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Alzheimer's Association Creates Care-Plan Toolkit for Clinicians

Posted By Administration, Wednesday, April 26, 2017

After Medicare began covering care-planning visits for patients with cognitive impairment, the Alzheimer’s Association developed a toolkit to help clinicians provide better care.

In January, Medicare began covering care-planning sessions for patients with cognitive impairment, including Alzheimer’s disease and other dementias. In response, the Alzheimer’s Association has created the Cognitive Impairment Care Planning Toolkit to help physicians, nurse practitioners, and physician assistants provide the best care under the new Medicare code.

A change to the G0505 Medicare code means healthcare providers can get reimbursed for a clinical visit to develop a comprehensive care plan for a patient. It also helps providers identify community support services that are appropriate for the patient.

The Alzheimer’s Association, along with its sister organization, the Alzheimer’s Impact Movement, had pushed for this change. They had advocated for the Centers for Medicare & Medicaid Services to cover cognitive and functional assessments and care planning for patients with cognitive impairments.

“Diagnosing patients and linking them to services is a challenge,” said Beth Kallmyer, the association’s vice president of constituent services. This toolkit is “an opportunity to make a big difference in how people are diagnosed and how they’re linked to services.”

Most people with dementia are treated by primary care physicians, even if they are diagnosed by specialists, Kallmyer noted. The association had heard from doctors that putting together a care plan is time-consuming and difficult, so it assembled a group of specialists to decide what the association could offer to help clinicians conduct the care-planning session and implement the new Medicare code.

The toolkit helps clinicians understand what the code covers and provides resources to use in these sessions. It includes best practices and materials such as an overview of the code, validated tools to assist with diagnosis (including the Dementia Severity Rating Scale), a safety assessment guide, a caregiver profile checklist, and an end-of-life checklist.

Part of the association’s mission is to provide and enhance care and support for everyone affected by Alzheimer’s. Care planning helps improve outcomes and maintain quality of life. “It’s huge for people living with the disease,” Kallmyer said, explaining that some patients get diagnosed with dementia but then don’t receive much follow-up care or any comprehensive care planning.

Having a plan in place helps people living with the disease as well as their caregivers. A comprehensive plan can empower patients by giving them a better understanding of their future and allowing them to plan better for it, Kallmyer said. “They can say to their family, ‘This is how I want things to go.’”

“Alzheimer’s is one of the costliest diseases out there,” she said. A care plan helps families plan for when the patient might need to turn to residential care, for example. “Having a plan in place makes a big difference for families every single day with this disease.”

Now, the association is working on raising awareness and getting the word out to all the association’s 80 chapters about the toolkit and the resources it offers. “They are our boots on the ground,” Kallmyer said.

Tags:  alzheimer's  Toolkit 

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Tumeric and Alzheimer's Disease

Posted By Administration, Monday, August 23, 2010
Updated: Friday, April 18, 2014

by Holly Lucille, ND, RN 1481271856_d1046f2f35_b  

In India, Alzheimer's disease is relatively uncommon. People over the age of 65 living in certain rural areas of India have a less than 1 percent (0.84%) chance of developing the disease. In the larger cities and rural areas of India, the risk is just 2.4 percent.(1,2)

Compare these findings to people over the age of 65 living in the United States. Again, depending on where we are living, our chances of developing Alzheimer's disease range from a little under 5 percent to an astonishing 17 percent.(3,4)

So what are people who are living in India doing that we aren't doing here in the US to account for these dramatic differences? The answer seems to be curry, that zesty spice and staple of Indian foods. Research has shown that a compound in curry not only prevents changes in the brain that lead to Alzheimer's disease, it actually reverses some of the damage already present.(5)

  • How can curry prevent these changes in the brain? Isn't that a lot to expect from a spice?
Evidently, it's not too much to expect from this spice. Curry comes from the turmeric plant - Curcuma longa is the plant's official name. Curcumin, a plant compound in turmeric, is the source of curry's instantly recognizable bright yellow pigment. When it comes to the scientific research of Curcuma longa, the terms curcumin and turmeric are both used. Both refer to the same thing - turmeric extract.(6)

There have been more than 1300 studies on turmeric and its health benefits for humans. Research has shown turmeric is able to help the body get rid of cancer-causing toxins. Turmeric also blocks estrogen receptors and enzymes that promote cancer. And it's been found to stop the growth of new blood vessels in cancerous tumors - an important factor in keeping cancer from getting larger and spreading throughout the body.(7-9)

But one of turmeric's most exciting health benefits is its ability to reduce, prevent, and stop inflammation. While inflammation is a normal and needed response to injury or disease, chronic inflammation can cause damage to tissues. And researchers are now finding inflammation plays a huge role in Alzheimer's disease.

 


  • I've always heard that Alzheimer's disease was caused by complex growths in the brain called plaques and tangles. How can simple inflammation cause such a devastating disease?

You are right. Plaques and tangles are indeed the hallmarks of Alzheimer's disease. But researchers looking at the brain damage caused by Alzheimer's have always noted the presence of inflammation wherever plaques and tangles form.(10) In the past, this inflammation was thought to be simply a consequence of Alzheimer's disease. Now scientists believe the inflammation itself starts a chain reaction ultimately contributing to the development of Alzheimer's disease.(11)

When cells in the brain are disrupted by inflammation, amyloid, a protein normally found in the brain, begins to act chaotically. This chaos results in the creation of beta-amyloid, a protein that is toxic to cells in the brain. Sticky deposits of beta-amyloid build up and collect around the cells, making dense clumps or plaques. Because the brain can't break the plaques down or get rid of them, they stay right where they are and slowly accumulate.(10,12,13)

Tangles result when long protein fibers that act like scaffolding for brain cells begin to twist and tangle. The cell is damaged and eventually dies. But the tangled proteins remain in the brain even after the dead neuron has been cleared away.(10,14) And inflammation might be the culprit causing the long protein fibers to start tangling.(15)

The consequence of these abnormalities of protein in the brain is more than the cell death they cause. They also act as roadblocks, interfering with electrochemcial messengers being shot from cell to cell. Therefore, the remaining healthy cells’ activity is diminished as well.

Research of identical twins has repeatedly shown that if one twin has Alzheimer's disease, the other has a 60% chance of developing the disease, too. Scientists from the Karolinska Institute in Stockholm, Sweden, looked at information from 20,000 twins collected in the 1960s and found 109 pairs of siblings where only one twin had been diagnosed with Alzheimer's. When the Swedish researchers analyzed data about the twins' health, they found the twin with Alzheimer's disease almost always had chronic gum disease. While bleeding gums are definitely not the cause of Alzheimer's disease, the inflammation that plays a large part of chronic gum disease may signal an inflammatory process stuck in overdrive.(16)

In fact, the inflammatory process might occur years before the onset of Alzheimer's, and be the result of any number of infections people can contract. That's why current research is searching for ways to protect brain cells from inflammation. And why some countries have low rates of Alzheimer's disease, like India.

  • Why curry? Couldn't other lifestyle differences account for the low rates of Alzheimer's disease in India?

That's a good question. When researchers begin studying a disease, like Alzheimer's, they look for trends to help them determine how and why the disease occurs. For example, we all now know the connection between cigarette smoking and lung cancer. But, it wasn't until the 1930's that doctors noticed the trend for cigarette smokers to have more lung cancer than people who didn't smoke.(17)

So it has been with researchers studying Alzheimer's disease. They know Alzheimer's disease has an important connection to inflammation. They also know turmeric reduces inflammation. And when researchers noticed these trends - that people in India eat high amounts of curry from turmeric and have very little Alzheimer's disease - they began to theorize that turmeric might be able to prevent or even treat the illness. And the research they designed around these trends has unequivocally found turmeric to be one common denominator.(18-21)

  • What have the turmeric studies shown so far?

Simply amazing findings are coming from curry research. Not only does turmeric slow down cancer growth, it's also been found to correct the cystic fibrosis defect in mice, help prevent the onset of alcoholic liver disease, and may slow down other serious brain diseases like multiple sclerosis.(22)

Researchers from the University of California Los Angeles (UCLA) studying turmeric have found it to be more effective than the drugs currently being investigated for Alzheimer's disease treatment and prevention. The researchers have discovered the actual structure and shape of turmeric allows it to penetrate the blood-brain barrier effectively and bind to beta amyloid.(23) Other research findings shows turmeric helps remove beta-amyloid that's already built up in the neurons.(24) Turmeric helps maintain healthy brain cellular metabolism, helps the cells repair themselves, and keeps the cells connected to each other.(25,26) In other words, turmeric helps brain cells stay healthy.

And now the UCLA Alzheimer's Disease Research Center (ADRC) is using turmeric in clinical trials and studying the effect of this powerful spice in patients diagnosed with this devastating disease. Clinical trials are the gold standard of medical research. But it's rare in Alzheimer's disease. And it's even more rare when all-natural herbs and spices like turmeric are used in hopes that positive benefits will be discovered. The head of UCLA's research team was recently interviewed and stated that setting out to hopefully prove turmeric's ability to prevent and treat Alzheimer's disease was “tremendously exciting.”(27)

  • I recently read that one of the nonsteroidal anti-inflammatory drugs (NSAID) was found to prevent Alzheimer's disease. Is this true?
Scientists recently studied ibuprofen, one of the NSAIDs investigated for Alzheimer's Disease Prevention.(28) Ibuprofen belongs to a family of drugs that includes naproxen, indomethacin, nabumetone, and several others. These drugs are used most often to get rid of headaches, mild arthritis, and other kinds of pain and inflammation.(29) In the studies, the average dose of ibuprofen was 800mg a day. Patients took the product for two years. While the results suggested that ibuprofen might reduce the risk of developing Alzheimer's, ibuprofen's side effects are too harmful to be a valid lifelong prevention aid treatment.(28) Ibuprofen, like other NSAIDs, can cause gastrointestinal bleeding when used at high dosages over a long period of time. Long term use of ibuprofen can also lead to analgesic nephropathy, a kind of kidney damage caused by NSAIDs.(29)

As we discussed earlier, turmeric appears to block and break up brain plaques that cause the disease and helps reverse some of the damage already present.(19,21,26) Ibuprofen does not provide any protection against free radical damage. No anti-inflammatory medicine can do this.(29)

  • If I eat curry will I be protected against Alzheimer's disease? There aren't many foods or recipes I make that require curry, do I need to eat it every day? And how much do I need?

If you enjoy Indian cuisine, by all means, enjoy these delicious foods. You'll benefit your brain and your appetite. But you make a good point, American meals rarely contain curry. That's why supplements that contain extracts are suddenly quite popular. In fact, there are numerous turmeric/curcumin supplements on the market today.

But like all nutritional supplements, some turmeric supplements are superior to others. You need to read their labels to make sure the turmeric extract you are buying will provide the protection you need. Look for high-potency turmeric extract from turmeric (Curcuma longa) rhizome. And make sure the extract is standardized to contain 90% curcuminoids, the active ingredient in turmeric responsible for the positive research findings.

Conclusion

Researchers once thought that preventing for Alzheimer's disease would elude them for decades. In fact, several scientists privately speculated the disease might never be ameliorated. They thought the origin of the disease was too complex and the symptoms of the disease were too profound. That's why the ongoing research on turmeric is so exciting. A safe, natural, and effective way to protect against Alzheimer's disease almost seems too good to be true. But, the nation of India and its low incidence of Alzheimer's disease are proof these are not just fluke findings - making turmeric extract a supplement to remember.

References

1. Jha S, Patel R. Some observations on the spectrum of dementia. Neurol India. 2004;52:213-4.

2. Vas CJ, Pinto C, Panikker D, et al. Prevalence of dementia in an urban Indian population. Int Psychogeriatr. 2001;13:439-50.

3. The Alzheimer's Disease Fact Sheet. Alzheimer's Disease Education & Referral Center. A service of the National Institute of Aging. Accessed on September 8, 2005. Available at: http://www.alzheimers.org/pubs/adfact.ht ml#Contents.

4. Chandra V, Pandav R, Dodge HH, et al. Incidence of Alzheimer's disease in a rural community in India: the Indo-US study. Neurology. 2001;57:985-9. 5. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res. 2005;2:131-6.

6. Curcuma longa (turmeric). Monograph. Altern Med Rev. 2001;6 Suppl:S62-6.

7. Sharma RA, Gescher AJ, Steward WP.Curcumin: The story so far. Eur J Cancer. 2005;41:1955-68.

8. Weber WM, Hunsaker LA, Abcouwer SF, Deck LM, Vander Jagt DL. Anti-oxidant activities of curcumin and related enones.Bioorg Med Chem. 2005;13:3811-20.

9. Karunagaran D, Rashmi R, Kumar TR. Induction of apoptosis by curcumin and its implications for cancer therapy. Curr Cancer Drug Targets. 2005;5:117-

10. Curtis SM, Porth CM. Alzheimer's disease. In: Porth CM. Pathophysiology: Concepts of Altered Health States. 5th ed. Philadelphia, Pa: Lippincott; 2002: 914- 917.

11. Fryer JD, Holtzman DM. The bad seed in Alzheimer's disease. Neuron. 2005;47:167-8.

12. Kranenburg O, Bouma B, Gent YY, et al. Beta-amyloid (Abeta) causes detachment of N1E-115 neuroblastoma cells by acting as a scaffold for cell-associated plasminogen activation. Mol Cell Neurosci. 2005;28:496-508.

13. Morgan C, Colombres M, Nunez MT, Inestrosa NC. Structure and function of amyloid in Alzheimer's disease. Prog Neurobiol. 2004;74:323-49.

14. Liazoghli D, Perreault S, Micheva KD, Desjardins M, Leclerc N. Fragmentation of the Golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons. Am J Pathol. 2005;166:1499-514.

15. Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol. 2005;18:315-21.

16. Andel R, Crowe M, Pedersen NL, Mortimer J, Crimmins E, Johansson B, Gatz M. Complexity of work and risk of Alzheimer's disease: a population-based study of Swedish twins. J Gerontol B Psychol Sci Soc Sci. 2005;60:P251-8.

17. Heady JA, Kennaway EL. The increase in deaths attributed to cancer of the lung. Br J Cancer. 1949;3:311-20.

18. Park SY, Kim DS. Discovery of natural products from Curcuma longa that protect cells from beta-amyloid insult: a drug discovery effort against Alzheimer's disease. J Nat Prod. 2002;65:1227-31.

19. Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005;280:5892-901.

20. Ono K, Hirohata M, Yamada M. Ferulic acid destabilizes preformed beta-amyloid fibrils in vitro. Biochem Biophys Res Commun. 2005;336:444-449.

21. Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. J Neurosci Res. 2004;75:742-50.

22. Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci. 2004;1030:434-41.

23. Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005;280:5892-901.

24. Giri RK, Rajagopal V, Kalra VK. Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor. J Neurochem. 2004;91:1199-210.

25. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001;21:8370-7.

26. Cole GM, Morihara T, Lim GP, Yang F, Begum A, Frautschy SA. NSAID and Antioxidant Prevention of Alzheimer's Disease: Lessons from In Vitro and Animal Models. Ann N Y Acad Sci. 2004;1035:68-84.

27. The Univerity of California at Los Angeles (UCLA) Alzheimer's Disease Research Center (ADRC) Current studies: Mild to Moderate Alzheimer's Disease and Curcumin. Information available at the ADRC Website: http://www.npistat.com/adrc/Treatment. asp.

28. Pasinetti GM. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in betaamyloidosis and clinical dementia. J Alzheimers Dis. 2002;4:435-45.

29. What You Need to Know About Nonsteroidal Anti-Inflammatory Medications (NSAIDs). The Cleveland Clinic Health Information Center. Accessed on September 8, 2005. Available at: http://www.clevelandclinic.org/health/h ealthinfo/ docs/0700/0714.asp?index=4901.

Tags:  alzheimer's  tumeric 

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The Relationship Between Alzheimer's Disease and Diabetes: Type 3 Diabetes?

Posted By Administration, Friday, April 9, 2010
Updated: Friday, April 18, 2014

Zina

Published in Alternative Medicine Review, Volume 14, Number 4 2009

by Zina Kroner, DO

 

 

 

Abstract 

In recent years, Alzheimer’s disease (AD) has been considered to be, in part, a neuroendocrine disorder, even referred to by some as type 3 diabetes. Insulin functions by controlling neurotransmitter release processes at the synapses and activating signaling pathways associated with learning and long-term memory. Novel research demonstrates that impaired insulin signaling may be implicated in AD. Post-mortem brain studies show that insulin expression is inversely proportional to the Braak stage of AD progression. It was also demonstrated that neurotoxins, coined amyloid beta-derived diffusible ligands (ADDLs), disrupt signal transduction at synapses, making the cell insulin resistant. ADDLs reduce plasticity of the synapse, potentiate synapse loss, contribute to oxidative damage, and cause AD-type tau hyperphosphorylation. Diabetes and AD have signs of increased oxidative stress in common, including advanced glycation end products (AGEs), when compared to normal subjects. Diabetic patients appear to have an increased risk for AD because AGEs accumulate in neurofibrillary tangles and amyloid plaques in AD brains. This research should encourage a more proactive approach to early diagnosis of diabetes and nutritional counseling for AD patients. (Altern Med Rev 2009;14(4):373-379) 

Introduction 

The epidemic of insulin resistance/prediabetes and type 2 diabetes may be associated with the emergence of higher rates of Alzheimer’s disease (AD). New research delineates a direct correlation between sugar imbalance and AD. AD is associated with consistent pathological findings, including neurofibrillary tangles, amyloid-beta deposits, and signs of oxidative stress. No common link among the proposed pathological processes has been identified. Novel evidence demonstrates that impaired insulin signaling may significantly contribute to the pathogenesis of AD, contributing to the idea that it is actually a neuroendocrine disease. Neurotoxins called amyloid beta-derived diffusible ligands (ADDLs) have been implicated as a cause of impaired insulin signaling. Advanced glycation end products (AGEs) are found in higher concentration in both hyperglycemia and AD, contributing to oxidative stress and cell damage. These AGEs are known to be further modified to reactive advanced glycation end products, (RAGEs), which can generate oxidative injury. 

Understanding the mechanism of action of this neuroendocrine disorder, termed type 3 diabetes by some, may shed light on new tools for diagnosing and treating AD and for the need for early intervention in obese patients with insulin resistance. 

The Clinical Link: Diabetes and AD 

The research linking diabetes and AD has its roots in the groundbreaking Rotterdam study. Of 6,370 elderly subjects studied for 2.1 years, 126 developed dementia; 89 of these were specifically diagnosed with AD. Type 2 diabetes doubled the risk of a patient having dementia and patients on insulin had four times the risk.As rates of insulin resistance and diabetes in the senior population are both increasing, this landmark study, conducted almost a decade ago, has been getting more attention in recent years since further studies have solidified the connection between diabetes and AD.

Since type 2 diabetes is reaching epidemic proportions and is under-diagnosed, and AD may be associated with hyperglycemia, more attention should be drawn to early diagnosis of diabetes. The Gertner Institute for Epidemiology and Health Policy Research in Israel, in a recently published 25-year, cross-sectional study of 623 adults, demonstrated that approximately 13 percent of the studied population had undiagnosed type 2 diabetes. This study reinforces the importance of early diagnosis of type 2 diabetes by identifying patients with risk factors, including hypertension, hypertriglyceridemia, and a large waist circumference (males: ≥40 inches [102 cm], females: ≥35 inches [88 cm]) – factors seen in metabolic syndrome. These results encourage early detection via screening methods targeting those with traits of metabolic syndrome in otherwise healthy adults.

Another study demonstrating the high prevalence of diabetes showed almost one-third of elderly patients in a sample of 7,267 subjects had diabetes, and three-fourths had impaired fasting glucose (glucose lev- els >99 but <126) or diabetes.

Elevated body mass index (BMI), adiposity, impaired fasting glucose, and diabetes increase the risk of AD substantially. The latest study, utilizing data on 2,322 participants in the Baltimore Longitudinal Study of Aging, shows the incidence of AD increased in men who gained weight between the ages of 30 and 45 and in women with a BMI >30 at ages 30, 40, and 45.7 This suggests more emphasis should be placed on early weight-loss strategies for preventing AD. 

A 2008 Swedish study showed a statistically significant increase in the risk of developing AD in men who develop type 2 diabetes in midlife. The researchers followed 2,269 men for 32 years and found that those with low insulin production at age 50 were 150-percent more likely to develop AD than those with adequate insulin production. This association was greatest in patients who did not have the apolipoprotein E4 (ApoE4) genetic predisposition to AD (which renders individuals less efficient at breaking down beta-amyloid plaques), thereby making diabetes a possible independent risk factor for AD. This study illustrates the importance of maintaining healthy blood glucose control in middle-aged men as a possible means of preventing AD later in life. 

A recent investigation suggests that AD is associated with metabolic syndrome. After studying 50 patients diagnosed with AD and comparing them to 75 cognitively normal controls, the AD patients had a greater waist circumference, higher triglyceride and glucose levels, and lower high-density lipoprotein cholesterol. Patients with metabolic syndrome are diagnosed with AD at a younger age than AD patients without metabolic syndrome.

Type 3 Diabetes: Is It Actually a Unique Condition? 

The term type 3 diabetes was coined in 2005 by Suzanne de la Monte, MD, MPH, Associate Professor of Pathology and Medicine and neuropathologist at Brown Medical School. Her team, examining postmortem brain tissue of AD patients, found that AD may be a neuroendocrine disease associated with insulin signaling. The team termed it type 3 diabetes because it harbors elements of both types 1 and 2 diabetes, since there is both a decrease in the production of insulin and a resistance to insulin receptors.

The team analyzed 45 postmortem brains of patients of varying Braak stages of AD neurodegeneration and found that insulin expression was inversely proportional to the Braak stage, with an 80-percent decrease in the number of insulin receptors in AD patients compared to normal subjects. In addition, the ability of insulin to bind to the receptors was compromised. There was a reduced level of mRNA corresponding to insulin, insulin-like growth factor-1 (IGF-1) and -2 polypeptides, and their receptors. The research team also noted a reduction in the tau protein, which is regulated by insulin and IGF-1. This phenomenon ultimately could lead to neuronal cell death and AD exacerbation.  

The postmortem studies inspired a rat study in which intracerebral injection of streptozotocin resulted in a chemical depletion of insulin and an alteration of IGF-signaling mechanisms together with oxidative injury. The combination of alterations resulted in neurodegeneration, including reduction in brain size and other neurological changes seen in AD.

AD is characterized by a reduction in the utilization of glucose, and treatment with insulin has been associated with improved memory. Insulin, important in memory processing, crosses the blood-brain barrier and is even produced in brain tissue itself. AD patients have less insulin and fewer insulin receptors than non-AD patients, and correction of insulin levels improves cognition. Insulin binds to insulin receptors in the brain, most of which are located in the cerebral cortex, olfactory bulb, hippocampus, cerebellum, and hypothalamus. Since there are more insulin receptors in the cognitionpertinent areas of the brain, it is logical to consider the association between insulin and cognition.

Several studies utilizing intranasal, intravenous, and intracerebral administration of insulin demonstrate improved cognition. A study utilizing intranasal insulin showed that its administration enhanced verbal recall in normoglycemic adults with early AD or cognitive impairment. In the study, 25 participants were randomly assigned to receive either placebo (n=12) or 20 IU intranasal insulin (n=13) twice daily. After 21 days of treatment, changes in cognition were measured. The fasting plasma glucose and insulin levels were unchanged with treatment. However, when compared with the placebo treated subjects, the insulin-treated subjects retained more verbal information and displayed superior attention and functional status. 

A study utilizing intravenous (IV) insulin assessed cognitive performance in 22 adults with AD and 15 normal adults receiving five consecutively higher IV doses of insulin resulting in five plasma insulin levels (10, 25, 35, 85, and 135 microU/mL), while plasma glucose levels of ~100 mg/dL were maintained. Cognitive performance was measured after 120 minutes of infusion. AD patients who were ApoE4-positive were found to have improved memory at lower insulin levels of 25 microU/mL, compared to their ApoE4-negative counterparts, who required a higher blood insulin level of 35 and 85 microU/mL before an improvement in memory was noted. Interestingly, normal adults also showed improved memory at insulin levels of 25 and 85 microU/mL. This shows that AD patients who are ApoE4-negative may not be as sensitive to insulin.  

A study utilizing intracerebroventricular insulin showed that its administration enhanced memory formation in rodents undergoing a step-through passive avoidance task These studies suggest that insulin may have a role in enhancement of cognition and memory. The other implication is that patients with the ApoE4 genetic predisposition to AD may not reap the benefits of improvement in AD by glycemic control. 

Based on a recent epidemiological study, individuals who are ApoE4-positive are not more likely to be insulin resistant than those who are ApoE4-negative. Therefore, insulin resistance and being positive for the ApoE4 allele are independent risk factors for AD; having both may pose an additive risk. 

Pathophysiological Connections between Insulin and AD 

AD is characterized by both low insulin levels and insulin resistance within the central nervous system (CNS), as opposed to type 2 diabetes, which is characterized by high insulin levels and insulin resistance outside of the CNS. Insulin resistance and hyperinsulinemia cause a reduction in brain insulin. Several mechanisms might explain why insulin mediates memory facilitation. As noted, insulin receptors are found in areas of the brain responsible for cognition. Insulin activates signaling pathways associated with learning and long-term memory. According to de la Monte, insulin helps to regulate processes such as neuronal survival, energy metabolism, and plasticity. These processes are required for learning and memory.  Peripheral insulin resistance, therefore, affects cognition.

In addition to regulating blood sugar levels, insulin functions as a growth factor for all cells, including neurons in the brain. Thus, insulin resistance or lack of insulin, in addition to adversely affecting blood sugar levels, contributes to degenerative processes in the brain.

When insulin levels reach an exceedingly high level, the beta-amyloid peptide, the hallmark of AD that accumulates in senile plaques, is modulated. Exaggerated elevation of plasma insulin levels causes amyloid peptide levels in the cerebrospinal fluid to increase, resulting in memory insult.

Amyloid beta-Derived Diffusible Ligands 

A group of researchers at Northwestern University studied why brains of AD patients are both low in, and resistant to, insulin. According to William Klein, PhD, who led the research, amyloid beta-derived diffusible ligands may be responsible for the phenomenon. ADDLs are oligomers similar in morphology and size to prions that have been linked to neurodegenerative disease. ADDLs may contribute to lowered insulin levels and insulin resistance in AD brains. Because the ADDLs are so small, they are more diffusible and therefore more harmful than amyloid. 

In healthy brains, insulin binds to a receptor at a synapse, resulting ultimately in memory formation. Klein’s team found that ADDLs disrupt this mechanism of communication by binding to the synapse and changing its shape, thereby causing dysfunction. Because the shape of the synapse is altered, insulin cannot effectively bind, disrupting signal transduction and resulting in insulin resistance. ADDLs have been shown to reduce the plasticity of the synapse, potentiate synapse loss, cause oxidative damage, and result in AD-type tau hyperphosphorylation, mechanisms linked to AD. Since ADDLs have been shown to affect neuronal insulin receptor signaling, it has been suggested that insulin resistance in the AD brain is a response to  ADDLs, inducing a neurological form of diabetes.  Neurons with no ADDLs show an adequate number of insulin receptors. 

Measuring ADDL levels may potentially be a novel tool for diagnosing AD. In 2005, the ultrasensitive bio-barcode assay was used to measure ADDL concentration in cerebrospinal fluid. Of 30 subjects, ADDL concentrations were found to be higher in those diagnosed with AD compared to non-AD patients. This test is not readily available and less invasive testing is underway. An ADDL vaccine is being studied and ADDL-blocking drugs are being considered by Klein et al.


Insulin and the Cholinergic Hypothesis 

The cholinergic hypothesis that suggests AD is caused by an inadequate production of acetylcholine may also have links to blood sugar abnormalities and insulin resistance. The researchers at Brown point out that insulin also participates significantly in neurological function by stimulating the expression of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine synthesis. Therefore, suboptimal insulin levels as well as poor insulin receptor sensitivity can ultimately contribute to a decrease in acetylcholine, which further elucidates a possible bio-chemical link between diabetes and AD.

AGEs and Oxidation – Common Thread between Diabetes and AD 

Another mechanism linking diabetes with AD is that both diseases, as mentioned previously, are associated with increased oxidative stress and production of AGEs. Although the association between vascular dementia and AGEs is well established, new research points to a link between AGEs and AD. AGEs are formed by a sequence of events originally identified in 1912 as the end-products of the Maillard reaction, during which reducing sugars can react with the amino groups of proteins to produce cross-linked complexes and unstable compounds. 

AGEs have been found in retinal vessels, peripheral nerves, kidneys, and the CNS of diabetics. AGEs couple with free radicals and create oxidative damage, which in turn leads to cellular injury. Diabetic patients could have an increased risk of AD via AGE production. Oxidative stress on its own also causes AGEs, creating a vicious cycle.

AGEs are also known to modify plaques and neurofibrillary tangles, both implicated in AD. AGEs have been identified in neurofibrillary tangles (consisting of tau protein) and senile plaques (consisting of beta-amyloid protein). Since type 2 diabetes accelerates the production of AGEs, it may be another causative factor in the development of AD. It has been proposed that a potential biomarker for early detection of AD may be measurement of toxic AGEs in the serum or cerebrospinal fluid.

Conclusion 

Understanding that AD has its foundation in neuroendocrinology is persuasive evidence that there should be greater emphasis on early diagnosis of metabolic syndrome, insulin resistance, and type 2 diabetes. Referring to AD as type 3 diabetes has its foundation in the fact that the CNS in AD is characterized by a paucity of insulin and resistance of the insulin receptors. This results in cognitive dysfunction, since insulin is crucial for neurological signaling processes to occur. Insulin also participates in neurological function by stimulating the expression of ChAT, the enzyme responsible for acetylcholine synthesis; acetylcholine is in turn a necessary neurotransmitter for cognition. AGEs, found in greater amounts in diabetic patients compared to controls with normal glucose regulation, have also been found in high concentration in AD brains. 

The links between hyperglycemic states and AD can allow for better future diagnostic strategies. Since ADDLs may contribute to lowered insulin levels and insulin resistance in AD brains, the future of diagnosis may entail the measurement of ADDLs. Measurement of AGEs has also been proposed. 

Treatment strategies utilizing this information require more research. The knowledge that there is a reduction of the sensitivity to insulin in AD patients who are not ApoE4-positive suggests that optimization of blood sugar levels may have therapeutic benefits. Insulin-sensitizing agents may potentially be used in the setting of early AD. 

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