Dissecting the Gene Dose-effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer's Disease

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Feb 14

PMID 23405083

Citations 45

Authors

Christopher A Hostage

Kingshuk Roy Choudhury

Pudugramam Murali Doraiswamy

Jeffrey R Petrella

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) ε4 and ε2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer's Disease (AD).

Materials And Methods: We analyzed MR and genetic data on 662 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database-198 cognitively normal controls (CN), 321 mild-cognitive impairment (MCI) subjects, and 143 AD subjects-looking for dose-dependent effects of the ε4 and ε2 alleles on hippocampal volumes. Volumes were measured using a fully-automated algorithm applied to high resolution T1-weighted MR images. Statistical analysis consisted of a multivariate regression with repeated-measures model.

Results: There was a dose-dependent effect of the ε4 allele on hippocampal volume in AD (p = 0.04) and MCI (p = 0.02)-in both cases, each allele accounted for loss of >150 mm(3) (approximately 4%) of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen's d = -0.16 and -0.19 for AD and MCI, respectively). There was also a dose-dependent, main effect of the ε2 allele (p<0.0001), suggestive of a moderate protective effect on hippocampal volume-an approximately 20% per allele volume increase as compared to CN with no ε2 alleles (Cohen's d = 0.23).

Conclusion: Though no effect of ε4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE ε4 and ε2 alleles on hippocampal morphology across the spectrum of cognitive aging.

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References

Holland D, Dale A . Nonlinear registration of longitudinal images and measurement of change in regions of interest. Med Image Anal. 2011; 15(4):489-97. PMC: 3115407. DOI: 10.1016/j.media.2011.02.005. View

Tupler L, Krishnan K, Greenberg D, Marcovina S, Payne M, MacFall J . Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve. Neurobiol Aging. 2006; 28(11):1644-56. DOI: 10.1016/j.neurobiolaging.2006.07.001. View

Mahley R, Rall Jr S . Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2001; 1:507-37. DOI: 10.1146/annurev.genom.1.1.507. View

Petersen R, Aisen P, Beckett L, Donohue M, Gamst A, Harvey D . Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010; 74(3):201-9. PMC: 2809036. DOI: 10.1212/WNL.0b013e3181cb3e25. View

Teter B, Raber J, Nathan B, Crutcher K . The presence of apoE4, not the absence of apoE3, contributes to AD pathology. J Alzheimers Dis. 2002; 4(3):155-63. DOI: 10.3233/jad-2002-4305. View

Schuff N, Woerner N, Boreta L, Kornfield T, Shaw L, Trojanowski J . MRI of hippocampal volume loss in early Alzheimer's disease in relation to ApoE genotype and biomarkers. Brain. 2009; 132(Pt 4):1067-77. PMC: 2668943. DOI: 10.1093/brain/awp007. View

Jack Jr C, Petersen R, Xu Y, OBrien P, Waring S, Tangalos E . Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer's disease. Ann Neurol. 1998; 43(3):303-10. PMC: 2752747. DOI: 10.1002/ana.410430307. View

den Heijer T, Oudkerk M, Launer L, van Duijn C, Hofman A, Breteler M . Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology. 2002; 59(5):746-8. DOI: 10.1212/wnl.59.5.746. View

Dale A, Sereno M . Improved Localizadon of Cortical Activity by Combining EEG and MEG with MRI Cortical Surface Reconstruction: A Linear Approach. J Cogn Neurosci. 2013; 5(2):162-76. DOI: 10.1162/jocn.1993.5.2.162. View

10.

Han X, Jovicich J, Salat D, van der Kouwe A, Quinn B, Czanner S . Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade and manufacturer. Neuroimage. 2006; 32(1):180-94. DOI: 10.1016/j.neuroimage.2006.02.051. View

11.

Fischl B, Liu A, Dale A . Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex. IEEE Trans Med Imaging. 2001; 20(1):70-80. DOI: 10.1109/42.906426. View

12.

Drzezga A, Grimmer T, Henriksen G, Muhlau M, Perneczky R, Miederer I . Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology. 2009; 72(17):1487-94. DOI: 10.1212/WNL.0b013e3181a2e8d0. View

13.

Segonne F, Dale A, Busa E, Glessner M, Salat D, Hahn H . A hybrid approach to the skull stripping problem in MRI. Neuroimage. 2004; 22(3):1060-75. DOI: 10.1016/j.neuroimage.2004.03.032. View

14.

Basso M, Gelernter J, Yang J, MacAvoy M, Varma P, Bronen R . Apolipoprotein E epsilon4 is associated with atrophy of the amygdala in Alzheimer's disease. Neurobiol Aging. 2005; 27(10):1416-24. DOI: 10.1016/j.neurobiolaging.2005.08.002. View

15.

Nagy Z, Esiri M, Jobst K, Johnston C, Litchfield S, Sim E . Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease. Neuroscience. 1995; 69(3):757-61. DOI: 10.1016/0306-4522(95)00331-c. View

16.

Cherbuin N, Anstey K, Sachdev P, Maller J, Meslin C, Mack H . Total and regional gray matter volume is not related to APOE*E4 status in a community sample of middle-aged individuals. J Gerontol A Biol Sci Med Sci. 2008; 63(5):501-4. DOI: 10.1093/gerona/63.5.501. View

17.

Chiang G, Insel P, Tosun D, Schuff N, Truran-Sacrey D, Raptentsetsang S . Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects. Neurology. 2010; 75(22):1976-81. PMC: 3014234. DOI: 10.1212/WNL.0b013e3181ffe4d1. View

18.

Rebeck G, Kindy M, LaDu M . Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3. J Alzheimers Dis. 2002; 4(3):145-54. DOI: 10.3233/jad-2002-4304. View

19.

Sled J, Zijdenbos A, Evans A . A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging. 1998; 17(1):87-97. DOI: 10.1109/42.668698. View

20.

Liu Y, Paajanen T, Westman E, Zhang Y, Wahlund L, Simmons A . APOE ε2 allele is associated with larger regional cortical thicknesses and volumes. Dement Geriatr Cogn Disord. 2010; 30(3):229-37. DOI: 10.1159/000320136. View