are major risk factors in LOAD. Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

How early in your lifespan you can start to assess and track for specific biomarkers that are linked to the risk and earliest stages of late-onset Alzheimer's disease (LOAD), and have you given that much thought? In fact, there has been a significant shift in the progressive medical and research community over the last ten years in the understanding that you really have to start looking at your risk factors earlier in life….by midlife, because at midlife the brain damage associated with LOAD begins to hit a pivotal crisis point in terms of your risk for LOAD later in life—particularly if you are more susceptible to the disease. Now, I've talked about this in my book, and my articles and my social media posts many times as Alzheimer's disease has a long stage of development, and the prevailing wisdom over these last few years has been that it has a timeline of 20 to 30 years or so where it develops. And, bear in mind, it is a silent disorder in the asymptomatic stage of LOAD—the preclinical stage, which might have its roots in cardiometabolic disease (type 2 diabetes/cardiovascular disease). Case in point, the findings of a recently published study—an offspring study of the Framingham Heart Study, revealed that: “These findings show for the first time that cardiovascular risk factors, including HDL which has not been consistently reported as a strong risk factor in Alzheimer's disease, contribute to the risk of Alzheimer's disease starting as early as age 35.” (Dr. Zhang) Undoubtedly, if you have a family history of cardiometabolic disease, or dementia, you may want to start looking at these risk factors to gain an understanding of where you might stand in relation to your risk for a dementia and Alzheimer's disease later in life. Please listen to the podcast to get the rest of the story! Ralph Sanchez, MTCM, CNS, D.Hom. www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

In the fifth episode of The Alzheimer's Solutions Revolution podcast with Ralph Sanchez, I talk with my co-host Susan Brender, as we continue with our special podcast series called Think Ahead. In this week's episode, I'll provide an overview on the role of tau protein and neurofibrillary tangles (tau tangles) in the progression and development of late-onset Alzheimer's disease (LOAD). The toxic accumulation of tau tangles in brain cells (neurons) are one of the two hallmark lesions associated with Alzheimer's disease (AD). The aggregation of beta-amyloid peptides (protein) into amyloid plaque is the other toxic hallmark lesion linked to the onset and progression of LOAD. Additionally, I'll give an a summary on the importance that tau protein plays in a critical component in the conveyance network and cytoskeletal structure that is an essential element of neuronal function and structure. The cytoskeletal conveyance structure of the neuron contributes to the shuttling of mitochondria to the neurons axonal terminal and synapse in order to provide the energy metabolism required for synaptic function. Please listen in and be informed! Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

In this Alzheimer's Solution Revolution episode #4, I'll give an overview of episode #3, and I'll provide several key insights about a protein that is associated with the pathology of Alzheimer's disease—beta-amyloid protein, which forms the proverbial amyloid plaque that is often cited as a principal lesion of the disease process. Additionally, in this Think Ahead podcast, I pick up where we left off on the last episode (#3) with regard to the genesis of Alzheimer's, disease in the brain, and the role of beta-amyloid protein aggregates in the progression of Alzheimer's disease in aging. I illustrate how the disease process can progress from the preclinical stage (asymptomatic) to a mild cognitive impairment stage, and eventually a diagnosis of a dementia associated with Alzheimer's disease, Please listen in to continue learning how amyloid precursor protein is processed to produce beta-amyloid protein particles and aggregates, which underlies the earliest stage (preclinical) of the Alzheimer's disease continuum that can span decades before an eventual diagnosis of dementia. Lastly, we touch on the role of the APOE gene and the ApoE4 variant—the most validated late-onset Alzheimer's disease genetic risk variant— with regard to beta-amyloid accumulation in the brain, and how research has significantly progressed over the years to illuminate how we can leverage these new findings to reduce the risk for late-onset Alzheimer's disease. We end with what to anticipate in an additional podcast coming soon in the Think Ahead series—the role of tau protein and neurofibrillary tangles in Alzheimer's disease. Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

In this 3rd episode of The Alzheimer's Solutions Revolution Podcast, I, Ralph Sanchez, talk with my good friend and co-host Susan Brender, as we begin this special podcast series designated as the Think Ahead podcast series. In the Think Ahead series, which will be published here over the coming weeks, I'll provide an extensive overview on the numerous risk factors associated with late-onset Alzheimer's disease (LOAD), and I expand on the research that sheds light on how you can modify and reduce your risk for LOAD and dementia as you age. In the first Think Ahead episode, I lay down the foundation for understanding the genesis and difference between early onset Alzheimer's disease (EOAD) and LOAD, and the science-based findings that illuminates the association between many risk factors—including genes and genetic variants, that are linked to Alzheimer's disease. Additionally, I'll begin the overview on the hallmark protein-based lesions (amyloid plaques and neurofibrillary tangles) that are associated with Alzheimer's is discussed. More on that topic to come in subsequent Think Ahead podcasts here at The Alzheimer's Solution Revolution podcast channel. Please, listen and empower yourself with a basic understanding of the early stages of EOAD and LOAD that includes the genetic determinants and genetic risk factors for each, and the stages of the disease process that leads to cognitive impairment and dementia in aging.

Should you supplement with a basic MVM to sustain a healthy brain in aging? Has any physician or practitioner emphasized just how important a MVM supplement might be for your brain and heart as you get older? Well, as promised on my welcome episode last week, I'll be expanding on a study and recent research with regard to the supplementation with vitamins, minerals and certain nutrients found in foods, and it's role in the heart-brain axis in this episode of The Alzheimer's Solution Revolution Podcast. The study that I will be referring to today looked at the potential benefits of a cocoa extract and a multivitamin-mineral supplement (MVM) together, and separately vs. combinations of the two and a vs placebo on Global Cognitive Function which was measured by a composite global functioning score—cognitive assessments that are commonly used in trials and clinical settings to assess cognitive function. The outcome? "Taking a daily multivitamin (MVM) for 3 years is associated with a 60% slowing of cognitive aging, with the effects especially pronounced in patients with cardiovascular (CVD) disease,." The MVM benefit on cognition peaked at 2 years and remained stable over time and included significant improvement measures of memory composite score and executive function. Surprisingly o beneficial effect was linked to the intake of cocoa flavanols—a plant chemical which part of the larger polyphenol phytochemical family— over the 3 year study period. However, there is much more to the story regarding the potential role of flavanols and many other polyphenols and I cover that in detail in this episode that includes how vitamins, minerals and polyphenols benefit and optimize cognitive function and protect it against the onset of dementia in aging. Listen in as I dive into all the juicy details! Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution

Welcome! Indeed, this is the inaugural episode of the The Alzheimer's Solution Revolution Podcast! This is your host. Ralph Sanchez, and I am grateful that you are reading and/or listening in to what this podcast will bringing to you on a weekly basis. The purpose of this welcome edition is to share a little about me and my experience and background in health care and medicine that emphasized a progressive paradigm and model of healthcare termed functional medicine. Essentially, the overall scope of this podcast will to bring you cutting edge information on how you can enhance your wellness, your brain health, and your wellness longevity—your healthspan. Now, the inspiration as well as for the inclusion of word "Revolution" in my podcast title stems from the fact that over the the past 20 plus years, proposed solutions to the Alzheimer's pandemic have gone from none to many studies and experts in the field now advocating prevention measures for dementia and late-onset Alzheimer's disease that must begin earlier in life. I'll be expanding on all of this over the next few weeks in order to lay a foundation for this podcast and the type of information I will be sharing and talking about, and then I'll have guests that on the show that bring a unique set of skills, resources, and experience for you to benefit from. So please, look for me wherever you enjoy looking for and listening to your favorite podcasts, and you can learn more about me and my mission in my book, and my brain health program—BrainDefend, at my website—www.TheAlzheimersSolution.com or at www.BrainDefend.com Lastly a review at Apple or Google podcasts or wherever you go to search for podcast would be very much appreciated and if you subscribe to this podcast, you'll be sure to be automatically alerted about the newest edition of the podcast when it's released. Thank you for stopping by and listening and I can't wait to be back next week to continue this Alzheimer's Solution Revolution podcast journey with you! God bless...Ralph Sanchez, MTCM, CNS, D.Hom www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution https://www.linkedin.com/in/ralph-sanchez https://www.instagram.com/alzheimers_solution