More research on Senile Dementia/Alzheimer’s disease and its connection with dysinsulinism
In part VIII of this series I began my discussion on how disturbances in insulin metabolism can alter brain chemistry, leading to formation of the generally recognized cause of Alzheimer’s disease/senile dementia, amyloid beta (Aβ), commonly known as “amyloid plaques.” Furthermore, I pointed out that the research suggesting that Aβ is a major cause of Alzheimer’s disease/senile dementia is actually quite controversial and that, instead, aggregates of Aβ that form neurotoxic soluble oligomers (AβOs) are much more likely causational factors. Next, I presented several quotes from different studies that provided compelling evidence that not only do disturbances in insulin metabolism lead to increased production of AβOs but AβOs can trigger removal of insulin receptors in the brain, suggesting a very potent vicious circle between disturbances of insulin metabolism and existence of the factors most directly linked with Alzheimer’s disease/senile dementia development, AβOs.
In part IX of this series, I would like to continue my exploration of this connection between insulin, Aβ, AβOs and Alzheimer’s disease/senile dementia by first reviewing a clinical study that supports the metabolic tie-ins discussed in the last newsletter. However, before I do so, I would like to briefly return to my discussion that began part VIII of this series on why I feel it is so important to feature this research on the connection between insulin metabolism and Alzheimer’s disease/senile dementia. As I mentioned, based on what I see in the popular electronic and printed media, this research, for reasons I do not entirely understand, is being virtually ignored. Why? One obvious reason is that it focuses more on prevention rather than a cure, never a popular subject among the public or the media when discussing either acute or chronic illnesses. Nevertheless, I remain enthusiastically committed to discussing what all too few are discussing. One reason is that prevention, even though it is too slow and uninteresting for many, can have a major impact in terms of reducing the incidence of one of today’s most dreaded chronic illnesses. However, there is one other reason that was recently featured in the paper “Dementia care, women’s health, and gender equity” by Bott et al (1). As you will see from the following quotes, rising incidence levels of Alzheimer’s disease/senile dementia are more than just a story about the lives of the afflicted. It is also a somewhat heartrending story about the lives of those, primarily women, who care for the afflicted.
This paper begins with a discussion of rising incidence and the reality of treatment:
“Age is the greatest risk factor for dementia, and the number of cases of dementia will continue to rise as a function of an aging population (approximately 8.4 million by 2030). The mainstay of treatment is functional support, and 83% of caregiving comes from unpaid sources: family. The average person with dementia requires 171 hours of care per month, which is more than 100 hours more care per month than those without dementia (mean of 66 hours per month).”
However, as noted in the quote below, the provision of this large volume of care appears to come with a gender bias:
“Women provide nearly two-thirds of all elder care, with wives more likely to care for husbands than vice versa and daughters 28% more likely to care for a parent than sons.”
Unfortunately, even though this care provided by women is of high quality, it comes at a price:
“The best long-term care insurance in our country is a conscientious daughter. Making up 47% of the workforce in 2015, burgeoning caregiving demands will disproportionately fall on working-age women, as will the associated decreases in self-esteem.”
Why would there be decreases in self-esteem? Consider the somewhat unpleasant realities of care of those suffering from Alzheimer’s disease/senile dementia:
“While caregiving for loved ones with dementia can certainly be meaningful, dispiriting routine tasks such as toileting, undergarment changing, and bathing are enduring challenges. Lack of daily predictability in dementia-linked symptoms intensifies the burden. Women are disproportionately at risk for lowering or exiting their career trajectory owing to caregiving demands. The combined stresses of caring for family members with dementia and the lack of time to attend to personal needs care erode caregivers’ health. For women who remain in the workforce, dementia care responsibilities can increase costs to their employers from absenteeism, productivity loss, stress-related disability claims, and health benefits plan spending.”
Will this gender bias change anytime soon? The authors suggest:
“It remains to be seen whether men can be persuaded to assume equal share of the burden of caregiving. While gender parity in childcare is modestly growing, gender parity in dementia is unlikely to occur anytime soon.”
What can we do now to begin to change this somewhat sobering scenario? Even though it is not very exciting and will take time to produce significant results, I am convinced that right now, given the lack truly effective means of illness reversal from either the alternative or allopathic communities, prevention is our best option.
DOES EVIDENCE EXIST THAT SUGGESTS PREVENTION INVOLVING OPTIMIZATION OF INSULIN METABOLISM WOULD BE CLINICALLY EFFECTIVE?
Hopefully, the physiologic and biochemical information I have provided thus far and will present makes a strong argument that optimization of insulin metabolism is one the best approaches in terms of prevention. However, does clinical information exist that supports this contention? I believe that the study that I am about to review answers this question in the affirmative.
In “Cognitive impairment is correlated with insulin resistance degree: the ‘PA-NICO-study'” by Fava et al (2) 335 diabetic subjects and 142 non-diabetic subjects were evaluated. All were approximately 65 ± 10 years of age. All were evaluated as to the degree of insulin resistance using what is known as the Homa-Index (HI). Based on this index they were rated either as normal HI (NHI) (non-diabetic with an index of <2.6), moderate HI (MHI) (An index above 2.6 and below 10) and high HI (HHI) (An index above 10). To assess cognitive function the following tools were employed:
“To test global cognitive function, the Mini Mental State Examination (MMSE), a widely used dementia screening tool and Alzheimer Disease’s Assessment-Scale Cognitive-Subscale (ADAS-Cog) were administered at baseline.”
Another assessment tool was also employed:
“In addition, the Alzheimer’s-Disease-Cooperative-Study (ADCS) Activities-Daily-Living (ADL) scale was completed by the patient’s caregiver and used to rate the participant’s ability to perform daily activities with the past month.”
Follow-up assessments were performed every 12 months for 6.8 years. What were the results? Fava et al (2) point out:
“In this prospective case-control study, we evaluated cognitive functions in patients with diabetes and insulin resistance, and their correlation with insulin resistance (IR)-degree over time. Cognitive assessment was performed by MMSE and ADAS-Cog-subscale while ADCS-ADL was performed to assess quality of life measurement. We found that the higher IR-degree, assessed by HOMA-index, was associated with greater decline in cognitive performances. In fact, diabetic patients with an HOMA-index greater than 10, reported most impaired scores in MMSE and ADAS-Cog-scores compared with patients with moderate-HOMA-index over the follow-up period. In addition, in the HHI group, after examining the relationship between the ADAS-Cog-subscore, we found that particularly 5 out of 11-tasks (recall word, orientation, naming, word finding ability and spoken language ability) showed an association with IR-degree.”
These findings led the authors to conclude:
“On the basis of our results we hypothesize that IR severity more than IR-status itself, could affect cognitive impairment in subjects with diabetes. Probably, in diabetic subjects, it is necessary to reach a certain degree of metabolic impairment, in our case measured through IR, before having a compromise of cognitive performance.”
I know I am preaching to the choir when I point out how well we in the nutritional and functional medicine communities have performed concerning optimization of insulin metabolism utilizing lifestyle modifications and selected supplemental interventions. I feel it is important that we recognize that our outstanding work in this area is more than just about reducing diabetes incidence and severity. It is also now becoming increasingly clear that what we have been doing all these years has and will continue to play an ever expanding role in addressing the growing crisis of Alzheimer’s disease/senile dementia that impacts not only the sufferers but those who care about them and care for them.
MORE RESEARCH ON THE INVOLVEMENT OF INSULIN IN BRAIN AND CNS FUNCTION
In part VIII of this series I provided a basic overview of the involvement of insulin in brain and CNS function. I would now like to provide additional information, starting with the paper “The role of insulin resistance and glucose metabolism dysregulation in the development of Alzheimer’s disease” by Arrieta-Cruz and Gutierrez-Juarez (3). The first quote I would like to feature expands upon some of the information on the insulin/brain function connection that was discussed in part VIII of this series:
“The presence of insulin and the insulin receptor (IR) in the CNS suggests that the brain is a target for the action of insulin. Indeed, insulin exerts multiple effects in the brain, including neurotrophic, neuromodulatory, and neuroendocrine actions. Insulin reaches the brain via the blood brain barrier (BBB) or, in some instances, through its local production in the brain. IR has been found in high concentrations in several areas of the brain, including the olfactory bulb, hypothalamus, hippocampus, and cortex of rodent and human brains.”
Before continuing, please note again in the above quote the statement that in some instances insulin can be produced in the brain. This is in marked contrast to the quote presented in part VIII of this series by Rani et al (4) which stated that no insulin is produced in the brain. Is it important to resolve this conflict? According to Csajbok and Tamas (5) in their paper “Cerebral cortex: a target and source of insulin?” the answer is yes. The authors state:
“Whether insulin is produced locally in the central nervous system is not a trivial question to answer.”
Why does conflict exist on this point? The authors suggest:
“Initial studies on the subject suggested that immunoreactive insulin is present in the rat brain in concentrations 10 to 100 times higher than in the plasma, but this was challenged by subsequent findings, leading to the conclusion that ‘little or no insulin is produced in [the] brain.'”
Csajbok and Tamas (5) go on to discuss the reason for these divergent findings, which have to do with limitations in insulin assessment technology. Nevertheless, the authors feel that the most recent research in this area makes it clear that insulin is produced in the brain:
“Recent work has overwhelmingly shown that insulin is also synthesized locally in the cerebral cortex. Neuron-derived insulin is capable of rapid modulation of synaptic and microcircuit mechanisms and is suggested to regulate on-demand energy homeostasis of neural networks.”
Now, with that controversy hopefully resolved, I would like to continue my discussion of the Arrieta-Cruz and Gutierrez-Juarez (3) paper on insulin metabolism in the brain. As the authors note, which was also mentioned in part VIII of this series, insulin receptors in the brain are extremely important for cognitive function:
“The presence of functional insulin receptors (IRs) in the hippocampus and cerebral cortex are important for cognitive function.”
In addition, insulin plays a major role in the metabolism of the proteins involved in formation of senile plaques:
“More recent studies have indicated that insulin regulates the metabolism of the proteins Aβ and tau, the main components of senile plaques and neurofibrillary tangles, respectively, and constituents of the characteristic neuropathological lesions in AD.”
The next quote I would like to present from this paper makes an interesting and important point that I touched upon in part VIII. As I mentioned, it has been generally assumed that the connection between insulin and Aβ is a “one-way street” so to speak in that insulin dysregulation creates increased Aβ formation and not the other way around. Arrieta-Cruz and Gutierrez-Juarez (3), in agreement with what I have stated before, suggest otherwise. This relationship indeed can also go in the reverse direction, creating a potent vicious circle that could certainly complicate efforts at correction:
“These results unraveled a novel neurotoxic action of Aβ that perturbs hypothalamic glucoregulation, leading to increased hepatic glucose production and hyperglycemia. Furthermore, our findings provide a previously lacking piece of experimental evidence for a direct link between Aβ toxicity and altered glucose metabolism.”
To me, existence of this vicious circle supports my hypothesis suggested in part VIII of this series that, even though the evidence is clear that the existence of increased levels of Aβ and Aβ oligomers (AβO) in the Alzheimer’s disease/senile dementia brain are not the sole cause of dysfunction as suggested by many in the media and allopathic community, it still must be regarded as an important contributing factor. Arrieta-Cruz and Gutierrez-Juarez (3) conclude their paper by emphasizing not only the important role of suboptimal insulin metabolism in Alzheimer’s disease/senile dementia but the vicious circle relationship between insulin/glucose metabolism and Aβ:
“In conclusion, studies on the molecular and cellular mechanisms involved in the pathophysiology of AD and its relationship with insulin and glucose metabolism support the idea that the metabolic alterations of type 2 diabetes mellitus are strongly associated to the development of Alzheimer’s disease. Importantly, our recent studies in rodents provided a piece of evidence supporting the novel concept that Aβ toxic action in the hypothalamus causes a dysregulation of glucose metabolism directly linking altered insulin action with Alzheimer’s disease.”
Up to now my discussions on insulin metabolism in relationship to brain chemistry and development of Alzheimer’s disease/senile dementia have primarily revolved around Aβ, AβO, and formation of senile plaques. However, even though this relationship is quite compelling in terms of the relationship between insulin metabolism and the development of Alzheimer’s disease/senile dementia, recent research suggests that there is much more to the insulin/dementia connection. This new information was discussed in great detail in the paper “Insulin resistance as a link between amyloid-beta and tau pathologies in Alzheimer’s disease” by Mullins et al (6). The first key point made by the authors is that, while insulin, as suggested above, can be produced in the brain, the vast majority is produced in the periphery and must be transported through the blood-brain-barrier (BBB):
“While there is evidence that insulin is produced de novo in different brain regions, the general consensus remains that a majority of the insulin in the brain arrives from the periphery through the BBB, where it is concentrated to levels 50x higher than in circulating plasma independently of peripheral hormonal states.”
Unfortunately, chronic illnesses such as obesity that lead to a prolonged state of hyperinsulinemia/insulin resistance can compromise insulin uptake into the brain via the BBB. In turn, the lack of optimal brain levels of insulin can be associated with the development of Alzheimer’s disease/senile dementia independent of plaque formation. The authors state:
“Insulin receptor expression is also reduced in the BBB when there is prolonged peripheral hyperinsulinemia. The rate of insulin transport across the BBB is also slowed by obesity and aging. Obesity decreases the transport of insulin across the BBB, and this deficit can be reversed by starvation and caloric restriction. Aging leads to an overall decrease in the number of insulin receptors at the BBB. Insulin transport is diminished as a consequence, with CSF insulin levels being lower in both obese and older individuals. Insulin levels in the brain tissue of older individuals are also lower. Additionally, decreased CSF levels of insulin correlate with poorer cognitive performance in patients with diabetes or AD.”
Why is brain insulin so important for optimal cognitive performance? Mullins et al (6) point out:
“While the significance of this evidence is still debated, recent studies show that functional insulin signaling components in forebrain regions may exert a neuroprotective role in areas responsible for various functions of memory.”
Another aspect of the relationship between insulin and the development of Alzheimer’s disease/senile dementia that I have yet to mention is the role of vascular pathology in relation to cognitive function and how insulin resistance contributes to vascular pathology in the brain. Concerning this important relationship the authors first note:
“Vascular function is tightly coupled to insulin signaling and central to this relationship is endothelial dysfunction, which manifests through deficient vasodilation and improper vasoconstriction throughout the body in the setting of insulin resistance.”
In relationship to dementia, Mullins et al (6) state:
“Significant vascular pathology is frequently seen in older individuals with dementia. In fact, until the significance of neuritic plaques (NP) and neurofibrillary tangles (NFT) was unequivocally demonstrated, the prevailing view was that vascular pathology is primarily responsible for the cognitive effects in AD. Vascular dementia is thought to be the second most common form of dementia after AD, whereas mixed pathology dementia is being increasingly reported in the literature, with more than half of all dementia cases being attributed to dual pathology.”
Therefore, it appears that, for many if not most cases of dementia, the pathologic basis is both the formation of senile plaques and suboptimal circulation. What is the common thread that appears to link the two? As you can probably guess, it is suboptimal insulin metabolism:
“There is emerging evidence that insulin resistance and diabetes have significant implications in vascular contribution of cognitive impairment and dementia (VCID). It is well known that cerebral blood flow is decreased in diabetic patients. Cerebral small vessel disease (CSVD) is the cause of approximately 20% of strokes and the underlying etiology for many of the other pathologies previously mentioned. Importantly, CSVD is aggravated by diabetes.”
Lactate production and Alzheimer’s disease/senile dementia
As you may recall from your first-year biochemistry classes, the endpoint of glycolysis is the production of pyruvate. Ideally most of the pyruvate is converted to acetyl CoA which enters the Krebs cycle to be converted to ATP. However, the process of converting pyruvate requires optimal activity of what is known as the “pyruvate dehydrogenase complex.” Unfortunately, the activity of this complex is inhibited by insulin resistance (7). Because of this inhibition, alternative routes of energy production will be employed by the body, one of the most notable of which is increased production of lactate via the Cori cycle. Could the increased lactate production that accompanies insulin resistance have an adverse impact on brain function, thus contributing to the development of Alzheimer’s disease/senile dementia? Mullins et al (6) state:
“…an important study found that regional lactate production is closely linked to interstitial Aβ levels, establishing an additional link between glycolytic energy metabolism and a key pathogenic protein in AD. Lactate is produced by astrocytes as a product of glycolysis and can be used as an alternate neuronal energy substrate in conditions that do not favor aerobic metabolism. More recently, elevated lactate in transgenic AD mice compared to wild type mice was seen in vivo and in association with memory deficits. A putative interplay between increased reliance on glycolysis, increased production of lactate and ensuing increased extracellular Aβ has the potential of establishing a feed-forward loop that perpetuates and aggravates Aβ pathology in AD.”
More on the vicious circle between insulin resistance and Aβ
Recall the statements made above that not only does insulin resistance promote the formation of Aβ but Aβ appears to retard optimal insulin action and promotes insulin resistance. In the statement below, Mullins et al (6) point out one powerful reason why the impact of Aβ on insulin function is so significant. As you will see, insulin, when properly functioning and occurring in optimal amounts, actually assists in the clearance of Aβ:
“It has been shown that insulin promotes brain Aβ clearance, preventing its extracellular accumulation and plaque formation.”
Next, the authors offer additional information on the vicious circle between insulin and Aβ and AβO:
“…these data suggest a feed-forward loop where Aβ oligomers aggravate brain insulin resistance, which in turn decreases Aβ clearance and increases the propensity for Aβ oligomerization. Moreover, a recent study showed that Aβ oligomers acting at the hypothalamus (through a mechanism involving NF-kB signaling) trigger peripheral insulin resistance, potentially establishing a second feed-forward loop between AD pathology, peripheral insulin resistance and brain insulin resistance.”
Tau proteins, insulin resistance, and Alzheimer’s disease/senile dementia
In one of the above quotes it was briefly mentioned that another protein besides Aβ, tau protein, has been linked with the development of dementia. The quotes that follow from the Mullins et al (6) paper discuss tau protein and its relationship with insulin metabolism and cognitive function in more detail. To introduce this discussion on tau proteins, consider the following:
“Tau is a member of a large group of proteins known as microtubule associated proteins (MAPs). In its native conformation, tau is a soluble and unfolded protein involved in microtubule stabilization and axonal outgrowth. However, hyperphosphorylated tau tends to aggregate and these tau aggregates are seen in various neurodegenerative diseases. In AD, tau forms intracellular neurofibrillary tangles, which alongside extracellular Aβ neuritic plaques constitute the two main histopathological hallmarks of the disease.”
Next, consider the following quotes which demonstrate how Aβ, tau, increased lactate and insulin resistance all work together to promote cognitive dysfunction:
“One of the main enduring mysteries in AD is the different distribution of neurofibrillary tangles and neuritic plaques in the disease. The various lines of evidence reviewed above and the novel analysis presented enable us to formulate a bold new hypothesis that considers insulin resistance as an important link between Aβ and Tau pathologies in AD and the main determinant of their regional distribution.”
The authors continue:
“As mentioned already, extensive temporo-parietal areas of the brain show significant reliance on glycolysis, which generates lactate. High lactate is associated with high interstitial Aβ, which assembles into Aβ oligomers. These Aβ oligomers promote serine phosphorylation of IRS-1, impeding downstream insulin signaling and leading to brain insulin resistance. A feed-forward loop is established between insulin resistance and Aβpathology leading to progressive Aβ in neuritic plaques across extensive parts of the brain. Chronic insulin resistance promotes tau hyperphosphorylation and this effect is more pronounced in regions that show low expression of insulin signaling proteins at baseline (earlier adult life). As a result hyperphosphorylated tau leads to the development of neurofibrillary tangles in a different and more restricted regional pattern than Aβ. The sum of these three interrelated pathologies (IR, Aβ, Tau) produces Alzheimer’s disease.”
As I hope you can see, there are so many aspects to the development of Alzheimer’s disease/senile dementia beyond the generally recognized development of Aβ plaques. These include suboptimal brain circulatory dynamics, increased brain lactate, and tau proteins. What is the common thread that not only links them together but provides a powerful foundation not only for prevention but reduced disease progression among current AD sufferers? Insulin.
The last quote I would like to present from the Mullins et al (6) paper highlights still one more way that insulin resistance in the brain can contribute to cognitive dysfunction. As you will see, insulin resistance also has a direct impact synaptic activity:
“Besides its role in the development of Aβ and tau pathology, brain insulin resistance can also directly affect synaptic function and cognition. For instance, in mice, down-regulation of insulin receptors in the hippocampus impairs hippocampal long-term potentiation and spatial learning, whereas their down-regulation in the hypothalamus results in decreased hippocampal brain derived neurotrophic factor (BDNF).”
SOME FINAL THOUGHTS FOR PART IX OF THIS SERIES
By now it should be obvious to all of you that the large body of research on the insulin connection with Alzheimer’s disease/senile dementia is tremendously exciting for me. Why? For me, it is the first causational hypothesis on dementia that carries with it an implicit and realistic assumption that, while no cure is offered for prior loss of cognitive function and brain activity, there does exist a potentially highly effective and practical solution not only for prevention but for slowing progression in those individuals who are already afflicted. This is in marked contrast to many if not most of the causational theories I hear being advanced by the mainstream media and many in the allopathic community that suggest occurrence is almost completely random and any predictability of disease for one individual is due to genetics and other influences that are completely out of the control of potential sufferers. Compounding the problem of this “luck of the draw” causational hypothesis is the usual suggestion accompanying it that the only solution is pharmaceutical intervention that, at best, reduces symptoms but offers no real hope for retarding progression or even modestly reversing disease progress.
Of course, what is even more exciting about the insulin hypothesis for Alzheimer’s disease/senile dementia is that it provides a major opportunity for those practitioners who are highly skilled at insulin metabolism optimization to make significant inroads in preventing the cognitive dysfunction epidemic that is being predicted by many as the baby-boomers increase in age. Who are these practitioners who are best able to predictably and cost effectively optimize insulin metabolism in large segments of the population? For me, objective analysis makes the answer clear – nutritional and functional medicine practitioners like you who are adept at instituting patient specific lifestyle recommendations and supplemental programs along with, when appropriate, recommendations for pharmaceutical intervention.
In part X of this series I will review more research on the insulin/cognitive dysfunction connection along with complementary research that explores the impact of glycemic imbalance and oxidative stress. Also I will return to the discussion on inflammation and Alzheimer’s disease/senile dementia focusing on its relationship with suboptimal insulin metabolism.
Moss Nutrition Report #274 – 06/01/2017 – PDF Version
REFERENCES
- Bott NT et al. Dementia care, women’s health, and gender equity. JAMA Neurology. 2017;published online May 8, 2017.
- Fava A et al. Cognitive impairmente is correlated with insulin resistance degree: the “PA-NICO-study”. Metab Brain Dis. 2017;published online ahead of print February 23, 2017.
- Arrieta-Cruz & Gutierrez-Juarez. The role of insulin resistance and glucose metabolism dysregulation in the development of Alzheimer’s disease. Rev Inves Clin. 2016;68:53-8.
- Rani V et al. Alzheimer’s disease: Is this a brain specific diabetic condition? Physiology & Behavior. 2016;164:259-67.
- Csajbok EA & Tamas G. Cerebral cortex: a target and source of insulin? Diabetologia. 2016;59:1609-15.
- Mullins RJ et al. Insulin resistance as a link between amyloid-beta and tau pathologies in Alzheimer’s disease. Frontiers in Neuroscience. 2017;9.
- Hagve M et al. Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance. Am J Physiol Endocrinol Metab. 2015;308:E613-E20.
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