Senile Dementia/Alzheimer’s Disease and its Connection with Dysinsulinism
By now I hope I have convinced those of you who have been reading this entire series that chronic inflammation plays a major role in the development and continuing loss of neurologic function in all neurodegenerative diseases, including senile dementia/Alzheimer’s disease. However, given the vicious circle relationship between inflammation and insulin resistance where it has been strongly suggested that chronic inflammation leads to insulin resistance and prolonged insulin resistance leads to chronic inflammation (1, 2), it would seem logical to conclude that, since chronic inflammation is universally present in the senile dementia/Alzheimer’s disease patient, insulin resistance must be universally present also.
Interestingly, despite what, to me, appears to be inescapable and obvious logic, I have found virtually no mention of insulin resistance in the many reports on senile dementia/Alzheimer’s disease that appear in both the printed and televised media. Instead, in the reports that I have seen where the “experts” are being interviewed the most common answer to questions about the underlying causes of senile dementia/Alzheimer’s disease is “we don’t know; more research is needed.”
This leads me to shake my head in frustration because I immediately wonder if these experts who say “we don’t know” have read the papers I am about to review on the intimate relationship between insulin resistance and senile dementia/Alzheimer’s disease. Of course, maybe these experts have read all of these papers and have dismissed them as total fallacy and flights of fancy. However, while I’m certainly no expert, these papers seem well written and convincing to me. Therefore, I feel the logical next step is to ask all of you what you think about the connection between insulin resistance and senile dementia/Alzheimer’s disease. Are the papers I am about to review convincing enough for all of us to conclude that the experts we see in the media are making a serious mistake in judgement when they continue to never mention insulin resistance when discussing neurodegenerative diseases? While I will make no attempt to speak for all of you, I am prepared to conclude, based on what I am about to present, it is long past time for the subject of insulin resistance and insulin metabolism in general to be an integral part of any serious discussion on senile dementia/Alzheimer’s disease from either a causational, preventive, or therapeutic standpoint.
To introduce the idea that insulin metabolism can have an impact on cognitive function, consider this quote from the paper “Metabolic, inflammatory, and microvascular determinants of white matter disease and cognitive decline” by Wang et al (2):
“Some researchers suggest that insulin resistance at the blood brain barrier reduces the amount of glucose that can reach the brain, resulting in neuronal injury. While others proposed that the diabetic state may lead to a hyperglycemic condition in the brain that would result in the formation of glycated end products, which in turn can induce neuroinflammation. Thus, both hyperglycemic and hypoglycemic conditions in the brain can lead to cognitive dysfunction.”
DOES THE DYSINSULINISM HYPOTHESIS OF SENILE DEMENTIA/ALZHEIMER’S DISEASE REPLACE THE LEADING THEORY OF ACCUMULATION OF AMYLOID PLAQUES?
As most of us know, accumulation of white matter amyloid plaques has long been considered the primary cause of aged-related loss of cognitive function. Does the research I am about to present on dysinsulinism relegate this causational hypothesis to the trash heap? Not at all. As you will see from the quotes that follow, there is an intimate relationship between disturbances in insulin metabolism and the formation of amyloid plaques. Furthermore, knowing that insulin metabolism and amyloid plaque formation are closely related will help us better understand the true role of these plaques in contributing to cognitive dysfunction. For, as you also probably know, many studies have been sharply critical of the idea that formation of amyloid plaques is the only or even a primary contributor to senile dementia/Alzheimer’s disease (AD).
Amyloid plaques – some basic information
The amyloid plaques that are the hallmark of aged-related cognitive dysfunction are composed of a substance named amyloid beta (Aβ). In the study “Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease” by De Felice and Ferreira (3) disturbances in the metabolism of Aβ are discussed in terms of the formation of amyloid plaques:
“Abnormal production, processing, and/or clearance of Aβ may lead to its accumulation and aggregation in the brain parenchyma and interstitial fluid. Early histopathological investigation of AD brains revealed the presence of fibrillar Aβ aggregates forming large, insoluble deposits known as amyloid plaques.”
Research performed subsequent to these findings suggested that the association between the two may be cause and effect. The authors point out:
“Further in vitro biochemical and cell biology studies, as well as studies using a number of transgenic mouse models of AD, provided strong support to what initially seemed to be a solid concept, namely that Aβfibrils/plaques played a crucial role in AD pathogenesis.”
Of course, as I suggested above, this theory carries considerable controversy since plaques have been found on autopsy in individuals without signs of senile dementia/Alzheimer’s disease. The authors state:
“…a large body of evidence accumulated during the past 15 years indicates that fibrils are probably not the most harmful structures generated by self-association of Aβ. Of direct clinical relevance, post-mortem analysis of the brains of individuals who died without signs of significant cognitive deterioration has revealed abundant brain amyloid deposits, whereas individuals lacking such deposits have been found to exhibit various extents of cognitive deterioration. Moreover, the best correlate of the extent of dementia is not brain amyloid burden but rather synapse loss, suggesting synapse deterioration and cognitive impairment are caused by a toxin other than fibrillary Aβ.”
De Felice and Ferreira (3) addressed this controversy by discussing the research by Klein and colleagues. They found the following:
“…Aβ self-aggregates to form neurotoxic soluble oligomers (AβOs), aggregates much smaller than fibrils that are not detected in classical neuropathological examination. Oligomers were recently detected at postsynaptic sites in AD hippocampi, and their levels are elevated in the brain and cerebrospinal fluid of AD patients. Interestingly, the absence of AβOs at the postsynapse was reported in cognitively intact elderly individuals whose brains presented amyloid deposits.”
Therefore, current thinking suggests that dementia is an issue of synapse failure related to accumulation of AβOs, not amyloid plaques:
“Klein’s discovery, confirmed and expanded by several groups, lead to a novel hypothesis on how AD progression leads to dementia: synapse failure and neuronal dysfunction are now considered to derive from the accumulation and impact of AβOs in AD brains.”
More information on the relationship between disturbances in insulin metabolism and dementia
I will continue this discussion of AβOs and senile dementia/Alzheimer’s disease shortly. Now I would like to provide more detail on the intimate connection between dysinsulinism and dementia. DeFelice and Ferreira (3) state:
“…impaired metabolic parameters such as hyperglycemia and hyperinsulinemia, positively correlate with development of AD-related pathology. Elevated blood glucose levels increase the hazard risk of dementia in both diabetic and nondiabetic individuals (by 40 and 18%, respectively) and are associated with cognitive decline and reduced hippocampal volume. These findings indicate that persistently elevated blood glucose levels negatively impact the brain, even in the absence of overt T2D or impaired glucose tolerance. A new view is thus emerging according to which even a prediabetes state maintained throughout a long period of life may constitute a significant risk factor for dementia. In harmony with this concept, AD was recently proposed to be a form of dementia caused by metabolic dyshomeostasis that manifests in the elderly as a result of a cumulative, lifelong impact on peripheral tissues and on the brain. In addition to this metabolic hypothesis, it is important to note that prediabetic hyperglycemia may be accompanied by a state of low-grade peripheral inflammation, which might directly impact brain insulin signaling. Thus, from a mechanistic point of view, the connection between AD and T2D may comprise both inflammatory and metabolic components. A corollary of this proposal is that poor lifestyle habits (e.g., lack of or insufficient physical activity or inadequate nutrition) known to predispose to T2D and obesity are increasingly thought to play important roles in susceptibility to AD later in life.”
As compelling as this discussion on the intimate relationship between lifestyle, inflammation, dysinsulinism, and dementia may be, I have only begun to discuss the published research on the subject. More to follow. However, I would now like to return to my discussion on AβOs by examining their connection with insulin metabolism.
AβOs and their relationship with dysinsulinism
What is the relationship between AβOs, dementia, and insulin metabolism? DeFelice and Ferreira (3) point out:
“Recent evidence indicates that AD can be considered a brain-specific form of diabetes. AD brains exhibit defective insulin signaling, altered levels and/or aberrant activation of components of the insulin signaling pathway, and, importantly, decreased responsiveness to insulin. Molecular clues into how the brain becomes resistant in AD came from studies demonstrating that AβOs trigger the removal of insulin receptors (IRs) from the plasma membrane in cultured hippocampal neurons, leading to reduced IR protein tyrosine kinase activity.”
More information on insulin receptors in the brain
DeFelice and Ferreira (3) provide additional information on the importance of insulin receptors in neurologic function:
“Insulin receptors (IRs) are widely distributed in the central nervous system (CNS), suggesting that insulin has important physiological roles in the brain. The hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new memories, presents particularly high levels of IRs. Insulin has been shown to be neuroprotective and to modulate synapse plasticity mechanisms. IR signaling further regulates circuit function and plasticity by controlling synapse density.”
SENILE DEMENTIA/ALZHEIMER’S DISEASE AND INSULIN METABOLISM: AN IN DEPTH EXAMINATION
As I mentioned above, what I have just discussed on the relationship between dementia and insulin was meant to be an introduction of the subject. Now I would like to discuss an outstanding review paper that provides an in depth examination of the insulin/dementia connection.
The first quote I would like to feature from “Alzheimer’s disease: Is this a brain specific condition?” by Rani et al (4) introduces a descriptor of senile dementia/Alzheimer’s disease that is not only gaining in popularity but really “says it all” in terms of the underlying theme of this installment:
“AD…is considered as type III diabetes due to similar functional abnormalities and the pathogenic mechanisms. Insulin receptor dysfunction or insulin resistance has been reported to be a common trigger and a major risk factor for the development of sporadic AD and type 2 diabetes mellitus.”
Is senile dementia/Alzheimer’s disease that simple? Is it really nothing more than diabetes of the brain, as suggested by the term “type III diabetes?” Probably not. Certainly other factors I have discussed in this series such as inflammation, cortisol resistance, kynurenine pathway disturbances play a role as well as factors I have yet to discuss. Nevertheless, I do feel that the term “type III diabetes” is appropriate insofar as it emphasizes that insulin metabolism is a key foundational factor that needs to be given proper emphasis for many reasons, not the least of which being the extent to which it is being ignored by many, if not most, both in the research and clinical communities.
The next quote I would like to feature presents more compelling evidence that insulin metabolism plays a major role in AD:
“An assuring argument could be made that AD is considered as a pure form of diabetic condition of brain. Alzheimer’s disease is associated with brain insulin resistance in the absence of T2DM, obesity or peripheral insulin resistance. Moreover, autopsy studies revealed that the molecular, biochemical and signalingabnormalities in AD are almost similar to those that occur in T1DM and T2DM.”
Some specifics on insulin function in the brain
What are the mechanics of insulin function in the brain in relation to cognition? The next three quotes provide an overview. First, consider the following:
“Insulin binds to insulin receptors (InsRs) which are abundantly present in the brain but selectively distributed. Rodent studies have shown that the highest concentration of insulin receptors is found in the nerve terminals of key brain regions, such as the olfactory bulb, hypothalamus, cerebral cortex, cerebellum and hippocampus. In the human being, brain insulin improves learning and memory and specific vocal memory. Insulin signaling is particularly essential in the limbic system and hypothalamus for cognitive function, independent to changes in peripheral glucose. The CNS clearly contains insulin, but it produces less or no insulin. Therefore, CNS insulin is derived from the circulation. Insulin crosses the blood-brain-barrier (BBB) largely because of the presence of a blood-to-brain saturable transport system. This transport system is itself regulated by nitric oxide, inflammatory events, hibernation, glucose, triglycerides, obesity and the diabetic state, independent of glucose. In the CNS, insulin and insulin-like growth factor signaling play critical roles in regulating and maintaining cognitive function.”
Before continuing, I would like to emphasize two important points from the above quote. First, despite the importance of insulin in optimal brain functioning, the brain produces no insulin. Therefore, since the brain is totally dependent on peripheral insulin production which is totally dependent on maintenance of optimal systemic health, I hope you can understand the futility of focusing exclusively on the CNS, which is typical of most dementia treatment protocols, both allopathic and alternative. The second key point is that the transport system that delivers insulin to the brain is dependent on several systemic issues, including the other foundational issue in this series, inflammation. Thus, as I emphasized above, even though the focus of this installment is insulin, the contents of the entire newsletter series must be kept in mind when putting the information I am describing to use clinically.
The next quote focuses on the usual area of emphasis for most clinicians, both allopathic and alternative, when attempting to address neurologic dysfunction, neurotransmitters. What is the impact of insulin on neurotransmitter activity? Rani et al (4) state:
“…insulin regulates the concentrations of neurotransmitters, which effect intellect, like acetylcholine (ACh). Insulin also modifies synaptic plasticity by modifying the endocytosis of AMPA receptor, which may lead to long-term depression of excitatory synaptic transmission in the hippocampus and cerebellum.”
The next quote addresses the role of insulin in memory and cognitive function:
“Insulin modulation of glucose metabolism appears to be one of the key components of hippocampal vulnerability. Moreover, insulin is likely to modulate memory via other molecular events. Such as increasing the probability of inducing long-term amplification by promoting N-methyl-D-aspartate receptor conductance, as reviewed elsewhere. Insulin also modulates cognitive functions via its effects on neurotransmission, e.g. low doses of insulin can reverse the amnestic effects of cholinergic blockade, high levels of insulin reduced neuronal norepinephrine reuptake and increasing N-methyl-D-aspartate (NMDA) receptor-mediated hippocampal synaptic transmission.”
Neurologic consequences of insulin dysfunction
What happens when insulin metabolism is functioning suboptimally? As we all know, many things. However, in the context of neurologic function, the quote below suggests which aspects of insulin dysfunction might be the most important:
“…impairment of insulin and insulin-like growth factor (IGF) signaling due to insulin/IGF resistance and/or trophic factor withdrawal leads to decreased energy metabolism manifested by reduced glucose uptake and ATP production. Reduced ATP adversely affects cellular homeostasis, membrane permeability and fundamental processes required for synaptic maintenance and remodeling, which are needed for learning and establishing new memory. The incidence of neurological disorders appears to be higher in individuals with type 2 diabetes and type 2 diabetes patients can be more than twice as likely to develop AD than non-diabetics.”
Concerning glucose metabolism in the brain, I would like to feature two quotes about the role of insulin receptors. First, insulin receptors in the brain are different than those found in the periphery:
“Insulin receptors which are located in the brain are different from those insulin receptors found in the periphery.”
Second, glucose utilization, as we know, is very important to optimal brain function. However, what you may not know is that glucose utilization in the brain is totally dependent on brain insulin receptors:
“Glucose is the only nutrient of mammalian brain whose breakdown is modulated by brain insulin through the neuronal insulin receptors and glucose metabolism produces a number of compounds essential for both usual function and normal arrangement of neurons.”
The specific impact of insulin dysfunction on senile dementia/Alzheimer’s disease
As was mentioned above, energy production related to suboptimal insulin and glucose metabolism can have an adverse effect on energy production in the brain. The specific impact of these phenomena on the creation of AD is discussed in the following quote from the Rani et al (4) paper:
“One of the unusual features of AD is the extreme drop in energy metabolism in affected brain areas. In the CNS the main role of insulin is to stimulate glucose uptake into tissues, through glucose transporters (GLUTs 1-8). Glucose is required for the synthesis of various neurotransmitters including acetylcholine, dopamine, GABA and glutamate, etc., which are primarily involved in synaptic plasticity and cognitive functions. Although, the cerebral energy pool is only somewhat reduced during the normal aging process, energy production and its utilization are impaired in sporadic AD.”
Of course, when we encounter situations involving suboptimal energy production, our train of thought generally goes immediately to one of the main reasons for suboptimal energy production, suboptimal mitochondrial function and the increased free radical activity that usually accompanies it. On this point Rani et al (4) states:
“Mitochondrial dysfunction impairs electron transport chain function, decreases ATP production and enhances ROS generation. Mitochondrial dysfunction and oxidative stress play major roles in the pathogenesis of both AD and type 2 diabetes mellitus, and represent a possible link.”
The authors then go on to discuss more about the involvement of mitochondria in brain function and how suboptimal mitochondrial function can lead to the Aβ accumulation discussed previously:
“Mitochondria deliver about 90% of the ATP necessary for normal functioning of neurons and mitochondrial dysfunction results in a loss of metabolic control and neural degeneration. As the CNS functions are solely dependent upon ATP generation, it is more vulnerable than other systems. Mitochondrial dysfunction and oxidative stress have also been linked to Aβ accumulation in experimental animal models of AD and that the onset of Aβ deposition is also linked with an increased level of ROS.”
Next Rani et al (4) discuss another way that dysinsulinism in the brain can contribute to the development of AD. It has to do with a concept many of you have probably heard about previously in relation to anxiety disorders where increased NMDA receptor activity leads to behavioral disturbances. It also involves another related concept you may have heard about in relation to heart function, disturbances in calcium metabolism (As you may recall, calcium channel blockers are used to reduce abnormal calcium ion metabolism that leads to disturbed heartbeat regulation). As you will see in the following quote, disturbances in NMDA receptor activity and calcium ion metabolism can also lead to the neurologic degeneration typically associated with AD:
“The cellular mechanisms that regulate Ca2+ homeostasis play a critical role in the aging brain. It has been reported that the activation of NMDA receptors induces faster mitochondrial Ca2+ uptake, since mitochondria are in closer proximity to NMDA receptors than other routes of Ca2+ entry. Insulin stimulates cell membrane expression of N-methyl-D-aspartate (NMDA) receptors, with increased neuronal Ca2+ influx. This Ca2+ ion apparently stimulates Ca2+ -dependent enzymes, including α-dependent enzymes and strengthen neuronal synaptic association. However, impaired insulin signaling has been linked with NMDA receptor over-activity and dysregulation in Ca2+ homeostasis which further leads to neuronal dysfunction and cell death. NMDA receptor over-activity allows transient mitochondrial Ca2+ loading, inhibits mitochondrial respiration and could initiate oxidative damage. Furthermore, the extent of the perturbation in the Ca2+ and the duration of the deregulation of the Ca2+ homeostasis is a constant.”
In turn, this disturbance in Ca2+ metabolism can lead to abnormal function in many tissues including neurons:
“In other words, a small change in free Ca2+ sustained over a long period of time will result in cellular damage as a large change over a short period. Indeed there is plenty of evidence for a close relationship between Ca2+homeostasis, the production of ROS and neuronal cell death. Impaired Ca2+ regulation and Ca2+ channel over-activity have also been described in various diabetic tissues (arteries, myocardium, muscle, etc.) and implicated in the pathogenesis of secondary complications. Peripheral nerves are one of the major targets of diabetic damage; there are various direct and indirect mechanisms by which diabetes-related disturbances in Ca2+ homeostasis could lead to neuropathy.”
I would suspect that much of what I have just discussed is not new to many of you. As I suggested, we have seen this terminology used to describe many clinical entities we have been discussing and dealing with for years such as cardiac dysfunction and peripheral diabetic neuropathy. With this in mind, what is the “big picture” message in relation to senile dementia/Alzheimer’s disease? It is not, as suggested by many researchers and commentators in the media, a mysterious, difficult to comprehend ailment that requires a whole new set of diagnostic and preventive modalities. Rather, it is a collection of the exact same metabolic imbalances we have been addressing for years in relation to extraneuronal ailments such as obesity, diabetes, chronic fatigue, gut dysfunction, fibromyalgia, etc. The fact that they are occurring in the brain in some susceptible patients has, in the past, intimidated us to the point where we often feel that what we have been doing for years as functional medicine practitioners for the “usual” chronic illnesses in not good enough for senile cognitive dysfunction. We need to find “something new.” Hopefully, I am convincing you that this is not the case. Don’t let the fact that the brain is involved scare you into deviating from your typical functional medicine approach that has been proven to be successful over the years for so many chronic illnesses. For me, the message from the research I am presenting makes it clear that what we have been doing for years for extraneuronal chronic illnesses is quite appropriate for situations where we desire to prevent senile dementia/Alzheimer’s disease or slow its progression.
Rani et al (4) conclude their paper with the following overview:
“Insulin resistance (IR) due to impaired insulin signaling is a common characteristic of both type 2 diabetes mellitus and AD, and probably represents the strong correlation between AD and diabetes. It is evident from the literature that brain insulin and insulin-like growth factor signaling play a major role in maintaining neuronal integrity and cerebral energy homeostasis. Impaired insulin signaling may cause a type 2 diabetes mellitus like milieu specific to the brain, which triggers activation of cellular signaling cascades that lead to Aβ and tau pathology, and other features of AD. IR can be considered as a major etio-pathogenic mechanism for the development of AD. Substantial evidence also suggests AD is a brain specific diabetic condition.”
More information on the relationship between insulin resistance, oxidative stress and senile dementia/Alzheimer’s disease
I would like to conclude this installment by discussing the portion of a paper entitled “Insulin resistance in Alzheimer’s disease” by Diehl et al (5) that focuses on a subject discussed above in the Rani et al (4) paper, insulin resistance, oxidative stress, and AD. The first quote I would like to present makes it clear how vulnerable the brain is to oxidative stress:
“The brain is particularly vulnerable to oxidative stress due to its high oxygen requirements, low antioxidant levels that only decrease further with age, and the sheer membrane lipid content available for destructive peroxidation. Many researchers now implicate oxidative stress as a causative factor upstream of Aβ and tau.”
The next quote discusses the intimate interrelationship between insulin resistance, oxidative stress, and the development of AD:
“Neurons become especially vulnerable to oxidative stress when insulin signaling is disrupted, and oxidative stress leads to further IR. Both IR and oxidative stress independently lead to the accumulation of Aβ and phosphorylated tau. Oxidative stress also occurs as a result of metabolic syndrome and obesity. This web of possibly inextricable connections firmly places IR, oxidative stress, and AD in a complex positive feedback system.”
To me, this quote affirms what I was stating previously. AD is not a complex mysterious human disorder unique to human physiology. Rather, it is a neurodegenerative process that is intimately interlinked with the metabolic imbalances we identify and address every day. Furthermore, because of this intimate, “vicious circle” interrelationship, we need to recognize and convey to both patients and the public that the best way to address neurodegeneration, particularly from a preventive perspective, is not the latest, very new, very exotic, and very expensive supplement or procedure. Instead, the best way to address AD is, as I suggested above, what we do every day.
With this concept in mind, consider the following quote from the Diehl et al (5) paper:
“One direct method for severing this oxidative-stress/IR knot would be to address oxidative stress by way of antioxidants. This has been a focus of numerous basic and clinical studies, in which antioxidant supplements, such as the free-radical scavenging vitamins C and E, estrogen, statins, fish oil, and resveratrol have all shown some effect in decreasing the risk of AD. Likewise, caloric restriction and exercise recruits a variety of antioxidant defenses with similar preventive effects.”
Of course, as you might expect, clinical trials of single antioxidant supplements with AD patients have not turned out well. Diehl et al (5) state:
“It is important to note that the evidence in support of antioxidant supplements in AD comes from animal and epidemiologic studies, whereas clinical trials have generally been negative.”
For me this reinforces the idea, as I have been suggesting in this series, that a comprehensive supportive protocol is needed that emphasizes all aspects of neurodegeneration that includes antioxidant supplementation plus other supplemental and lifestyle interventions that address the key issues I have been discussing such as chronic inflammation, kynurenine pathway imbalances, abnormal cortisol metabolism, etc.
In the next installment of this series I will be reviewing still more outstanding papers that make it clear that, contrary to the opinion of many researchers and media commentators, insulin resistance is an integral part of the senile dementia/Alzheimer’s disease picture. What is the potential outcome of this clarity? The picture that comprises neurodegenerative disease is not only a whole lot less mysterious and frightening but much clearer in terms of possible efficacious and cost-effective interventions.
Moss Nutrition Report #273 – 03/01/2017 – PDF Version
- Fougere B et al. Chronic inflammation: Accelerator of biological aging. J GerontolA Biol Sci Med Sci. 2016;published online ahead of print December 21, 2016.
- Wang M et al. Metabolic, inflammatory, and microvascular determinants of white matter disease and cognitive decline. Am J Neurodegener Dis. 2016;5(5):171-7.
- De Felice FG & Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes. 2014;63:2262-72.
- Rani V et al. Alzheimer’s disease: Is this a brain specific diabetic condition? Physiology & Behavior. 2016;164:259-67.
- Diehl T et al. Insulin resistance in Alzheimer’s disease. Translational Res. 2016;published online ahead of print.