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      Interaction between years of education and APOE ε4 status on frontal and temporal metabolism

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          Abstract

          Objective:

          To examine interactions between years of education and APOE ε4 status on gray matter volume and metabolism in cognitively healthy participants.

          Methods:

          Seventy-two healthy participants (28 APOE ε4 carriers and 44 noncarriers; from 23 to 84 years of age) with FDG-PET and structural MRI were included. A subgroup also underwent florbetapir-PET. We tested the interaction effect between years of education and APOE ε4 status (carrier vs noncarrier) on FDG-PET and structural MRI within the whole brain (voxel-wise) adjusting for age and sex. Computed florbetapir standardized uptake value ratios were used for complementary analyses.

          Results:

          We found an interaction between years of education and APOE ε4 status on frontotemporal FDG-PET metabolism, such that higher education was positively related to frontotemporal metabolism only in APOE ε4 carriers. Complementary analyses revealed that (1) this interaction was independent from amyloid load; (2) increased metabolism in APOE ε4 carriers in this region correlated with episodic memory performances; (3) lower educated APOE ε4 carriers showed decreased metabolism relative to noncarriers in medial temporal and prefrontal areas, while higher educated carriers were comparable to noncarriers in these areas and showed increased metabolism in the middle temporal lobe.

          Conclusions:

          Our results showed that education may counteract the effects of APOE ε4 on metabolism independently of amyloid deposition. Higher metabolism in higher (compared to lower) educated APOE ε4 carriers was found in regions that sustain episodic memory. Overall, our results point to education as a protective factor that may help to postpone cognitive changes in APOE ε4 carriers.

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          Most cited references25

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          Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

          The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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            Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

            Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
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              Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.

              We have used restriction isotyping (restriction enzyme isoform genotyping) for rapid typing of common apolipoprotein E isoforms (E2, E3, E4). ApoE restriction isotyping used oligonucleotides to amplify apolipoprotein E gene sequences containing amino acid positions 112 and 158. The amplification products were digested with HhaI and subjected to electrophoresis on polyacrylamide gels. Each of the isoforms was distinguished by a unique combination of HhaI fragment sizes that enabled unambiguous typing of all homozygotic and heterozygotic combinations. HhaI cleaves at GCGC encoding 112arg (E4) and 158arg (E3, E4), but does not cut at GTGC encoding 112cys (E2, E3) and 158cys (E2).
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                Author and article information

                Contributors
                Journal
                Neurology
                Neurology
                neurology
                neur
                neurology
                NEUROLOGY
                Neurology
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0028-3878
                1526-632X
                20 October 2015
                20 October 2015
                : 85
                : 16
                : 1392-1399
                Affiliations
                From INSERM U1077 (E.M.A.-U., J.G., M.F., A.P., F.M., B.L., S.E., V.D.l.S., B.D., G.C.); Université de Caen Basse-Normandie (E.M.A.-U., J.G., M.F., A.P., F.M., B.L., V.D.l.S., B.D., G.C.) and Ecole Pratique des Hautes Etudes (E.M.A.-U., J.G., M.F., A.P., F.M., B.L., V.D.l.S., B.D., G.C.), UMR-S1077; CHU de Caen, U1077 (E.M.A.-U., J.G., M.F., A.P., F.M., B.L., S.E., B.D., G.C.); and CHU de Caen (S.E., V.D.l.S.), Service de Neurologie, Caen, France.
                Author notes
                Correspondence to Dr. Chételat: chetelat@ 123456cyceron.fr

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by INSERM, DR Nord-Ouest (Lille, France).

                Article
                NEUROLOGY2015640953
                10.1212/WNL.0000000000002034
                4626241
                26408498
                8569c402-0e07-4740-bd98-7cc085df250c
                © 2015 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                : 09 January 2015
                : 23 June 2015
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