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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.
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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