Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia.
BACKGROUND
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.


METHODS
Cross-sectional.


METHODS
Metropolitan university medical center.


METHODS
Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE.


METHODS
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.
Bartzokis
George
G
Department of Neurology, The David Geffen School of Medicine at UCLA, USA. gbar@ucla.edu
Lu
Po H
PH
Geschwind
Daniel H
DH
Edwards
Nancy
N
Mintz
Jim
J
Cummings
Jeffrey L
JL
D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D003337:Corpus Callosum / Q000473:pathology*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005625:Frontal Lobe / Q000473:pathology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D011322:Primary Prevention / Q000379:methods; D011379:Prognosis
D001057:Apolipoproteins E