Apolipoprotein E polymorphism and Alzheimer's disease

Poirier, Judes; Bertrand, Philìppe; Kogan, Sandra; Gauthier, Serge; Davignon, Jean; Bouthillier, Donald

doi:10.1016/0140-6736(93)91705-q

Cited by 1,079 publications

(611 citation statements)

References 22 publications

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“…In Peters et al (2009), AD patients showed reduced CBF responses in various fronto-temporal areas during the encoding of short word lists as well as during the recognition phase of the task, but an increased response in the fusiform gyrus, a structure thought to be involved with orthographic processing. The hemodynamic changes seem to become established very early in the pathological process, as they are manifest in populations at risk of developing AD, i.e., individuals with mild cognitive impairment or those expressing the e4 allele of apolipoprotein E, the most consistent genetic factor linked to increased AD risk and lower age of onset (Poirier et al, 1993;Strittmatter et al, 1993). In these groups, neurovascular coupling is either impaired (Lind et al, 2006) or increased in a compensatory manner as in AD patients, being characterized by a larger response magnitude, and neuronal recruitment to achieve performance at the level of healthy elderly controls (Bookheimer et al, 2000;Yetkin et al, 2006;reviewed in Wermke et al (2008)).…”

Section: Neurovascular Dysfunction In Alzheimer's Diseasementioning

confidence: 99%

Neurovascular function in Alzheimer's disease patients and experimental models

Nicolakakis

Hamel

2011

J Cereb Blood Flow Metab

132

118

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The ability of the brain to locally augment glucose delivery and blood flow during neuronal activation, termed neurometabolic and neurovascular coupling, respectively, is compromised in Alzheimer's disease (AD). Since perfusion deficits may hasten clinical deterioration and have been correlated with negative treatment outcome, strategies to improve the cerebral circulation should form an integral element of AD therapeutic efforts. These efforts have yielded several experimental models, some of which constitute AD models proper, others which specifically recapture the AD cerebrovascular pathology, characterized by anatomical alterations in brain vessel structure, as well as molecular changes within vascular smooth muscle cells and endothelial cells forming the bloodbrain barrier. The following paper will present the elements of AD neurovascular dysfunction and review the in vitro and in vivo model systems that have served to deepen our understanding of it. It will also critically evaluate selected groups of compounds, the FDA-approved cholinesterase inhibitors and thiazolidinediones, for their ability to correct neurovascular dysfunction in AD patients and models. These and several others are emerging as compounds with pleiotropic actions that may positively impact dysfunctional cerebrovascular, glial, and neuronal networks in AD.

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Section: Neurovascular Dysfunction In Alzheimer's Diseasementioning

confidence: 99%

Neurovascular function in Alzheimer's disease patients and experimental models

Nicolakakis

Hamel

2011

J Cereb Blood Flow Metab

132

118

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“…While the underlying cause of late-onset AD (LOAD) remains unknown a number of genetic risk factors have been suggested (see (Tanzi and Bertram, 2005) for a review). The ε4 allele of apolipoprotein E (APOE) has been shown to be a strong independent risk factor in the development of LOAD, and is the only confirmed genetic risk factor for LOAD (Corder et al, 1995;Corder et al, 1998;Poirier et al, 1993;Strittmatter et al, 1993). APOE is a major lipid transport molecule in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

et al. 2010

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Pages: 25 Pages including 2 tables Abstract:2 Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).

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“…The recognised genetic factors include mutations of the genes encoding the amyloid precursor protein [14] and presenilin 1 and 2 [16,31], which are responsible for a small proportion of familial and usually early-onset AD cases. A fourth gene encoding apolipoprotein E (APOE) is also implicated in the risk of developing the disease [4,23,29,36]. However, although APOE-⑀4 is a major risk factor for AD, it is neither necessary nor sufficient for the development of the disease and the presence of other genetic or acquired factors has been postulated.…”

Section: Introductionmentioning

confidence: 99%

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

Sampietro

Caputo

Casatta

et al. 2001

Neurobiology of Aging

104

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NEUROBIOL AGING. In the present study we analysed the genotype of HFE, the gene involved in hemochromatosis, in 107 patients with sporadic late-onset AD and in 99 age-matched non-demented controls. We observed that patients carrying the mutant HFE-H63D allele had a mean age at onset of 71.7 Ϯ 6.0 years versus 76.6 Ϯ 5.8 years of those who were homozygous for the wild-type allele (p ϭ 0.001). The frequency of the HFE-H63D mutation was highest (0.22) in the patients aged Ͻ70 years at the time of disease onset, whereas it was 0.12 in those with disease onset at an age of 70 -80 years, and 0.04 in those aged more than 80 years. The APOE genotype did not significantly modify the effect of HFE on age at onset. We conclude that mild disturbances of iron homeostasis associated with a common genetic determinant may interact with other pathogenic mechanisms involved in AD. HFE mutations may anticipate AD clinical presentation in susceptible individuals.

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Apolipoprotein E polymorphism and Alzheimer's disease

Cited by 1,079 publications

References 22 publications

Neurovascular function in Alzheimer's disease patients and experimental models

Neurovascular function in Alzheimer's disease patients and experimental models

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

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