This episode (#12) continues the overview of neurosteroids and their critical function in the protection and enhancement of cognitive function.

In the previous 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 I’ll add cortisol—a glucocorticoid, pregnenolone and more on DHEA.

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 health and longevity wellness.

DHEA, pregnenolone, estrogen and progesterone, and other hormones in anti-aging centered 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 (e.g., cortisol receptors) and memory acquisition and consolidation.

Optimizing pathways that promote neurogenesis and neuroplasticity as we age is vital to healthy cognitive function and longevity wellness.

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 which 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.

In the central nervous system, excitotoxicity is a neurological insult linked to brain injury and 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 cortisol and neuroteroids in longevity wellness and the protection against cognitive decline and the risk for dementia.

• DHEA is the most abundant peripheral steroid hormone, and its central nervous system concentrations exceed peripheral levels; DHEA exerts a critical neuroactive role in synaptic function, brain plasticity, and the subsequent long-term preservation of cognitive function.

• The age-related decline in DHEA and pregnenolone—both parent hormones situated at the apex of the steroid hormone cascade—disrupts downstream metabolic conversion into estrogen, testosterone, progesterone, and allopregnanolone, thereby impairing neurogenesis and the potential resilience against Alzheimer’s-related neurodegeneration.

• The DHEA-to-cortisol ratio functions as a central biomarker of hypothalamic–pituitary–adrenal (HPA) axis integrity, with deviations in either direction indicating maladaptive stress physiology that accelerates the risk for insulin resistance, sarcopenia, cardiovascular disease, depression, dementia and late-onset Alzheimer’s disease (LOAD).

• Chronic cortisol elevations or stress-related adrenal exhaustion states (adrenal fatigue)—alters cortisol receptor (glucocorticoid receptor) signaling in the hippocampus—suppressing adult hippocampal neurogenesis, impairing memory consolidation, and promoting neuroinflammatory cascades associated with LOAD.

• Pregnenolone sulfate and DHEA sulfate (DHEAS) modulate NMDA and AMPA receptor-regulated calcium flux; dysregulation of this NMDA/AMPA-mediated calcium influx into neurons results in a calcium overload and excitotoxic cascades—a core feature in Alzheimer’s disease neuropathology.

• The GABA neurotransmitter/receptor complex acts as a counter-regulatory inhibitory mechanism to excititory neurotransmitter (glutamate) receptor activation; pregnenolone sulfate (PREGS) and DHEAS modulate GABA receptor activity (GABAergic tone) to maintain a balanced excitatory–inhibitory environment essential for synaptic homeostasis and cognitive resilience.

• Neurosteroid declines associated with stress and aging increases the neuronal susceptibility to beta-amyloid-mediated calcium dysregulation, and the downstream oxidative and pro-nflammatory injury to neurons.

• DHEA, pregnenolone, and their sulfated derivatives (DHEAS and PREGS) provide direct antioxidant and anti-inflammatory effects within neuronal environments, which buffers against chronic “inflammaging” processes that synergize with cortisol dysregulation to accelerate neurodegeneration.

• Neuroplasticity involves NMDA- and AMPA-dependent receptor cascades that regulate information encoding, memory formation and consolidation; neurosteroids act as modulators of these memory and learning cascades and thereby influence the capacity for optimizing a cognitive reserve across a lifespan.

• Adult hippocampal neurogenesis (AHN) persists throughout life, and neurosteroids—particularly DHEA, pregnenolone, and allopregnanolone—augment stem-cell proliferation, progenitor-cell differentiation which are essential steps in neurogenesis, and the maintenance of brain structure-function integrity that supports brain and cognitive resilience and reserve.

• Brain reserve and cognitive resilience and reserve are directly shaped by lifelong neurogenesis—a phenomenon mediated by neurosteroids and neurotrophic signaling pathways such as BDNF and nerve growth factor.

• The Nun Study findings illustrate that individuals may harbor extensive beta-amyloid and tau pathology, yet remain cognitively intact, reinforcing the protective role of sustained neurogenesis throughout life.

• Neurosteroid synthesis declines with aging and in part are driven by chronic stress, and pro-inflammatory age-related diseases, thus, neurosteroid biomarker assessments serve as essential evaluations in individuals vulnerable to cognitive decline and late-onset Alzheimer’s disease.

Epidsode 12

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

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www.linkedin.com/in/ralph-sanchez

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Welcome once again!

This is you host Ralph Sanchez and this is episode #11 here at The Alzheimer’s Solution Revolution podcast channel.

This episode will also correspond to #7 in a series—the Think Ahead podcast series.

A reminder that the Think Ahead is a 10-episode series that will be available to download after we have completed their publication here on this channel.

Today, I’ll continue with Susan Brender—a co-host who participated in many of these Think Ahead episodes that were produced a couple of years ago, and we’ll be talking more about hormones to continue where we left off in episode # 10.

In that last episode titled, “Why Low Estrogen Levels in Women is Linked to an Increased Risk for Alzheimer’s Disease”, we discussed a few salient points about the role of estrogen in aging women and the risk for Alzheimer’s disease—particularly with regard to glucose metabolism and estrogen’s function as a neuroprotective hormone—two very important points about estrogen in women’s brain health and brain aging.

And in this episode—#11, I’ll sharing a little more about estrogen metabolism and will also add some vital information about the role of progesterone in brain health, and a brief review of a progesterone metabolite—allopregnanolone.

Plus, we’ll do a brief overview of testosterone and DHEA which are also critical neurosteroids in aging individuals.

Neurosteroids are steroids or steroid hormones that are synthesized in the brain and they are vital in cognitive function.

In fact, the decline of these neurosteroids in aging is linked to impairments in learning and memory function, and the risk for neurological diseases such as late-onset Alzheimer’s disease.

Now before we begin with Susan’s intro, a reminder and a disclaimer that all of the information I share here on this channel is meant for educational purposes only.

Please consult with a physician if you feel anything is going south with regard to your health OR your brain health. which may require a medical diagnosis, attention, or treatment.

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• Progesterone levels approach zero post-menopause, making it a pivotal hormone replacement option for maintaining mood, sleep regulation, and neuroprotection—factors strongly implicated in cognitive aging and in the risk late-onset Alzheimer’s disease (LOAD).

• Estrogen vs. Progesterone: While estrogen declines by 40–60%, progesterone nearly disappears. Clinical hormone replacement strategies should consider both the symptom profile and an individual’s unique metabolic landscape.

• Neurosteroids including progesterone, allopregnanolone, DHEA, pregnenolone, and testosterone, play essential roles in neuronal resilience, synaptic function, and cognitive integrity. Declines in these hormones in aging individuals are increasingly associated with pathophysiological mechanisms underlying Alzheimer’s disease.

• Allopregnanolone—major metabolite of oral progesterone may stimulate hippocampal neurogenesis and synaptic repair. This episode highlights allopregnanolone’s potential as a regenerative therapeutic candidate for mild cognitive impairment and LOAD.

• DHEA functions as a versatile prohormone; in women, it enhances androgenic and estrogenic pathways more efficiently than in men. Chronic stress–related DHEA depletion may contribute to cognitive decline.

• Testosterone therapy studies in men showed benefits in mood, cognition, and vitality. However, clinicians should monitor aromatization of testosterone into estrogen to prevent hormonal imbalance and unintended estrogenic side effects.

• Phytoestrogens such as genistein and daidzein (from soy and other plants) are briefly discussed. The capacity of phytoestrogens to modulate estrogen receptor signaling, reduce oxidative stress, and promote neuroprotection highlights their potential as therapeutic adjuncts in LOAD prevention.

• The adrenal stress assessment and the cortisol:DHEA ratio is clinically useful biomarker evaluation. Elevated cortisol with low DHEA indicates adrenal exhaustion which may provide insights regarding neurosteroid depletion and impaired cognitive function.

• Hormone metabolism—nutritional and supplemental strategies can modulate hormone metabolism toward neuroprotective and anti-carcinogenic pathways, and optimized both cognitive health and longevity.

• Fat issue (adipose) aromatization—peripheral conversion of testosterone and androstenedione to estrogen in adipose tissue affects both men and women; understanding this mechanism is essential for managing hormonal therapies in aging populations.

• Personalized monitoring and comprehensive lab evaluation with regard to neurosteroid therapies, adrenal function, and metabolic markers are a fundamental for safe and effective hormone replacement and cognitive protection strategies in patients at risk for LOAD.

Epidsode 11

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

www.facebook.com/TheAlzheimersSolution

www.linkedin.com/in/ralph-sanchez

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In the U.S., two-thirds of diagnosed cases of dementia and Alzheimer’s disease are women.

And, a number of studies have shown that lower estrogen levels “before, during, and after menopause” is a risk for late-onset Alzheimer’s disease (LOAD).

However, the risk factors associated with declining estrogen levels and late-onset Alzheimer’s disease (LOAD) in women as they age is not widely known.

One key bridge that connects declining estrogen levels in postmenopausal women in the risk for LOAD is mitochondrial energy metabolism deficits.

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 levels in postmenopausal women 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.

Additionally, female ApoE4 carriers may be at higher risk for glucose hypometabolism and an earlier onset of myelin breakdown.

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.

• Women and Alzheimer’s Risk: Approximately two-thirds of Alzheimer’s patients diagnosed after the age of 65 are women, therefore, the early intervention strategies for prevention earlier in life are critical.

• Estrogen’s Critical Role: Estrogen isn’t just a hormone; it’s a regulator of brain glucose metabolism and mitochondrial energy production.

• Energy Crisis in the Brain: Loss of estrogen triggers brain glucose hypometabolism which increases the risk for cognitive decline.

• ApoE4 + Low Estrogen = High Risk: Women carrying the ApoE4 gene variant face a compounded risk for Alzheimer’s.

• Estrogen as a Defender: Beyond hormone balance, estrogen acts as an antioxidant and activates protective enzymes like glutathione peroxidase.

• Phytoestrogens as Allies: Plant-based estrogens such as genistein can partially mimic estrogen’s protective effects and reduce oxidative stress.

• Hormone Therapy: Proceed with Caution: While beneficial for some, estrogen therapy carries cancer-related risks—bioidentical and natural options may be safer.

• Your Mother’s Mitochondria Matter: Mitochondrial DNA is inherited from mothers, influencing energy metabolism and Alzheimer’s risk.

• Midlife is Your Window of Opportunity: Interventions such as ketogenic diets, medium chain triglyceride (MCT) oil, and lifestyle changes at midlife protects against the risk for cognitive decline in later life.

• Pregnenolone and DHEA: Hormone replacement therapy can support brain health but must be under the expert supervision of a clinician.

• A healthy lifestyle, and diet that is abundant in antioxidant-rich foods are essential for reducing the risk for Alzheimer’s disease in the aging process.

Epidsode 10

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

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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 intestinal 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.

One 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 parent 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:

• gut bacteria associated with SIBO and it’s association with the risk for cognitive decline, and the therapeutic role of probiotic strains and therapy for cognitive health, 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 several probiotic strains and the neuroprotective benefit of 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!

* The Gut–Brain Axis: A bidirectional communication system with profound effects on cognition, mood, and neurological health.

• Lifelong Observance: The assessment and therapy of a gut microbiome health program is not a one-time effort; it requires a lifelong vigilance and support that shapes healthy aging and brain resilience.

• Gut Disorders & Cognitive Heath: Chronic conditions like small intestinal bacterial overgrowth (SIBO) and inflammatory bowel disease (IBD) drive systemic inflammation molecules, which contribute mightily to mood disorders, and the risk for cognitive decline, dementia, and Alzheimer’s disease.

• Microbiome Diversity Matters: A diverse microbial community supports brain health, while reduced diversity correlates with cognitive decline.

• Key Gut Microbial interventions: Akkermansia and other probiotics strengthen gut and blood brain barrier integrity; harmful species like Sutterella and Klebsiella promote inflammation and neurodegeneration.

• Barrier Integrity: A “leaky gut” combined with a compromised blood brain barrier allows gut endotoxins to fuel neuroinflammation cascades.

• The Infectious Theory of Alzheimer’s Disease: numerous studies implicate unhealthy gut bacteria and fungal microbes (e.g., Candida), and viral pathogens in neurodegenerative processes.

• Short-Chain Fatty Acids (SCFAs): Beneficial metabolites of resistant starches that enhance gut barrier function, brain energy metabolism, vascular health, and Brain Derived Neurotrophic Factor (BDNF) expression.

• Diet as a Lever: Fiber-rich, whole-food diets rich in resistant starches foster a brain-protective microbiome, while refined carbohydrates and high-sugar diets fuel dysbiosis, and the risk for vascular dementia and late-onset Alzheimer’s disease (LOAD).

• FODMAP (Fermentable, Oligo-saccharides, Di-saccharides, Mono-saccharides And Polyols) sensitivities: Not all fibers are tolerated equally; individual responses highlight the need for personalized dietary strategies.

• GV-971, a seaweed-derived prebiotic drug approved in China, showcases the significance of targeting gut-driven inflammation and gut derived amyloid in the risk for LOAD.

• Probiotics & Prebiotics: Both demonstrate neuroprotective benefits; resistant starches and probiotic strains such as Akkermansia and Lactobacillus plantarum are promising interventions for cognitive and metabolic health.

• Gut Health Signals: Symptoms like bloating, chronic digestive upset and bowel movement issues, fatigue, and brain fog may indicate a brewing dysbiosis and should not be ignored.

• Mind–Gut Connection: The microbiome influences not only cognition and memory, but also mood regulation, anxiety, and emotional health.

• Functional Health Testing: Advanced gut and metabolic tests can identify gut health and microbiome imbalances early, allowing for targeted interventions for gut and brain health.

• Actionable Steps: Prioritize a diverse, fiber-rich diet, consider targeted prebiotic and probiotic support, monitor gut health regularly, and seek professional guidance for individualized care.

Epidsode 9

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

www.facebook.com/TheAlzheimersSolution

www.linkedin.com/in/ralph-sanchez

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 (LOAD).

The metabolic 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 and 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.

And this episode provides a summary on how obesity and cardiometabolic disease drive pro-inflammatory pathways and insulin resistance in the body and brain. and subsequently increases the risk for LOAD.

Plus, I’ll also provide an overview about a couple of very important risk biomarkers—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, vascular dementia, and LOAD.

Laboratory assessments of those very biomarkers, and many others are critical risk factors that you and your physician can track and leverage for a proactive intervention and dementia risk reduction approach.

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 monitored as one ages—particularly if there is a family history of cardiometabolic disease, dementia, or late-onset Alzheimer’s disease.

Think ahead and please, do listen in to the podcast and read my book on the topic on the role of cardiometabolic disease, and the onset of brain insulin resistance and type 3 diabetes in late-onset Alzheimer’s disease.
 

• The brain damage associated with LOAD starts early in life—and the preclinical phase of Alzheimer’s (asymptomatic)—when damage is already occurring in the brain—begins decades before symptoms appear. That’s why early assessment and intervention strategies earlier in life is critical.

• For example, belly fat isn’t just excess fat—it is metabolically active and a source of inflammation. Chronic inflammation—driven by fat tissue and poor metabolic health—is a core driver of both heart disease and LOAD. Managing belly fat and diet is critical earlier in life.

• ApoE4, a common genetic risk variant for LOAD, significantly increases your risk for LOAD when chronic inflammation and poor metabolic health are concomitant risk factors—but diet and lifestyle interventions can significantly lower this risk even if you are an ApoE4 carrier.

• Hemoglobin A1c and fasting glucose are powerful and accessible biomarkers that reflect your metabolic health. Keeping A1c (a measure of glycation) below 5.5% can dramatically reduce the risk for cognitive decline as you age.

• Advanced glycation end products (AGEs) are toxic. AGEs derived from elevated blood sugar and high-temperature cooking of meats—increases the risk for vascular damage and cognitive decline.

• Metabolic health is vital for brain health. The biological glycation process and insulin resistance are not just diabetic concerns—they’re factors that disrupt the integrity of your cognitive performance and brain health. The disease process associated with LOAD includes many such metabolic derangements that drive the disease process.

• Midlife is a crucial window of time for taking control of your risk for LOAD. Taking proactive steps in midlife, including diet and lifestyle interventions, monitoring risk biomarkers, and optimizing metabolic health, can significantly reduce your risk for LOAD.

Epidsode 8

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

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How does your unique genome increase the risk for Alzheimer’s disease as you age?

In today’s episode—#7, I’ll be giving a comprehensive overview on the APOE gene, the ApoE4 genetic variant, and other genes and their genetic variants that are 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 underlie 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 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 they are major risk factors in late-onset Alzheimer’s disease.

• The ApoE genetic variant, ApoE4, is the most well-known genetic risk factor for late-onset Alzheimer’s disease (LOAD). However, LOAD is a polygenic (more than one gene) and several other genes and genetic variants such as Clusterin (APOJ), ABCA1, ABCA7, TREM2, and MTHFR 677T—also are associated with an increased risk for LOAD.

• Several unfavorable diet and lifestyle risk factors in turn affects how ApoE4 is expressed in terms of cholesterol, glucose, and insulin dysmetabolism. ApoE4 is also associated with driving inflammation, the increased processing and aggregation of beta-amyloid protein, and brain shrinkage (atrophy) in regions of the brain tied to memory.

• The brain comprises about 2% of our total body weight, yet it contains about 25% of the human body’s cholesterol. The brain’s structure is highly dependent on cholesterol in maintaining healthy cell membranes, signal transmission between neurons, and in the recovery from injuries.

• Clusterin, or APOJ, is the second most common apolipoprotein in the brain after APOE. APOJ is an essential apolipoprotein in fat transport, mitochondrial integrity, and in the clearance of harmful beta-amyloid buildup. However, certain apolipoprotein variants weaken these beneficial effects.

• ABCA1 and ABCA7 genes which encode for ABCA1 and ABCA7 proteins are critical in the transport and metabolism of lipids (fats) such as cholesterol and phospholipids, and also support the clearance (phagocytosis) of beta-amyloid by immune cells (macrophages and microglia).

• The TREM2 gene is another key factor with regard to brain’s immune cells (microglia) regulatory role of inflammatory responses and clearance of damaged proteins. A rare TREM2 mutation (R47H) is associated with dysregulated microglial inflammation responses, and the reduced capacity of microglia in beta-amyloid and other debris clearance.

• Carriers of both the ApoE4 and MTHFR 677T gene variants are at an increased higher risk for Alzheimer’s and heart disease. Both risk variants are linked to high homocysteine levels, inflammation, and poor blood vessel health.

• High levels of homocysteine (hyperhomocysteinemia)—a byproduct of protein metabolism—are toxic to the brain and blood vessels. Hyperhomocysteinemia is associated by vitamin B deficiencies and is more common in people with the MTHFR 677T gene variant which is linked to folate dysmetabolism.

• Genetic testing for key variants like ApoE4 and MTHFR 677T are inavluable risk assessments. Both genetic variants are modifiable risk factors which may shed priceless insights that can be leveraged in the prevention of dementia and LOAD through diet and lifestyle interventions.

Epidsode 7

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

www.facebook.com/TheAlzheimersSolution

www.linkedin.com/in/ralph-sanchez

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Welcome, everyone!

This is Ralph Sanchez, and I am so pleased to bring you episode #6 to you here at the Alzheimer’s Solution Revolution Channel.

I am very much looking forward to today’s topic, which is centered on the assessment of risk biomarkers for late-onset Alzheimer’s disease.

I’ll begin this overview with a question.

Has your physician ever advised you on the possibility that you might be at an increased risk for dementia or late-onset Alzheimer’s disease (LOAD)?

And in the regard, just how early in life is it prudent to begin the process of a personalized risk evaluation?

In fact, there has been a significant shift in the medical and research community mindset over the last 10 years, and the consensus is that midlife, or earlier, is a critical window of time to begin doing so.

Why?

Because by midlife the brain damage associated with LOAD which begins earlier in life, begins to hit a pivotal tipping point in terms of your risk for LOAD—particularly if you are more susceptible to the disease.

Thus, midlife potentially is a critical juncture that shapes what your cognitive health future and life will look like.

Now, I’ve talked about this in my book, articles, newsletters, and social media posts many times as Alzheimer’s disease has a lengthy time frame of development and progression.

Indeed, the prevailing wisdom over these last few years has been finally emerged that the course of LOAD has a timeline of 20 to 30 years or so in which the disease process progresses.

And bear in mind, LOAD is a silent disorder in the asymptomatic stage—the preclinical stage, which often has its roots in cardiometabolic disease (type 2 diabetes/cardiovascular disease).

So today, I’ll be giving you some vital information on recent research findings that showcases what I just covered regarding your potential risk for LOAD, and how you can manage your healthy aging and reduce your risk for dementia through the assessment of biomarkers.

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.”

Undoubtedly, if you have a family history of cardiometabolic disease, or dementia, it is critical to start looking at these risk factors earlier in life.

The pathology linked to the late-onset Alzheimer’s disease continuum and vascular dementia spans decades, and it can be arrested or reversed in the early stages of the disease process.

Think ahead, and lease listen to the podcast to get the rest of the story!

Ralph Sanchez, MTCM, CNS, D.Hom.
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• The assessment of risk biomarkers for late-onset Alzheimer’s disease (LOAD) is best leveraged early in life for determining an optimal and personalized intervention program.

• Biomarkers that can be tracked via blood chemistry assessments and many other functional health evaluations can provide invaluable insights into metabolic dysfunction, immune system health, chronic inflammation patterns, gut and microbiome health, and hormone imbalances, enable priceless insights regarding risk factors associated with an increased risk for LOAD.

• A recent sub-study of The Framingham Heart study has shown that cardiovascular risk biomarkers may contribute to the risk for LOAD starting as early as age 35.

• The onset of cognitive impairment in the aging process is strongly associated with cardiovascular disease and type 2 diabetes which also increases the risk for stroke (traumatic brain injury). These major age-related disease of our time are modifiable which underscores the importance of early assessments and interventions.

• Genetic risk variants, such as the ApoE4 variant, can provide invaluable insights into the risk for both cardiovascular and late-onset Alzheimer’s disease.

Epidsode 6

Timestamp Highlights

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 aberrant tau protein aggregates, and the formation of 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) is one of the two hallmark lesions associated with Alzheimer’s disease (AD). The aggregation of beta-amyloid peptides (protein) and their formation of amyloid plaque is the other toxic hallmark lesion linked to LOAD.

Additionally, I’ll give 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 all-important shuttling of mitochondria and nutrients to the neuron’s axonal terminal and synapse in order to provide the energy metabolism required for optimal synaptic function and plasticity.

• How beta amyloid peptides aggregate and interrupt synaptic function.

• Tau protein is an important component of a microtubule network in the neuron, and it is a crucial cytoskeletal network that supports neuronal function.

• The microtubule skeletal network is an important transport system that facilitates the shuttling of nutrients and mitochondria from the cell body to the synapse terminals.

• Mitochondrial transport via the microtubule network is a critical factor in the stability and integrity of the neuron and synaptic function.

• Beta-amyloid aggregates within the neuron stimulate the breakdown of the cytoskeletal network, and the subsequent formation of neurofibrillary tangles.

• Research has shown that the formation of neurofibrillary tangles correlates more significantly with cognitive decline than beta-amyloid plague.

• The concept of brain plasticity is a term that refers to the malleability and adaptability of brain’s structural and functional dynamics which is vital in the brain’s capacity to integrate information and various experiences, and consolidate that sensory and intellectual input into memory and learning processes.

Epidsode 5

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Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

www.facebook.com/TheAlzheimersSolution

www.linkedin.com/in/ralph-sanchez

www.instagram.com/alzheimers_solution

In this fourth episode of The Alzheimer’s Solutions podcast with Ralph Sanchez, I the host, talk with my co-host Susan Brender, who has partnered with me to produce a special “Think Ahead” podcast series.

In this week’s episode, I’ll give an overview of the previous 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.

• Which are the top risk factors—that are often cited by studies—which are associated with an increased risk for Alzheimer’s disease?

• The diagnosis process of Alzheimer’s is difficult, and in the beginning stages there are virtually no symptoms or signs. There are many causes of dementia or cognitive impairment and they are not typically investigated in at-risk individuals.

• The three leading causes dementia are Alzheimer’s, vascular disease, and Lewy body disease. It is very common to have these diseases and the lesions associated with them comingling at the same time.

• Some medications can be a huge risk factor for nutrient deficiencies that can raise the risk for late-onset Alzheimer’s and dementia. For example, regularly taking antacids can block the absorption of B12, which can lead to cognitive impairment in aging.

• Tau and amyloid proteins are constituents of brain function and structure. However, these proteins are abnormally processed and assemble into abnormal aggregations in Alzheimer’s disease.

• Amyloid plague is a result of beta- amyloid protein (peptide) aggregates (oligomers—see illustration at top of page).

• Genetic variants of genes play a role in raising the susceptibility to excess processing and aggregation of amyloid and tau protein. However, just because one is more at genetically at risk for the pathology associated with late-onset Alzheimer’s disease, it does not necessarily mean that you are destined to have it take over your brain as you age.

• Memory and learning mechanisms are a fundamental component of synaptic function and brain plasticity or neuroplasticity. Beta-amyloid protein particles disrupt the vital synaptic signaling mechanisms and cascades that are crucial for memory and learning. Alzheimer’s disease begins—at the synapse!

Timestamp Highlights

Please listen in!

Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®

www.TheAlzheimersSolution.com

www.facebook.com/TheAlzheimersSolution

www.linkedin.com/in/ralph-sanchez

www.instagram.com/alzheimers_solution