Apolipoprotein E: risk factor in Alzheimer Disease

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/1994; 54(4):643-9.
Source: PubMed


The apolipoprotein E gene (APOE) has three common alleles (epsilon 2, epsilon 3, and epsilon 4) that determine six genotypes in the general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-epsilon 4 allele. We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group. In the AD group, homozygosity for epsilon 4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-epsilon 4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.

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    • "APOE4 is a major risk factor for late-onset AD. It is reported that the increased risk for AD is approximately 3.6 times and 8 times in people with one ␧4 allele and two ␧4 alleles, respectively, compared to individuals with no ␧4 alleles [7] [9]. The influence of ApoE4 protein on AD "
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    ABSTRACT: Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4.
    Journal of Alzheimer's disease: JAD 04/2014; 41(4). DOI:10.3233/JAD-140375 · 4.15 Impact Factor
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    • "There are three possible allelic variations of APOE (2, 3, and 4), with 3 being the most frequent. The APOE-4 allele has been strongly associated with risk for AD, and the risk conferred is gene dose dependent, with those individuals carrying two APOE-4 alleles having the highest risk for developing the disease (Tsai and others 1994). In addition to its role in AD, the APOE-4 genotype is associated with a number of memory-related phenotypes such as smaller hippocampal volume, lower functional activation during memory tasks, and thinning in medial temporal regions (Donix and others 2010). "
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    ABSTRACT: Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.
    The Neuroscientist 08/2011; 18(5):516-32. DOI:10.1177/1073858411415113 · 6.84 Impact Factor
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    • "Further, interactive effects of age and APOEε4 were found with decreased activation in older APOEε4 subjects, but not younger APOEε4 subjects in the inferior frontal—anterior temporal region, one of the first areas to develop amyloid plaques in patients with Alzheimer's disease. These data provide further support for the growing body of evidence that suggests the association between the APOEε4 allele and Alzheimer's disease (Roses 1996, 2006; Tsai et al. 1994) and the possibility of using patterns of neural activation as an intermediate phenotype for evaluating Alzheimer's disease risk. These findings argue that the ε4 allele is associated with compensatory or non-selective mechanisms during working memory, and that Alzheimer's disease (and not just aging) attenuates the ability to engage that extra activation. "
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    ABSTRACT: How and when the known genetic risk allele, apolipoprotein E-epsilon4 (APOEepsilon4), confers risk to Alzheimer's disease has yet to be determined. We studied older adults and found that APOEepsilon4 carriers had greater neural activation in the medial frontal and parahippocampal gyrus during a memory task (cluster-corrected p < .01). When compared to a group of younger adults, interactive effects of age and APOEepsilon4 were found in the inferior frontal-anterior temporal region, one of the first areas to develop amyloid plaques in patients with Alzheimer's disease, and, in the posterior cingulate, one of the earliest areas to show decreased cerebral metabolism in Alzheimer's disease. Thus, abnormally high activation in fronto-temporal areas are present in both younger and older APOEepsilon4 carriers confronted with a working memory task when compared to non-APOEepsilon4 carriers. This effect, however, appears to diminish with age.
    Brain Imaging and Behavior 06/2010; 4(2):177-88. DOI:10.1007/s11682-010-9097-9 · 4.60 Impact Factor
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