Episode # 12
The Alzheimer's Solution Revolution
#12 DHEA, Pregnenolone, and the DHEA to Cortisol Ratio in Longevity Wellness and the Protection and Optimization of Cognitive Function
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EPISODE 5
Summary and Audio
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 will add pregnenolone and more on DHEA 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 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 neuroteroids in longevity wellness and the protection against cognitive decline and the risk for dementia.
Top Takeaways
• 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
Timestamp Highlights
In this Episode
[00:01:40] Definition of neurosteroids, detailing their cholesterol-derived biosynthesis in the body and brain, and the transport of hormones across the blood brain barrier.
[00:02:30] Emphasis on age-related steroid hormone decline and its significance for body and brain wellness vitality and longevity trajectories.
[00:03:31] DHEA is the most abundant steroid in circulation and there is an elevated concentration of DHEA in the central nervous system.
[00:03:46] Description of the adrenal stress assessment profile—DHEA, cortisol, and their ratio—as a diagnostic indicator of HPA axis behavior under chronic stress conditions.
[00:04:10] DHEA and cortisol decline, and a skewed DHEA/cortisol ratio, are risk factors that are associated with insulin resistance, metabolic syndrome, cardiovascular disease, osteoporosis, hypertension, depression, cognitive decline, and dementia.
[00:04:54] Chronic stress patterns (fight-or-flight responses) and cortisol spikes in the long-term activation of the hypothalamic-pituitary-adrenal (HPA) axis are significant risk factors in age-related diseases.
[00:05:55] Fond memories of my discovery of Dr. Robert Sapolsky book “Why Zebras Don’t Get Ulcers” illustrating cortisol’s stress-induced damage on migrating salmon.
[00:06:45] Cortisol’s destructive impact on newly formed brain cells (neurogenesis) and the inhibition of neurogenesis in a key memory and learning center—the hippocampus.
[00:07:14] The effect of prolonged stress hormone (glucocorticoids) exposure in hippocampal neuron loss and brain shrinkage (atrophy), and its relationship to depression, memory loss, and dementia.
[00:08:01] Additionally, low cortisol states associated with chronic stress responses, blunts cortisol’s essential regulatory effects on glucose metabolism, inflammation, immune function, blood pressure, and the sleep-wake cycle (circadian rhythm).
[00:09:03] Discussion of cortisol’s role in memory acquisition and consolidation, highlighting how cortisol signaling abnormalities impair memory encoding and retrieval.
[00:09:14] Introduction to “inflammaging” as a chronic low-grade inflammatory state linked to both high and low cortisol, reinforcing the need for stress hormone evaluations in aging individuals.
[00:09:44] The role of cortisol secretion during sleep and its role in memory consolidation and hippocampal memory encoding mechanisms.
[00:10:37] DHEA’s role in long-term stress patterns and its depletion linked to chronic HPA activation and the aging process.
[00:10:55] The role of DHEA as a cortisol antagonist—the decline of DHEA levels is a factor in cardiometabolic, immune, and neurological health risks.
[00:11:40] Description of DHEAS (DHEA sulfate) in circulation as a key biomarker for neurogenesis, synaptic plasticity, and central nervous system resilience.
[00:12:22] Synaptic plasticity or neuroplasticity, is a phenomenon that describes the the malleable or plastic integrity of synaptic function, and synpatic receptor-mediated signaling cascades essential for learning and memory.
[00:14:10] Reminder of pregnenolone and DHEA’s role as parent hormones or prohormones, which are at the apex of the steroid hormone hierarchy, and the downstream metabolic cascade of sex steroids and neurosteroids (estrogen, testosterone, progesterone, allprenanolone).
[00:14:51] Role of neurosteroids—DHEA and pregnenolone—and their sulfated forms (DHEAS, PREGS) as neuroprotective agents that enhance structural and functional brain integrity.
[00:15:16] NMDA and AMPA receptor regulation by DHEAS and PREGS, and the regulation of calcium flux dynamics in synaptic signaling.
[00:16:04] Description of GABA neurotransmitter receptor modulation by neurosteroid sulfates (DHEAS, PREGS), and its importance in maintaining a balance of excitatory–inhibitory stimulation on receptors by excititory/inhibitory neurotransmitterrs—glutamate, GABA, respectively.
[00:16:40] Role of “excitotoxicity” in the pathogenesis of Alzheimer’s disease (AD) which is characrerized by NMDA/AMPA receptor overactivation and the subsequent excess calcium influx into neurons.
[00:17:21] Beta-amyloid triggers excitotoxic cascades linked to the NMDA/AMPA receptor-driven neronal injury and death.
[00:17:53] Characterization of DHEA and pregnenolone sulfate (DHEAS, PREGS) as cytoprotective against stress-induced neuronal toxicity.
[00:18:11] Overview of DHEAS, and PREGS in their anti-inflammatory and antioxidant actions, including protection from beta-amyloid-induced neuronal injury..
[00:18:38] Reminder of downstream neurosteroid metabolites—DHEAS, PREGS—progesterone, testosterone, estrogen, allopregnanolone—each contributing distinct neuroprotective benefits.
[00:19:24] Introduction to neurogenesis research documenting adult hippocampal neurogenesis and its essential role in maintaining a cognitive resilience in aging (neurogenesis-driven cognitive resilience).
[00:20:14] Description of aging individuals who maintain their cognitive function in later years despite the characteristic neuropathology (plaques and tangles) associated with AD.
[00:20:34] Highlights of the Nun Study, and the nuns followed in the study, that maintained exceptional cognitive function despite the presence of advanced pathological beta-amyloid and tau protein lesions (plaques and tangles) at the time of death.
[00:21:43] The importance of diet and lifestyle-driven neurogenesis as a phenomenon that builds a brain reserve and cognitive reserve, which is essential to a resilient brain against dementia and AD in advanced old age.
[00:22:54] Evidence shows that higher neurosteroid levels are associated with enhanced neurogenesis and the protection against aging and AD-related memory impairment.
[00:23:18] Animal model findings showing DHEA-driven neural stem-cell proliferation and allopregnanolone-driven neural progenitor-cell proliferation in neurogenesis.
[00:24:00] Introduction of neurotrophic factors such as BDNF (brain-derived neurotrophic factor) and nerve growth factor that interact with neurosteroid pathways to modulate neurogenesis.
[00:24:41] Closing statement and quote regarding the decline of neurosteroid levels that occur in aging, chronic stress, inflammation, depression, and neurodegenerative diseases, which underscores the importance of sex steroid biomarker evaluations in the risk for cognitive decline and late-onset Alzheimer’s disease.
Please listen in!
Ralph Sanchez, MTCM, CNS, D.Hom
BrainDefend®
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