Christopher Alan Hostage BS, Presenter: Nothing to Disclose

Kingshuk Choudhury PhD, Abstract Co-Author: Nothing to Disclose

P. Murali Doraiswamy MD, Abstract Co-Author: Research Consultant, Avid Radiopharmaceuticals, Inc Research Consultant, Bristol-Myers Squibb Company Research Consultant, Eli Lilly and Company Research Consultant, Neuronetrix, Inc Research Consultant, Medivation, Inc Research Grant, Avid Radiopharmaceuticals, Inc Research Grant, Bristol-Myers Squibb Company Research Grant, Eli Lilly and Company Research Grant, Neuronetrix, Inc Research Grant, Medivation, Inc Stockholder, Sonexa Therapeutics, Inc Stockholder, Clarimedix, Inc Speaker, Forest Medical, LLC

Jeffrey Robert Petrella MD, Abstract Co-Author: Advisory Board, Janssen Alzheimer Immunotherapy Speakers Bureau, Quintiles

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

We analyzed MR and genetic data on 676 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database—201 normal controls (CN), 329 mild-cognitive impairment (MCI) subjects, and 146 Alzheimer's Disease (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 1.5T MPRAGE MR images. Analysis included separate pooled and by-diagnosis Analysis of Covariance (ANCOVA) as adjusted for age, intra-cranial volume, and diagnosis as appropriate. ADNI was approved by the ethics committees of all participating sites. The current analysis of the ADNI database was deemed IRB exempt by the Duke IRB.

Across all subjects, we found a dose-dependent effect of APOE ε4 for decreasing left, right, and total hippocampal volumes (p<0.0001, ANCOVA). MCI subjects had dose-dependent smaller right and total hippocampal volumes by APOE ε4 copy number (p<0.0002); a dose-dependent effect was not seen in CN or AD. APOE ε2 presence was significantly associated with an increased total hippocampal volume across all subjects (p<0.005).

Despite limitations such as a relatively small number of homozygotes and cross-sectional design, 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.

These results have important implications for our understanding of the mechanisms of APOE ε4-mediated acceleration of AD pathophysiology.

Hostage, C, Choudhury, K, Doraiswamy, P, Petrella, J, Dissecting the Gene Dose-Effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer’s Disease.  Radiological Society of North America 2012 Scientific Assembly and Annual Meeting, November 25 - November 30, 2012 ,Chicago IL. http://archive.rsna.org/2012/12021107.html