Abstract
Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.
Highlights
INTRODUCTIONEpidemiological studies of the incidence of Alzheimer’s disease (AD) distinguish between two classes of individuals with clinical and histopathological features of the disorder—those with an autosomal dominant inheritance—an early onset group; and those with the sporadic form of the disease—a late onset group
Epidemiological studies of the incidence of Alzheimer’s disease (AD) distinguish between two classes of individuals with clinical and histopathological features of the disorder—those with an autosomal dominant inheritance—an early onset group; and those with the sporadic form of the disease—a late onset group.Investigators have observed genetic defects in individuals with the familial forms of the disease
The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis and the Inverse Warburg hypothesis. We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming, and natural selection
Summary
Epidemiological studies of the incidence of Alzheimer’s disease (AD) distinguish between two classes of individuals with clinical and histopathological features of the disorder—those with an autosomal dominant inheritance—an early onset group; and those with the sporadic form of the disease—a late onset group. The model for the sporadic forms of AD proposed in Demetrius and Simon (2012) as well as in Demetrius and Driver (2013), implicates these two factors, energy and age, as the critical elements in the origin of neurodegenerative diseases This neuroenergetic perspective posits that the primary cause of sporadic forms of AD is an age-induced energy deficit in the mitochondrial activity of neurons, and the up-regulation of oxidative phosphorylation as a compensatory mechanism of energy production to maintain the viability of the impaired cells. The amyloid cascade hypothesis and the energetic selection model are two conceptual frameworks that have been invoked to explain the origin of sporadic forms of AD (Hardy and Selkoe, 2002; Hardy, 2009; Demetrius and Simon, 2012; Demetrius and Driver, 2013) Both models acknowledge the epidemiological fact that age is a primary risk factor for the disease.
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