Brain Insulin Resistance in Alzheimer Disease and Its Potential Treatment With a Mediterranean Diet and GLP-1 Analogues

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This article explains why brain insulin resistance is a risk factor for Alzheimer disease and how that risk may be reduced by lifestyle changes and drug treatments to reduce brain insulin resistance.

At the end of this article, participants should be able to:

1. Understand the mechanisms responsible for peripheral and brain insulin resistance.

2. Recognize the connection between brain insulin resistance and cognitive impairment.

3. Identify 2 novel treatments that might improve clinical outcomes.

Alzheimer disease (AD) poses a public health risk of epidemic proportions worldwide.¹ Until recently, it was defined as a type of dementia associated with abnormally high densities of amyloid-β (Aβ) plaques and neurofibrillary tangles in the forebrain. As defined now, however, AD encompasses the pathophysiological processes producing these biological and behavioral states.² Over the course of a decade or more, AD progresses in three stages: (1) a preclinical stage with no apparent behavioral symptoms, (2) an early clinical stage known as mild cognitive impairment (MCI due to AD), and (3) frank dementia.³ This last stage, the most common of the neurodegenerative dementias, is among the most devastating of chronic human disorders, ultimately robbing its victims of their identity, capacity to care for themselves, and the ability to consistently recognize or communicate with others.

While over 100 pharmacological treatments for AD have been proposed and tested, most seeking to reduce brain levels of Aβ, none has proved more than minimally effective.⁴ If this situation persists, the number of Americans with AD today is expected to grow from 5.2 million today to at least 13.8 million by 2050, with health care costs for those afflicted rising from $203 billion to $1.2 trillion.³

This article explains the rationale and evidence for 2 novel treatments of AD: a reformulated Mediterranean diet and an antidiabetic agent, liraglutide, marketed as Victoza.

Peripheral and brain insulin resistance are common and early features of AD

AD shares many age-accelerated features of type 2 diabetes mellitus (T2D), among them reduced insulin responsiveness of tissues outside the CNS (ie, peripheral insulin resistance), elevated inflammatory and oxidative stress, increased amyloid aggregation (pancreatic islet amyloid in T2D), tau hyperphosphorylation, and cognitive decline.⁵ The many shared features of the two disorders suggest that they share some causal factors, which is consistent with evidence that T2D raises risk of AD by about 60%.⁶

Of the shared features of AD and T2D, the one most likely to be a causal factor in AD is peripheral insulin resistance, which is found in 76% of Americans 65 years or older.^7,8 Peripheral insulin resistance by itself is a risk factor for AD and is associated with AD brain pathology, abnormal brain insulin signaling, and cognitive deficits.⁹ As shown in rats, peripheral insulin resistance induced by a high-fructose diet triggers brain insulin resistance, reduces synaptic plasticity, and impairs cognition.¹⁰ Peripheral insulin resistance induced by a high-fat diet in a mouse model of AD similarly exacerbates brain insulin resistance, raises brain levels of Aβ, and worsens cognitive deficits.¹¹

These findings indicate that peripheral insulin resistance promotes brain insulin resistance and can thereby impair cognition. That the brain in AD is insulin-resistant was only recently demonstrated physiologically. Our research team⁹ showed this using ex vivo stimulation. We measured brain responses to physiological doses of insulin (1 nM) applied to brain tissue from AD dementia patients and healthy controls of the same sex and similar age who had died within about 6 hours of autopsy. To reveal whether any abnormality in brain responsiveness to insulin was a general factor in AD, we excluded patients with a history of diabetes. We specifically tested an insulin signaling pathway whose disruption in peripheral tissues is known to cause insulin resistance. In that signaling pathway, insulin binding of its receptor (IR) at the cell surface activates insulin receptor substrate 1 (IRS-1) within the cell, leading to activation of phosphatidylinositol-3 kinase (PI3K), then Akt, and finally the mammalian target of rapamycin (mTOR).

In all the brain areas we studied, including the hippocampal formation (HF = hippocampus + dentate gyrus + subiculum), when insulin was applied to AD tissue, it consistently induced less activation of the signaling pathway than when it was applied to healthy tissue. In the HF of the AD dementia patients, the reduction in activation was 29% to 34% at the level of the IR, 90% at the level of IRS-1, 96% at the level of PI3K, 89% at the level of Akt, and 74% at the level of mTOR.⁹ The first molecule in the insulin signaling pathway to show severe dysfunction was thus IRS-1, which consequently appeared to be a central factor in brain insulin resistance. Increasing the dose of insulin tested to 10 nM, which is higher than intranasal insulin doses tested thus far, was unable to significantly increase tissue responsiveness.

Our subsequent ex vivo stimulation studies have shown lesser, but significant, brain insulin resistance in the HF of patients with MCI (H-Y Wang et al, unpublished data, 2013). Given that nearly half the American populace aged 45 to 64 years has prediabetes (ie, peripheral insulin resistance but not hyperglycemia),⁷ it is likely that brain insulin resistance begins to develop with normal aging but accelerates in the transition from the preclinical to the MCI stage of AD. Peripheral hyperglycemia is not necessary for development of brain insulin resistance, because that occurred in our patients with MCI or AD dementia even though they lacked a history of diabetes.

AD is not type 3 diabetes mellitus (T3D), but rather an insulin resistance syndrome

Many have interpreted the similarities between T2D and AD coupled with evidence of brain insulin resistance in the latter disorder as evidence that AD represents a third type of diabetes mellitus targeting the brain. This is misleading for at least 2 reasons. First, the term “diabetes” is inappropriate: the defining diagnostic feature shared by type 1 diabetes mellitus and T2D is not insulin resistance, but hyperglycemia, which is not a known feature of the brain in AD or animal models of that disorder. Second, while brain glucose metabolism is reduced in AD, that phenomenon appears unrelated to brain insulin resistance, which does not play a role in neuronal glucose uptake.⁹ The term “T3D” incorrectly implies, then, that the many deleterious effects of hyperglycemia and decreased cellular glucose uptake are playing a role in brain insulin resistance.

Rather than T3D, brain insulin resistance in AD is more aptly described as a neuronal form of Reaven insulin resistance syndrome,¹² a condition characterized by insulin resistance coupled to at least a subset of its associated abnormalities in other tissues (eg, inflammation, dyslipidemia, and endothelial dysfunction). This syndrome, a core element of the more expansive metabolic syndrome, is not a separate medical disorder but rather an aspect of different clinical conditions (eg, T2D, cardiovascular disease, and essential hypertension).¹² Our work suggests that both MCI and AD can be added to that list of medical conditions.

IRS-1 inhibition by Aβ and cytokines can trigger braininsulin resistance in AD

Aβ oligomers and several inflammatory cytokines (eg, tumor necrosis factor α and interleukin-6) activate a number of enzymes that serine phosphorylate IRS-1 and thereby inhibit its activation by the IR.^9,13 Such phosphorylation is known to cause peripheral insulin resistance in adipocytes and skeletal muscle.¹⁴ Brain insulin resistance appears to have the same cause, because the previously noted reductions in insulin-induced IRS-1 activation seen in brains of persons with AD dementia occur in the presence of abnormally high basal levels of IRS-1 serine phosphorylation (IRS-1 pS).⁹ Basal phosphorylation at 2 sites, IRS-1 pS616 and IRS-1 pS636, are consistently elevated in insulin-resistant brain tissues and may thus be biomarkers of brain insulin resistance.⁹ Levels of IRS-1 pS616 and IRS-1 pS636 rise to some extent in brains of normal persons with advanced aging, consistent with the view that brain insulin resistance is a feature of normal aging that is markedly accelerated in AD. This process appears closely associated with cognitive decline, because levels of IRS-1 pS and other markers of impaired insulin signaling in the hippocampus are strongly and negatively associated with global cognition, episodic memory, and working memory scores of both persons without and patients with MCI and AD dementia.⁹

Brain insulin resistance can promote most AD pathologies and cognitive deficits

Insulin is best known as a pancreatic β cell hormone secreted in response to elevated plasma glucose levels after meals. The classic functions of such secretion are to stimulate glucose uptake by adipose and muscle tissue and to inhibit no longer needed free fatty acid release by adipose tissue and glucose production by the liver. But insulin is also synthesized in the brain, including the adult cerebral cortex and hippocampus,¹⁵ where the density of insulin receptors is appreciable in pyramidal cell layers.¹⁶ Indeed, most insulin in the brain, with the possible exception of the hypothalamus, seems locally derived since loss of pancreatic β cells or alterations in their insulin secretion has little, if any, effect on total levels of brain insulin.¹⁷ It is likely, then, that brain insulin resistance outside the hypothalamus reflects decreased responsiveness to locally derived, not pancreatic, insulin.

Unlike insulin in peripheral tissues, insulin in the brain does not control cellular uptake of glucose, although it might modulate such uptake.⁹ But insulin does far more than regulate glucose metabolism in both peripheral tissues and the brain. In the brain, it promotes most functions disrupted in AD, namely (1) Aβ clearance; (2) tau phosphorylation; (3) blood flow regulation; (4) inhibition of apoptosis, inflammatory responses, and lipid catabolism; (5) facilitation of transmitter receptor trafficking; (6) synaptic plasticity; and (7) memory formation.^18,19

Brain insulin resistance consequently has the potential to cause or contribute to the full spectrum of AD pathology and symptoms. The rate at which insulin resistance develops in the brain may thus play a large role in determining the rate at which AD progresses.

Exercise and diet may slow progression of age-related brain insulin resistance

Between the ages of 45 and 64 years, the prevalence of prediabetes⁷ and T2D8 in the US rises steeply, which reflects a steep rise in peripheral insulin resistance. This can raise the risk of brain insulin resistance as explained above. Although more research is needed to test its actual effectiveness, the most obvious means of lowering this risk is exercise and weight loss for those who are overweight.¹⁹ Exercise increases insulin sensitivity not only in peripheral tissues but also in the HF,²⁰ where it facilitates spatial learning²⁰ and can increase cognitive performance in persons with MCI.²¹ While a weight loss effect on brain insulin sensitivity has not been reported, that is expected given that obesity is also an AD risk factor²² and that adipose tissue in obesity secretes elevated levels of fatty acids and inflammatory cytokines,²³ both of which can cross the blood-brain barrier and activate IRS-1 serine kinases known to cause insulin resistance in neurons as they do in adipose and muscle cells.^9,13,14

Probably just as important as exercise and weight loss for the overweight in reducing brain insulin resistance is long-term adherence to a diet that minimizes peripheral insulin resistance.¹⁹ The best established and most potent of these is the Mediterranean diet generally characterized by an abundance of fruits and vegetables, olive oil as the principal fat, and only low to moderate amounts of dairy products (mainly yogurt and cheese), fish, and white meats with wine drunk in moderation at meals.^24,25 A meta-analysis of 50 studies testing 534,906 people found adherence to this diet was associated with reduced peripheral insulin resistance and other cardiovascular risk factors.²⁶ Randomized clinical trials have since shown that 6.5 years of adherence to the Mediterranean diet of Estruch and colleagues²⁵ as opposed to a low-fat diet reduces the incidence of major cardiovascular events²⁵ and enhances cognition.²⁷ Adherence to the Mediterranean diet slows cognitive decline with aging, and at least one study reports that it slows progression from MCI to AD dementia.²⁸

Modifications of the Mediterranean diet of Estruch and colleagues²⁵ should enhance its ability to lower peripheral and brain insulin resistance. One version of this diet already incorporates 2 elements known to lower peripheral insulin resistance and enhance cognition: extra virgin olive oil^29,30 and fish rich in ω-3 fatty acids^29,31 (eg, salmon), components of which are known to protect the brain from Aβ pathology,^31,32 which can elevate brain IRS-1 pS and thereby induce brain insulin resistance. Other nutrients not necessarily part of the Mediterranean diet, however, are also known to lower peripheral insulin resistance, readily cross the blood-brain barrier, and enhance cognition. These are curcumin (a component of the spice turmeric)^33,34; dietary fiber (especially in whole grains)³⁵; and flavonoid-rich blueberries, cocoa, and epigallocatechin gallate (EGCG) in green tea).^36-39 Like olive oil and ω-3 fatty acids, curcumin⁴⁰ and EGCG^41-44 protect against Aβ pathology. This is potentiated in the case of EGCG by ω-3 fatty acids, which increase vascular and brain uptake of ingested EGCG.⁴²

EGCG, curcumin, and the ω-3 fatty acid docosahexaenoic acid (DHA) deserve special attention because their noted ability to protect the brain against Aβ pathology may be linked to their ability to reduce brain insulin resistance. Amyloid precursor protein (APP)/presenilin 1 (PS1) mouse models of AD⁴⁴ and mice on a high-fat diet⁴⁵ have elevated HF levels of IRS-1 pS616 or IRS-1 pS636, suggestive of brain insulin resistance as explained above. In APP/PS1 mice, ingested EGCG reduces HF levels of IRS-1 pS636 and improves cognition.⁴⁴ In mice on a high-fat diet, supplementing the diet with curcumin and/or DHA reduces HF levels of IRS-1 pS616 and improves cognition.⁴⁵ The same study also showed that DHA prevents Aβ-induced elevation of IRS-1 pS616 in hippocampal neuronal cultures.⁴⁵

In light of these research findings, there is reason to believe that the Mediterranean diet as augmented by Estruch and colleagues²⁵ may potentiate its ability to reduce brain insulin resistance and thereby slow progression from preclinical to the MCI stage of AD.

Liraglutide appears capable of restoring brain insulinsensitivity in early AD

While exercise and better diets may slow progression to clinical stages of AD and even mitigate symptom severity in MCI,^21,28,31 randomized clinical trials reported to date do not provide consistent evidence that such lifestyle changes initiated after diagnosis of MCI or AD dementia markedly slow cognitive decline.^21,46 At those stages of AD, simply reducing peripheral insulin resistance is ineffective, as indicated by clinical studies that ultimately show the failure of many T2D treatments to reduce AD risk or improve cognition in AD dementia-namely treatments with peripherally administered insulin, metformin, sulfonylureas, and thiazolidinediones such as rosiglitazone and pioglitazone.^47,48 The last 2 drugs are clinically compromised by their elevation of risk for heart failure in those with prediabetes or T2D.⁴⁹

Despite the failure of drugs to normalize peripheral insulin resistance in patients with AD, the demonstrated ability of intranasal insulin to improve cognition in patients with MCI and early AD dementia^50,51 shows that augmenting brain insulin signaling remains a promising means of treating AD. Intranasal insulin administration by itself, however, is unlikely to overcome the levels of brain insulin resistance seen in AD as noted above. The T2D drugs specified above might have failed as AD treatments because they may be rapidly metabolized, cannot readily cross the blood-brain barrier, and/or lack potency in reducing neuronal insulin resistance.

Fortunately, antidiabetics called glucagon-like peptide 1 (GLP-1) analogues do not have these limitations and are showing considerable potential as anti-AD drugs. To understand this, some background information is needed. GLP-1 is 1 of 2 incretin peptides, which are so named because their secretion by the intestines in response to food increases glucose-stimulated insulin release by the pancreas.⁵² Like insulin, GLP-1 is also produced in the brain⁵³ and has many functions, including neuroprotection⁵⁴ and potentiation of insulin sensitivity.⁵⁵

Since GLP-1 is quickly metabolized, degradation-resistant analogues have been developed for use in treating T2D. Two of those approved by the FDA are exenatide (synthetic exendin-4, marketed as Byetta) and liraglutide. Both effectively reduce peripheral insulin resistance and have excellent safety profiles with a low incidence of hypoglycemia,^56,57 which is expected given that GLP-1 increases glucose-stimulated, not basal, pancreatic insulin secretion. Pancreatitis has occurred in a very small number of those taking GLP-1 analogues; this may reflect the fact that the drug is prescribed for diabetes, which is a risk factor for pancreatitis.^56,57 A recent meta-analysis found no evidence that GLP-1 analogues increase the risk of pancreatitis.⁵⁸

Peripherally administered GLP-1 analogues, including exendin-4 and liraglutide, cross the blood-brain barrier^59,60 and are thus able to bind GLP-1 receptors distributed widely in the brain, including pyramidal cells of the cerebral cortex and HF.⁶¹ The GLP-1 analogues have a remarkable number of beneficial effects on neurons, many of which may derive from their ability to block Aβ-induced neuronal insulin resistance as shown by Bomfim and colleagues¹³ In mouse models of AD, these drugs reduce Aβ plaque loads; block Aβ-stimulated inflammatory responses; promote neurogenesis, neuronal survival, and synaptic integrity; restore long-term potentiation; and reduce cognitive deficits.^13,54,60,62 Both exendin-4 and liraglutide reduce the candidate biomarkers of brain insulin resistance (IRS-1 pS616 and IRS-1 pS636) in the APP/PS1 mouse model of AD.^13,63

We have now demonstrated that liraglutide restores brain insulin sensitivity in the APP/PS1 mouse model of AD.⁶⁴ Using our ex vivo stimulation method, we showed that the HF in such mice is as insulin-resistant at 7.5 months as the HF in elderly AD patients and that 2 months of daily liraglutide administration (25 nmol/kg IP) beginning at 5 months in these mice virtually restored normal HF responses to insulin in the IR→IRS-1→PI3K→Akt pathway. The same drug treatment was previously found to restore long-term potentiation and cognitive functions in this animal model of AD.⁶²

Our most recent work suggests that liraglutide could be very potent in reducing brain insulin resistance in the HF of patients with MCI (H-Y Wang et al, unpublished data, 2013). As noted above, HF tissue from patients with MCI is insulin-resistant to a lesser degree than HF tissue from patients with AD. After exposure to 100 nM of liraglutide for an hour, the HF of patients with MCI was found to be much more responsive to 1 nM of insulin. Indeed, this treatment resulted in virtually normal insulin responsiveness in tissue from patients with non-amnestic MCI and substantially improved insulin responsiveness in tissue from patients with amnestic MCI. The same treatment also significantly improved insulin responsiveness in the HF of patients with AD, but the improvement in responsiveness remained far from normal.

GLP-1 analogues thus emerge as very promising novel treatments for AD at an early clinical stage, treatments not dependent on reducing peripheral insulin resistance to affect brain function. This puts a premium on early diagnosis of MCI due to AD, which is becoming possible with current methods to image Aβ plaque levels with positron emission tomography scans.⁶⁵ The first clinical trial of liraglutide for MCI is in a subject recruitment stage at Hammersmith Hospital in London.⁶⁶ The first completed clinical trial of a GLP-1 analogue (exenatide) for a neurodegenerative disorder in which dementia is associated with peripheral insulin resistance (Parkinson disease)⁶⁷ raises hope, since it demonstrated the ability of such drugs to significantly improve cognition even in relatively advanced cases.⁶⁸

Summary and Conclusions

AD is an age-related neurodegenerative disease leading to the most common form of dementia. Its prevalence is increasing rapidly because of the rising number of elderly persons in the population and the absence of truly effective therapies. A promising strategy is finding a treatment of brain insulin resistance, which is a common and early phenomenon in AD closely tied to cognitive decline and potentially capable of promoting the full spectrum of biological abnormalities in that disorder. This is best characterized as an insulin resistance syndrome, not T3D. Peripheral insulin resistance raises brain levels of brain Aβ and cytokines, which leads to the inhibition of IRS-1 that triggers brain insulin resistance. Exercise and a Mediterranean diet can lower peripheral (and potentially brain) insulin resistance, slow progression toward clinical stages of AD, and mitigate MCI symptom severity. Quicker and more potent effects are expected at clinical stages of AD with GLP-1 analogues, including liraglutide, which can reduce brain insulin resistance markedly in MCI but only to a much lesser degree in AD dementia. Early diagnosis of MCI due to AD is thus important in maximizing the potential of GLP-1 analogues as therapeutic agents in AD.

Disclosures:

Dr Talbot is a Research Faculty Member in the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr Talbot has no disclosures to report.

Patricia L. Gerbarg, MD (peer/content reviewer), has no disclosures to report.

Helen Lavretsky, MD (peer/content reviewer), reports that she has received a research grant from Forest Research Institute and that she is a consultant for Lilly.

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