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Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals
Implications for Cognitive Decline and Dementia
George Bartzokis, MD;
Po H. Lu, PsyD;
Daniel H. Geschwind, MD;
Nancy Edwards, MA;
Jim Mintz, PhD;
Jeffrey L. Cummings, MD
Arch Gen Psychiatry. 2006;63:63-72.
Context Apolipoprotein E (APOE) genotype is the most influential Alzheimer disease (AD) risk factor after advanced age. The APOE4 alleles decrease and the APOE2 alleles increase age at onset of AD. Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions. This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD.
Objective To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown.
Design Cross-sectional.
Setting Metropolitan university medical center.
Participants Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE.
Main Outcome Measures Calculated transverse relaxation rates, an indirect measure of white matter structural integrity, for late-myelinating frontal lobe white matter (Fwm) and early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and the genu (Gwm).
Results The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm. Furthermore, APOE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in Swm. In Fwm and Gwm, APOE4+ individuals had a steeper slope of decline in relaxation rates with age than APOE2+ individuals; those with APOE3/3 alleles had an intermediate slope.
Conclusions In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD. Combining APOE status with noninvasive measures of myelin breakdown may be useful in assessing treatment strategies for the primary prevention of AD.
Author Affiliations: Department of Neurology (Drs Bartzokis, Lu, Geschwind, and Cummings and Ms Edwards), Laboratory of Neuroimaging, Division of Brain Mapping, Department of Neurology (Dr Bartzokis), and Department of Psychiatry and Biobehavioral Sciences (Drs Mintz and Cummings), The David Geffen School of Medicine at UCLA, Los Angeles, Calif; Department of Psychiatry, VA Greater Los Angeles Healthcare System, West Los Angeles (Drs Bartzokis, Lu, and Mintz and Ms Edwards).
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