Review article
Nutrition and Alzheimer's disease: The detrimental role of a high carbohydrate diet

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Abstract

Alzheimer's disease is a devastating disease whose recent increase in incidence rates has broad implications for rising health care costs. Huge amounts of research money are currently being invested in seeking the underlying cause, with corresponding progress in understanding the disease progression. In this paper, we highlight how an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer's disease. A first step in the pathophysiology of the disease is represented by advanced glycation end-products in crucial plasma proteins concerned with fat, cholesterol, and oxygen transport. This leads to cholesterol deficiency in neurons, which significantly impairs their ability to function. Over time, a cascade response leads to impaired glutamate signaling, increased oxidative damage, mitochondrial and lysosomal dysfunction, increased risk to microbial infection, and, ultimately, apoptosis. Other neurodegenerative diseases share many properties with Alzheimer's disease, and may also be due in large part to this same underlying cause.

Section snippets

Introduction and background

It has been well established that the brain of patients with Alzheimer's disease (AD) is characterized by the build-up of a signature plaque containing an abundance of the protein amyloid-β (Aβ) [1]. As a consequence, hundreds of millions of research dollars are currently being invested by the pharmaceutical industry towards finding and testing drugs that interfere with Aβ synthesis. The assumption is that, by reducing the supply of Aβ, the plaque build-up would be attenuated, and this might

Alzheimer's disease: the effect of a long-standing exposure to glucose and oxidizing agents

Cell membranes need constant maintenance to repair and replace their fats and cholesterol subsequent to oxidative damage. The strong influence of Ancel Keys [31], beginning in the 1960s, has led to dietary avoidance of fats and cholesterol along with over-zealous prescription of cholesterol-reducing medications over the same decades in which there has been a parallel rise in AD prevalence. Although this epidemiological coincidence is not proof, it gives weight to underlying research showing a

Impaired glutamate homeostasis

Impaired glutamate homeostasis is often associated with neurodegenerative diseases [52], [53]. Glutamate is arguably the most important neurotransmitter. It is secreted into the synapse to enable signal transport from one neuron to another. Neurotransmitter release at the synapse requires membrane fusion. Cholesterol has been shown to increase lipid mixing in the synapse by a factor of 5, at physiological concentrations [54]. Membrane-bound cholesterol is present in high concentration in the

ApoE and Aβ

In this section, we develop several arguments for how Aβ establishes a reduction in dependence on mitochondrial activities, with the goal, in our view, of reducing the risk of oxidative damage to the cell. Researchers have recently found that ApoE in the astrocytes controls the levels of Aβ in neurons: whether it induces an increase or a decrease in Aβ concentrations depends upon the status of lipids in the cell [60], [61], [62]. ApoE enhances Aβ clearance when it is lipidated; i.e., when

Infection and compromised immune response

Pathogens are likely to flourish in the bloodstream if excess glucose and AGE debris are abundant. An increased prevalence of bacterial infection is associated with diabetes, and this is likely due to the ability of AGEs to suppress superoxide production by immune system cells [77]. Indeed, there is evidence that AD may also be related to an increased likelihood of infective agents appearing in the brain [78]. A recent study showed that AD patients had a significantly higher concentration of an

Late-stage Alzheimer's disease: neuronal apoptosis

As more and more damage is incurred by the cell membranes, without sufficient replenishment of the supplies of fats and cholesterol to repair them, an increase in ion leakage across all membranes leads to further depletion of ATP and further exposure to pathogens and oxidative damage. Over time, the accumulated depletion of ATP leads to lysosomal dysfunction, likely because of an inability to maintain a sufficiently acidic pH for the digestive enzymes to work properly. In parallel, the further

Discussion

AD is a devastating disease, in terms of both mental anguish and health care costs. Epidemiological indicators suggest that the incidence of AD in the U.S. and likely the Western world is currently increasing at an alarming rate [84], [85], and disproportionately with the increase in the aged population. In the last decade, significant research money has been invested in trying to understand the underlying cause(s) of AD.

It has long been recognized that the accumulation of Aβ plaque in the

Learning points

  • •

    The amyloid-β present in Alzheimer's plaque may not be causal, since drug-induced suppression of its synthesis led to further cognitive decline in the controlled studies performed so far.

  • •

    Researchers have identified mitochondrial dysfunction and brain insulin resistance as early indicators of Alzheimer's disease.

  • •

    ApoE-4 is a risk factor for Alzheimer's disease, and ApoE is involved in the transport of cholesterol and fats, which are essential for signal transduction and protection from oxidative

References (87)

  • R. West et al.

    Better memory functioning associated with higher total and low-density lipoprotein cholesterol levels in very elderly subjects without the apolipoprotein e4 allele

    Am. J. Geriatr. Psychiatry

    (2008)
  • T.H. Haines

    Do sterols reduce proton and sodium leaks through lipid bilayers?

    Prog. Lipid Res.

    (2001)
  • K. Honjo et al.

    Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease?

    Alzheimers Dement.

    (2009)
  • B. Levi et al.

    Long-term fructose consumption accelerates glycation and several age-related variables in male rats

    J. Nutr.

    (1998)
  • I. Laffont et al.

    Early glycation of apolipoprotein E: effect on its binding to LDL receptor, scavenger receptor A and heparan sulfates

    Biochim. Biophys. Acta

    (2002)
  • R. Suzuki et al.

    Diabetes and insulin in regulation of brain cholesterol metabolism

    Cell Metab.

    (2010)
  • S. Kikuchi et al.

    Glycation: a sweet tempter for neuronal death

    Brain Res. Brain Res. Rev.

    (2003)
  • V.V. Shuvaev et al.

    Increased protein glycation in cerebrospinal fluid of Alzheimer's disease

    Neurobiol. Aging

    (2001)
  • N. Sasaki et al.

    Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases

    Am. J. Pathol.

    (1998)
  • G.M. Teasdale et al.

    Association of apolipoprotein E polymorphism with outcome after head injury

    Lancet

    (1997)
  • A.L. Sheldon et al.

    The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention

    Neurochem. Int.

    (2007)
  • T. Borisova et al.

    Cholesterol depletion attenuates tonic release but increases the ambient level of glutamate in rat brain synaptosomes

    Neurochem. Int.

    (2010)
  • H. Tsai et al.

    Cholesterol deficiency perturbs actin signaling and glutamate homeostasis in hippocampal astrocytes

    Brain Res.

    (2006)
  • Q. Jiang et al.

    ApoE promotes the proteolytic degradation of Aβ

    Neuron

    (2008)
  • S.D. Yan et al.

    Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid β-peptide

    Biochim. Biophys. Acta

    (2000)
  • M. Yudkoff et al.

    Response of brain amino acid metabolism to ketosis

    Neurochem. Int.

    (2005)
  • D. Paris et al.

    Statins inhibit A β-neurotoxicity in vitro and Aβ-induced vasoconstriction and inflammation in rat aortae

    Atherosclerosis

    (2002)
  • M. Dezfulian et al.

    Can phages cause Alzheimer's disease?

    Med. Hypotheses

    (2008)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • Eli Lilly and Company, 2010 PR Newswire, Lilly Halts Development of Semagacestat for Alzheimer's Disease Based on...
  • M. Fuhrmann et al.

    Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease

    Nat. Neurosci.

    (2010)
  • M.T. Heneka et al.

    Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer's disease

    J. Neurosci.

    (2002)
  • E. Steen et al.

    Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes?

    J. Alzheimers Dis.

    (2005)
  • N. Alikhani et al.

    Mitochondria and Alzheimer's disease: amyloid-β peptide uptake and degradation by the presequence protease, hPreP

    J. Bioenerg. Biomembr.

    (2009)
  • A.H. Schapira et al.

    Mitochondrial complex I deficiency in Parkinson's disease

    J. Neurochem.

    (1990)
  • V.L. Dawson

    Maiming mitochondria in familial ALS

    Nat. Med.

    (2004)
  • J.M. Dietschy et al.

    Cholesterol metabolism in the brain

    Curr. Opin. Lipidol.

    (2001)
  • A.D. Roses

    Apolipoprotein E alleles as risk factors in Alzheimer's disease

    Annu. Rev. Med.

    (1996)
  • I. Björkhem et al.

    Brain cholesterol: long secret life behind a barrier

    Arterioscler. Thromb. Vasc. Biol.

    (2004)
  • B. Dehouck et al.

    A new function for the LDL receptor: transcytosis of LDL across the blood–brain barrier

    J. Cell Biol.

    (1997)
  • I.L. Notkola et al.

    Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease

    Neuroepidemiology

    (1998)
  • M.M. Mielke et al.

    High total cholesterol levels in late life associated with a reduced risk of dementia

    Neurology

    (2005)
  • M. Mulder et al.

    Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4

    Alzheimer Dis. Assoc. Disord.

    (1998)

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      Furthermore, ApoE proteins transcribed and translated from the E4 variant of the gene are three times as AGE-binding than those of other ApoE gene variants [22]. This suggests that ApoE4(+) individuals might be more susceptible to the cascade effect proposed by Seneff et al. [20], which may explain why they are more at risk for developing AD. This may also explain why Henderson et al. [11] found a significant improvement in ApoE4(–) but not ApoE4(+) individuals, as the participants in the study were still consuming carbohydrates.

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