Appealing hypotheses have been proposed to explain how AD develops, undoubtedly providing major contributions to our understanding of AD pathogenesis. The revised amyloid cascade hypothesis (77
), which includes Aβ oligomers as synaptotoxins in AD, has received major attention. In familial forms of AD, mutations in the APP
and/or presenilin genes lead to increased Aβ production (78
), strongly suggesting a causative relationship between Aβ generation and pathogenesis in AD. However, in sporadic AD (which corresponds to greater than 90% of AD cases), the exact mechanism that leads to oligomer-amyloid accumulation in AD brain remains a mystery. The discovery that insulin resistance develops in AD brains might be seen as an additional complication, because insulin resistance itself is a complex metabolic disorder (79
). Nevertheless, this new link between AD and diabetes may in fact shed light on how sporadic AD develops.
Here, an alternative hypothesis is proposed in which a cross-talk between brain and peripheral tissues plays a central role in triggering the onset of sporadic AD (Figure ). Similar hypotheses have been put forward based on work from Craft and de la Monte (80
), providing important advances in elucidating the connection between AD and diabetes. In the hypothesis presented here, I highlight the central role of peripheral inflammation in causing sporadic AD and propose that such events can start very early in life.
A “cumulative hypothesis” for development of sporadic AD.
An unhealthy lifestyle (e.g., lack of or insufficient physical activity, inadequate nutrition), which may start in the first years of life and increase the prevalence of type 2 diabetes in youth (82
), might have an important role in susceptibility to AD later in life, as pointed out by Mark Mattson (83
). An unhealthy lifestyle triggers deleterious processes in peripheral tissue, leading to the activation of pathways related to chronic metabolic syndrome (including obesity, insulin resistance, and type 2 diabetes). Notably, an unhealthy lifestyle exerts several detrimental effects on brain aging (84
). Furthermore, poor sleep quality, as occurs in aging and in many obese individuals, may contribute to an increased risk of type 2 diabetes and AD (85
). According to this proposal, a cumulative impact on peripheral organs eventually results in defective brain metabolic homeostasis (see below), ultimately leading to AD (Figure ).
In addition, different types of injuries may impact the brain and/or peripheral organs throughout life. Such events may start very early in life, with stress caused by maternal separation or physical or emotional child abuse, including shaken infant syndrome associated with cerebral contusions. Although the long-term outcomes of mild brain injury in infants still need to be fully understood, learning difficulties and memory problems have been reported to occur in affected children (87
). Mild brain injury accelerates Aβ deposition, tau pathology, and cognitive deficits in transgenic AD mice (88
) and further leads to neurodegeneration and cognitive deficits in immature rats (90
). In any period of life, traumatic brain injury may further lead to AD, as evidenced by elevated production of Aβ in such events (91
). Additionally, brain insulin signaling declines with age (92
). This deficiency may be a consequence of decreased insulin uptake into the brain following sustained peripheral hyperinsulinemia (93
). This point, however, is still somewhat unclear, as an earlier study reported that AD patients have elevated insulin levels in their cerebrospinal fluid (CSF) under fasting conditions (94
). However, more recent studies demonstrated that CSF insulin levels are decreased in patients with mild AD (95
). Furthermore, a high saturated fat and high glycemic diet was found to lower CSF insulin concentrations in healthy adults (96
), corroborating the possibility that physiological mechanisms result in decreased brain insulin levels following peripheral hyperinsulinemia. Interestingly, impaired insulin sensitivity has been linked to cognitive deficits and structural and functional brain deficits in the elderly (97
Inflammation plays a key role in metabolic disorders, particularly in obesity and type 2 diabetes (98
). It is important to consider the causes of inflammation in peripheral tissues and to determine how this process could impact the brain, as activation of inflammatory signaling pathways is closely linked to the development of ER stress and insulin resistance (79
). A common pathway leading to peripheral insulin resistance involves lipid accumulation (e.g. palmitic acid, ceramides) in liver and skeletal muscle (100
). Prolonged consumption of food rich in saturated fatty acids is thought to be deleterious, as saturated fatty acids exert adverse health effects and are more likely to cause peripheral insulin resistance than unsaturated fatty acids. In fact, saturated fatty acids activate JNK and induce peripheral insulin resistance (102
), abnormalities that are also observed in AD brains (10
). Interestingly, enhanced brain fatty acid uptake and accumulation have recently been reported in patients with metabolic syndrome, a process reversed by weight reduction (103
). Also, ceramides, which are generated in the liver, have been proposed to cross the blood-brain barrier and cause brain insulin resistance and neurodegeneration (81
). A mechanism linking lipid homeostasis and Aβ production was recently demonstrated, as microRNAs were found to regulate an enzyme involved in ceramide synthesis and, in turn, Aβ generation (104
). Furthermore, cholesterol depletion inhibits Aβ generation (105
), and growing evidence suggests that other lipids may have important roles in AD (106
Moreover, microglial activation and inflammation-mediated neurotoxicity are suggested to be important in the pathogenesis of AD (107
). As disease progresses, Aβ deposits, neurofibrillary tangles, and damaged neurons, along with brain insulin resistance and ER stress (109
), are thought to provide feedback stimuli for inflammation.
Thus, inflammatory processes related to insulin resistance, such as inflammation caused by an unhealthy diet and physical inactivity, likely play a decisive role in linking peripheral and brain dyshomeostasis. The accumulation of and imbalance in certain lipids in peripheral tissues could lead to their continued release into the systemic circulation and their subsequent transport across the blood-brain barrier, which may affect the brain. In fact, nutritional inflammation impacts the hypothalamus (110
). Therefore, in brain regions that are affected in AD (e.g., hippocampus, frontal cortex), inflammation could lead to elevated Aβ production and to the progressive accumulation of Aβ oligomers in the brain. AD, which could thus be considered a form of dementia caused by metabolic dyshomeostasis, would manifest in the elderly as a result of this cumulative, lifelong impact on the periphery and the brain (Figure ).