The apolipoprotein E gene and its age-specific effects on cognitive function

Department of Epidemiology, Erasmus University Medical Center Rotterdam, The Netherlands.
Neurobiology of aging (Impact Factor: 5.01). 12/2008; 31(10):1831-3. DOI: 10.1016/j.neurobiolaging.2008.09.015
Source: PubMed


The E4 allele of the apolipoprotein E gene (APOE) is a well-established determinant of Alzheimer's disease but its relation to cognitive function is much less understood. We studied the age-specific effects of the APOE*E4 allele on cognitive function and cardiovascular risk factors in 2208 related individuals. APOE*E4 allele was significantly associated with reduced test scores for Adult Verbal Learning Test, particularly on the memory and learning sub domains, in persons older than 50 years of age. The effect of APOE*E4 was independent of the effect of APOE*E4 on vascular risk factors and most pronounced on learning ability. Our findings suggest that APOE*E4 has an effect on cognitive function predominantly in the elderly, independent of vascular risk factors.

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    • "In addition, genetic effects were more pronounced in older than younger individuals with respect to episodic memory and global cognitive ability. In line with this pattern, longitudinal studies have documented interactions between age and APOE on the memory and learning subdomains of the Adult Verbal Learning Test, with stronger negative effects of ε4 in persons older than 50 years than in those below 50 years (Liu et al. 2010). Similarly, in older adults aged 79 years, the ε4 allele was associated with more rapid decline in verbal memory and abstract reasoning across 8 years (Schiepers et al. 2012). "
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    ABSTRACT: Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.
    Full-text · Article · Feb 2015 · Neuropsychology Review
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    • "AD (Albert et al., 2011; Harris and Deary, 2011) and has been implicated in candidate gene studies for normal cognitive decrements (e.g., Small et al., 2004; Kozauer et al., 2008; Liu et al., 2010; Izaks et al., 2011; Wisdom et al., 2011; Davies et al., 2014) and mild cognitive impairment (Brainerd et al., 2011; Reinvang et al., 2013). Brainerd and colleagues reported that the ε4 variant was more represented in older adults classified as MCI than in a nondemented comparison group. "
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    ABSTRACT: Objective: Research has reported associations among selected genetic susceptibility biomarkers and risk of (a) normal cognitive aging decrements, (b) established mild cognitive impairment (MCI), and (c) sporadic Alzheimer's disease (AD). In focusing on the transitional normal-to-early MCI phase, we examine associations among three theoretically relevant polymorphisms (APOE [rs429358, rs7412], BDNF [rs6265], COMT [rs4680]) and both baseline cognitive status (MCI vs. normal aging) and two-wave (four-year) longitudinal stability or change profiles. The latter included three profiles: (a) stable as normal aging, (b) stable or chronic impairment (MCI-to-MCI), and (c) emergence of impairment (normal-to-MCI). Method: Genotyped older adults (n = 237 at baseline; age range = 64–91; 62% women) from the Victoria Longitudinal Study were examined for (a) independent and interactive associations of three genetic polymorphisms with (b) two objectively classified cognitive status groups (not-impaired controls (NIC) and MCI) at (c) both baseline and across a two-wave (four-year) longitudinal interval. Results: First, logistic regression revealed that the presence of at least one APOE ε4 allele (the risk factor for AD) was linked to greater baseline risk of objective MCI. Second, multinomial logistic regression revealed that (a) the presence of an APOE ε4 allele was associated with an increased risk of 4-year MCI status stability (chronicity), and (b) the COMT homozygous risk genotype (G/G or Val/Val) was associated with an increased risk of both MCI-to-MCI stability (chronicity) and emerging NIC-to-MCI conversion. Discussion: Both chronicity and emergence of objectively classified early cognitive impairment may be genetically heterogeneous phenomena, with influences from a panel of both normal cognitive aging (COMT) and AD-related (APOE) polymorphisms.
    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
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    • "Human ApoE4 is known to accelerate memory decline in ageing and AD10262728. Although intranasal insulin can improve cognition2930, this has little effect in ApoE4 elderly subjects31. "
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    ABSTRACT: Human ApoE4 accelerates memory decline in ageing and in Alzheimer's disease. Although intranasal insulin can improve cognition, this has little effect in ApoE4 subjects. To understand this ApoE genotype-dependent effect, we examined brain insulin signaling in huApoE3 and huApoE4 targeted replacement (TR) mice. At 32 weeks, lower insulin receptor substrate 1 (IRS1) at S636/639 and Akt phosphorylation at T308 were detected in fasting huApoE4 TR mice as compared to fasting huApoE3 TR mice. These changes in fasting huApoE4 TR mice were linked to lower brain glucose content and have no effect on plasma glucose level. However, at 72 weeks of age, these early changes were accompanied by reduction in IRS2 expression, IRS1 phosphorylation at Y608, Akt phosphorylation at S473, and MAPK (p38 and p44/42) activation in the fasting huApoE4 TR mice. The lower brain glucose was significantly associated with higher brain insulin in the aged huApoE4 TR mice. These results show that ApoE4 reduces brain insulin signaling and glucose level leading to higher insulin content.
    Full-text · Article · Jan 2014 · Scientific Reports
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