Review Article Neurodegener Dis 2019;19:60–77 Received: July 31, 2019 DOI: 10.1159/000503451 Accepted after revision: September 17, 2019 Published online: October 10, 2019 Poor Diet, Stress, and Inactivity Converge to Form a “Perfect Storm” That Drives Alzheimer’s Disease Pathogenesis Anthony G. Pacholko Caitlin A. Wotton Lane K. Bekar Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Keywords AD. In addition, we put forth the argument that exercise and High sucrose · Stress · Sex hormones · Neurodegeneration · supplementation with trace lithium can counteract many of Neuroinflammation · Exercise · Lithium the deleterious consequences associated with excessive ca- loric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogen- Abstract esis and that simple lifestyle and dietary changes can help North American incidence of Alzheimer’s disease (AD) is ex- counteract their effects. © 2019 S. Karger AG, Basel pected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-β and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, Introduction they do not explain the pathogenesis of the far more preva- lent sporadic late-onset variant of the disease. It is thus likely Advancements in medicine have led to an increased that lifestyle and environmental factors contribute to neuro- life expectancy. As such, neurodegenerative diseases are degenerative processes implicated in the pathogenesis of a growing concern. In America, it is estimated that 1 in 9 AD. Herein, we review evidence that (1) excess sucrose con- people over the age of 65 have Alzheimer’s disease (AD) sumption induces AD-associated liver pathologies and brain or a related dementia. As one of the costliest chronic dis- insulin resistance, (2) chronic stress overdrives activity of lo- eases, approximately 1 in 5 Medicare dollars is spent on cus coeruleus neurons, leading to loss of function (a com- AD and dementia. This is expected to be 1 in 3 dollars by mon event in neurodegeneration), (3) high-sugar diets and mid-century [1], independent of the enormous hourly stress promote the loss of neuroprotective sex hormones in cost to family and friends involved in caregiving. With men and women, and (4) Western dietary trends set the our aging population, this disease will bankrupt medical stage for a lithium-deficient state. We propose that these fac- systems throughout the industrialized world over the tors may intersect as part of a “perfect storm” to contribute coming generation. Is modern lifestyle a contributing to the widespread prevalence of neurodegeneration and factor? © 2019 S. Karger AG, Basel Lane K. Bekar, PhD Anatomy, Physiology, and Pharmacology University of Saskatchewan, College of Medicine E-Mail [email protected] Saskatoon, SK S7N 5E5 (Canada) www.karger.com/ndd E-Mail lane.bekar @ usask.ca Chronic stress (i.e., depression, anxiety, etc.), increased single stressor that is unable to induce pathology rapidly carbohydrate consumption (i.e., obesity, diabetes), chron- or robustly enough to be cost-effective or useful. In this ic inflammatory conditions (i.e., arthritis, cardiovascular review, we will summarize the pathological sequelae as- disease), loss of sex hormones (i.e., age, diet, stress), and sociated with multiple stressors ever present in modern lack of regular exercise are becoming the norm rather than lifestyles to help illustrate how these factors coming to- the exception. The physiological stress response has gone gether as the “perfect storm” may be contributing to the from being an occasional occurrence that evolved to pro- global AD crisis (Fig. 1). mote survival – via the fight-or-flight response – to a per- petual phenomenon brought on by the fast-paced lifestyle of the industrialized, globally interconnected world. Mak- Where Have We Gone Wrong? ing matters worse, our reliance on caffeinated beverages and salt-filled fast foods to make it through the day may The Western Diet be stripping our bodies of lithium, a neuroprotective min- Evolutionary Discordance and the Rise of eral that protects against inflammation and dietary insult. Agriculture Combined with a lack of time for sleep and exercise, it is According to the theories of natural selection and quite possible that daily lifestyle factors/decisions result in punctuated equilibrium, evolution represents a constant a predisposition for neurodegeneration. interaction between the genome of a species and the en- Accumulation of amyloid-β (Aβ) peptide deposits vironment in which it resides. Genetic traits are positive- (plaques), hyperphosphorylated protein tau misfolding ly or negatively selected in accordance or discordance (neurofibrillary tangles), and forebrain cholinergic defi- with constraints applied by a given environment. When cits are considered the hallmarks of AD pathology. A less- environmental pressures remain relatively consistent, ge- er known, though increasingly acknowledged, loss of lo- netic traits come to reflect an optimal pool for survival of cus coeruleus (LC) noradrenergic neurons in the dorsal the population [13, 14]. When rapid and permanent en- pons is associated with all neurodegenerative diseases [2– vironmental changes occur, individuals within the popu- 4]. The LC is the master stress center that plays a funda- lation experience evolutionary discordance, i.e., failure of mental role in regulating output from the hypothalamic- the genotype to match the requirements of the environ- pituitary-adrenal (HPA) axis. The loss of LC neurons in ment. Evolutionary discordance has been proposed to aging and neurodegenerative disease is likely a key factor manifest phenotypically as disease [14, 15]. in the dysfunction of the many cognitive processes involv- Prior to the advent of agricultural practices, human ing LC activity [2]. In addition to its role in the HPA axis, dietary choices were limited to wild plant- and animal- norepinephrine regulates central nervous system (CNS) based foods. In contrast, the post-agricultural diet (par- energy utilization [5], modulates thresholds for synaptic ticularly post-Industrial Revolution) is rich in cereals, re- plasticity [6], provides neurotrophic [7]/anti-inflamma- fined flour products, dairy, alcohol, and added sugars tory [8, 9] support, and aids in the distribution of cerebral [16–18]. These modern food sources, which were largely blood flow [10–12]. Deficits in any of these capacities can unavailable in pre-agricultural societies, account for potentially have an impact on cognitive function. Given much of the daily energy consumed by North Americans. its role in neurotrophic/anti-inflammatory support and It has thus been proposed that modern human genetic the significant loss observed at autopsy, it is postulated makeup is ill-suited to the present environment. In other that loss of LC is one of the earliest contributing factors words, modern dietary choices may have placed present leading to progressive neurodegeneration, thereby raising day individuals in a state of evolutionary discordance that the question of why we find a consistent loss of LC neu- has manifested in obesity, diabetes, cardiovascular dis- rons across all neurodegenerative conditions. eases, and neurodegenerative conditions [14, 15, 19–21]. Although genetic factors surrounding processing of amyloid precursor protein (APP) and the microtubule- Changing Patterns in the Western Diet associated protein tau have been proven responsible for a The Western diet is often considered to be a high-fat small subset of early-onset AD patients, limited progress diet. However, in the early 80s, the United States Depart- has been made regarding the etiology of sporadic late- ment of Agriculture, American Heart Association, and onset AD cases. Non-genetic models of sporadic AD have American Medical Association supported a reduction in been met with varying levels of success. While contribut- total dietary fat intake from 40 to 30% with hopes to curb ing valuable insight, these models generally only assess a the rising trend in heart disease that was associated with Modern Lifestyle Factors Contribute to Neurodegener Dis 2019;19:60–77 61 AD DOI: 10.1159/000503451 Western Chronic diet stress Fig. 1. High-sugar diets and states of per- petual stress culminate in a “perfect storm” Locus to drive neurodegenerative processes such Ceramides GCs Galanin coeruleus as increased β-amyloidogenesis and tau Color version available online protein phosphorylation, depletion of neu- roprotective sex hormones, induction and Sex Exercise aggravation of neuroinflammation, dis- Insulin hormones resistance ruption of glucocorticoid homeostasis, and loss of anti-inflammatory/neuroprotective adrenergic locus coeruleus neurons. Exer- pTau Inflammation Li cise antagonizes many of these processes. Aβ Lithium also attenuates many of the noted Li GSK3β pathologies, likely through inhibition of GSK3β. Sedentary lifestyles (lack of exer- Neurogenesis Exercise cise) coupled with a possible lithium defi- ciency may thus worsen the deleterious ef- Autophagy fects of caloric excess and chronic stress. elevated cholesterol levels. The result was that the reduc- activation of the insulin receptor while simultaneously re- tion in fat intake was replaced with an increase in carbo- ducing expression of its mRNA (reduced protein levels) hydrate and sugar consumption,