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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Available from: Robert J Ivnik, Jan 13, 2015
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    • "The score of each symptom was calculated as the product of the frequency and severity (maximum score = 12). The ApoE genotypes were determined using the restriction enzyme digestion approach previously described [19]. "
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    ABSTRACT: Sex differences in neuropsychiatric symptoms of Alzheimer’s disease (AD) have been demonstrated in previous studies, and apolipoprotein E (ApoE) ε 4 status influences psychiatric manifestations of AD. However, whether ApoE ε 4 status modifies the sex differences in neuropsychiatric symptoms of AD is still unclear. In this study, sex differences in neuropsychiatric abnormalities were stratified and analyzed by ApoE ε 4 status in mild AD and moderate to severe AD separately. The Clinical Dementia Rating (CDR) scale and the Neuropsychiatric Inventory (NPI) were used to assess dementia severity and neuropsychiatric symptoms. No sex differences were found in mild AD. In moderate to severe AD, among ε 4 positive individuals, disinhibition was significantly more prevalent (8.0% in men versus 43.2% in women, p = 0.003 ) and severer p = 0.003 in female patients. The frequency (16.0% in men versus 51.4% in women, p = 0.005 ) and score p = 0.004 of irritability were of borderline significance after strict Bonferroni correction. In conclusion, this study supported the modifying effect of ApoE ε 4 status on sex differences in neuropsychiatric symptoms of AD, and this modifying effect was pronounced in moderate to severe stage of AD. The interaction between gender and ApoE ε 4 status should be considered in studies on neuropsychiatric symptoms of AD.
    Full-text · Article · Oct 2015 · Behavioural neurology
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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.
    Full-text · Article · Apr 2014 · Journal of Alzheimer's disease: JAD
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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.
    Full-text · Article · Aug 2011 · The Neuroscientist
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