Abstract
The loss of cognitive function in Alzheimer’s disease is pathologically linked with neurofibrillary tangles, amyloid deposition, and loss of neuronal communication. Cerebral insulin resistance and mitochondrial dysfunction have emerged as important contributors to pathogenesis supporting our hypothesis that cerebral fructose metabolism is a key initiating pathway for Alzheimer’s disease. Fructose is unique among nutrients because it activates a survival pathway to protect animals from starvation by lowering energy in cells in association with adenosine monophosphate degradation to uric acid. The fall in energy from fructose metabolism stimulates foraging and food intake while reducing energy and oxygen needs by decreasing mitochondrial function, stimulating glycolysis, and inducing insulin resistance. When fructose metabolism is overactivated systemically, such as from excessive fructose intake, this can lead to obesity and diabetes. Herein, we present evidence that Alzheimer’s disease may be driven by overactivation of cerebral fructose metabolism, in which the source of fructose is largely from endogenous production in the brain. Thus, the reduction in mitochondrial energy production is hampered by neuronal glycolysis that is inadequate, resulting in progressive loss of cerebral energy levels required for neurons to remain functional and viable. In essence, we propose that Alzheimer’s disease is a modern disease driven by changes in dietary lifestyle in which fructose can disrupt cerebral metabolism and neuronal function. Inhibition of intracerebral fructose metabolism could provide a novel way to prevent and treat this disease.
Highlights
Alzheimer’s disease is the sixth most common cause of death in the United States
Step 1: Endogenous Fructose Is Produced in the Brain We suggest that disease begins when we unconsciously activate the fructose survival pathway by eating excess sugar and high fructose corn syrup (HFCS), with the greatest risk being from drinking soft drinks in which large amounts of fructose are ingested rapidly, resulting in more severe ATP depletion
The capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD)—electrophysiological correlates of learning and memory have shown to be seriously compromised by fructose feeding (Cisternas et al, 2015; Agrawal et al, 2016)
Summary
Alzheimer’s disease is the sixth most common cause of death in the United States. The prevalence of dementia is expected to double in the 20 years, and to affect 81 million people worldwide (Rizzi et al, 2014). Metabolic Syndrome, and Diabetes Metabolic syndrome, hypertriglyceridemia, type 2 diabetes, and obesity are all risk factors for Alzheimer’s disease (Seaquist, 2010; Solfrizzi et al, 2011; —, 2005; Rosales-Corral et al, 2015; Anjum et al, 2018) All of these conditions have been linked with increased dietary intake of sugar and HFCS (Johnson et al, 2013; Malik and Hu, 2015), experimental evidence links these conditions with endogenous fructose production (Lanaspa et al, 2013, 2018). Once energy stores are depleted (as occurs in Alzheimer’s subjects), there may not be enough substrate for further uric acid formation
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