Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E

Reiman, Eric M.; Caselli, Richard J.; Yun, Lang Sheng; Chen, Kewei; Bandy, Daniel; Minoshima, Satoshi; Thibodeau, Stephen N.; Osborne, David

doi:10.1056/nejm199603213341202

Cited by 1,244 publications

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“…Flory, Manuck, Ferrell, Ryan, and Muldoon (2000) extended these findings to middle-aged adults by showing that ApoE-ɛ4 carriers with a mean age of 46 had lower verbal memory performance than those with the ApoE-ɛ2 or ApoE-ɛ3 alleles. Also consistent with these results linking ApoE and cognition is the finding that the absence of the ApoE ɛ4 allele is associated with higher levels of cognitive functioning in very old (75-98 years) adults (Riley et al, 2000).However, some studies finding no differences in neuropsychological test performance as a function of ApoE genotype have also been reported (Plassman et al, 1997;Reiman et al, 1996; B. J. Small et al, 2000; G. E. Smith et al, 1998).…”

supporting

confidence: 55%

“…In a follow-up study, G. W. confirmed these findings in another sample of participants who had MCI but did not qualify for a diagnosis of dementia. In another study of individuals without dementia who were cognitively normal on neuropsychological evaluation, Reiman et al (1996) found that ApoE-ɛ4 homozygotes showed reduced rates of glucose metabolism in parietal, temporal, prefrontal, and posterior cingulate regions.Two studies using functional imaging have been reported. C. D. Smith et al (2000) carried out an fMRI study of object and face recognition in normal individuals.…”

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confidence: 96%

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The apolipoprotein E gene, attention, and brain function.

Parasuraman¹,

Greenwood²,

Sunderland³

2002

Neuropsychology

108

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The ɛ4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ɛ4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ɛ4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ɛ4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection.Apolipoprotein E (ApoE) is an amino acid glycoprotein that is important in lipid storage, transport, and metabolism (Mahley, 1988). Although synthesized mainly in the liver, ApoE is also found in the peripheral and central nervous systems, including the brain. ApoE has long been of interest in medicine, but its importance in neuroscience increased dramatically with the identification of the ɛ4 allele of the ApoE gene on chromosome 19 as a major risk factor for the development of late-onset Alzheimer's disease (AD) in older adults Strittmatter et al., 1993). This discovery led to a growing number of studies examining the role of the ApoE gene in normal brain function and cognition, as well as in disorders such as AD, brain injury, and stroke (Higgins, Large, Rupniak, & Barnes, 1997;Horsburgh, McCarron, White, & Nicol, 2000; J. D. Smith, 2000).Polymorphisms of the ApoE gene are associated with significant alterations in brain morphology (Plassman et al., 1997) and cognitive functioning, including attention (Greenwood, Sunderland, Friz, & Parasuraman, 2000) and memory (Bondi et al., 1995). Studies of ApoE may thus reveal information relevant to the genetics of attention and memory in normal individuals. At the same time, such studies may identify cognitive and neural changes that may be characteristic of preclinical stages of AD. In this article, we review the role of the ApoE gene in normal cognition and in the development of deficits indicative of early AD.Currently, no reliable methods exist for the early detection and treatment of AD. New techniques for preventing, slowing the progression of, and treating AD are being urgently sought. Such efforts would be aided considerably if AD could be detected prior to the clinical diagnosis of AD and before irreversible brain changes occur (Daffner & Scinto, 2000). Postmortem studies show that neuropathological changes occur decades before the onset of NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2006 January 25. Published in final edited form as:Neuropsychology. 2002 April ; ...

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confidence: 55%

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confidence: 96%

The apolipoprotein E gene, attention, and brain function.

Parasuraman¹,

Greenwood²,

Sunderland³

2002

Neuropsychology

108

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“…The reported decrease in glucose uptake mediated by stress or by high levels of GCs could place neurons in an energy-compromised environment, which could detrimentally affect neuronal responsiveness to pathophysiological events. In fact, glucose transport impairment precedes ATP depletion in brain, increasing neuronal vulnerability to excitotoxicity by compromising function of ion-motive ATPases (Mark et al, 1995), as it has been seen to occur in some neurodegenerative processes such Ab-induced toxicity, schizophrenia and others (Novelli et al, 1988;Kalaria and Harik, 1989;Sims, 1990;Mark et al, 1997;McDermott and De Silva, 2005) in which the reduction in glucose uptake occurs as an early step in the disease process prior to neuronal degeneration (Pettegrew et al, 1994;Reiman et al, 1996). On the other hand, GCs promote reduction in ATP levels (Tombaugh and Sapolsky, 1992;Lawrence and Sapolsky, 1994).…”

Section: Discussionmentioning

confidence: 99%

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

García‐Bueno

Caso

Perez‐Nievas

et al. 2006

Neuropsychopharmacol

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Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARg) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-D-12,14-prostaglandin J 2 (PGJ 2 , 120 mg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARg ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARg ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARg ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ 2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.

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“…The impairment in glucose uptake and metabolism starts decades before classic AD symptoms and worsens steadily with disease progression 4, 5, 6. Studies using positron emission tomography with 2‐[(18)F]fluoro‐2‐deoxy‐D‐glucose (FDG‐PET) have demonstrated a characteristic pattern of hypometabolism, which is most pronounced in the posterior cingulate and medial parieto‐temporal cortices, also notable for their higher reliance on aerobic glycolysis relative to the rest of the brain 7, 8.…”

Section: Introductionmentioning

confidence: 99%

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

Mullins

Reiter

Kapogiannis

2018

Ann Clin Transl Neurol

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ObjectiveBrain glucose hypometabolism is a prominent feature of Alzheimer's disease (AD), and in this case–control study we used Magnetic Resonance Spectroscopy (MRS) to assess AD‐related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites.MethodsJ‐modulated Point‐Resolved Spectroscopy (J‐PRESS) and Prior‐Knowledge Fitting (ProFit) software was used to measure glucose and other metabolites in the posterior cingulate/precuneus of 25 AD, 27 older controls, and 27 younger control participants. Clinical assessments for AD participants included cognitive performance measures, insulin resistance metrics and CSF biomarkers.Results AD participants showed substantially elevated glucose, lactate, and ascorbate levels compared to older (and younger) controls. In addition, the precuneal glucose elevation discriminated well between AD participants and older controls. Myo‐inositol correlated with CSF p‐Tau181P, total Tau, and the Clinical Dementia Rating (CDR) sum‐of‐boxes score within the AD group.InterpretationHigher glucose to creatine ratios in the AD brain likely reflect lower glucose utilization. Our findings reveal pronounced metabolic abnormalities in the AD brain and strongly suggest that brain glucose merits further investigation as a candidate AD biomarker.

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Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E

Cited by 1,244 publications

References 36 publications

The apolipoprotein E gene, attention, and brain function.

The apolipoprotein E gene, attention, and brain function.

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

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