Article

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: 5.94). 12/2008; 31(10):1831-3. DOI: 10.1016/j.neurobiolaging.2008.09.015
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
111 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It is unclear how the nutritional supplement chicken extract (CE) enhances cognition. Human apolipoprotein E (ApoE) can regulate cognition and this isoform-dependent effect is associated with N-methyl-D-aspartate receptor (NMDAR). To understand if CE utilizes this pathway, we compared NMDAR signaling in neuronal cells expressing ApoE3 and ApoE4. We observed that CE increased S896 phosphorylation on NR1 in ApoE3 cells and this was linked to higher protein kinase C (PKC) activation. However, ApoE4 cells treated with CE have lowered S897 phosphorylation on NR1 and this was associated with reduced protein kinase A (PKA) phosphorylation. In ApoE3 cells, CE increased calmodulin kinase II (CaMKII) activation and AMPA GluR1 phosphorylation on S831. In contrast, CE reduced CaMKII phosphorylation, and led to higher de-phosphorylation of S831 and S845 on GluR1 in ApoE4 cells. While CE enhanced ERK/CREB phosphorylation in ApoE3 cells, this pathway was down-regulated in both ApoE4 and mock cells after CE treatment. These results show that CE triggers ApoE isoform-specific changes on ERK/CREB signaling.
    Food & Function 09/2014; 5(9):2043-2051. · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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).
    Frontiers in Aging Neuroscience 09/2014; 6:236. · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831, CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age-specific, isoform-dependent effects of ApoE on neuronal signaling.
    Scientific Reports 10/2014; 4:6580. · 5.08 Impact Factor

Full-text

Download
101 Downloads
Available from
Jun 5, 2014