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Brain Insulin Resistance in Alzheimer Disease and Its Potential Treatment With a Mediterranean Diet and GLP-1 Analogues: Page 3 of 4


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 oil29,30 and fish rich in ω-3 fatty acids29,31 (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 EGCG41-44 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 dementia50,51 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.


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