Altered brain white matter integrity in healthy carriers of the APOE 4 allele: A risk for AD? (original) (raw)
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The APOE ϵ 4 allele modulates brain white matter integrity in healthy adults
2010
The Apolipoprotein E (APOE) ε4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease (AD) and is also associated with structural gray matter (GM) and functional brain changes in healthy young, middle-aged and elderly subjects. Because APOE is implicated in brain mechanisms associated with white matter (WM) development and repair, we investigated the potential role played by the APOE polymorphism on WM structure in healthy younger (age range: 20-35 years) and older (aged 50-78 years) adults using diffusion tensor imaging (DTI). General reduction of fractional anisotropy (FA) and increase in mean diffusivity (MD) values was found in carriers of the APOE ε4 allele relative to non-carriers. No significant interactions between genotype and age were observed, suggesting that differences in WM structure between APOE ε4-carriers and non-carriers do not undergo significant differential changes with age. This result was not explained by differences in brain morphology or cognitive measures. The APOE ε4 allele modulates brain WM structure before any clinical or neurophysiological expression of impending disease.
The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer's disease
Alzheimer's & Dementia, 2013
Background: In this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Methods: We analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group. Results: We found significant effects of diagnosis (P corrected , .05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P , .001) of APOE ε4 carrier status on MD in HCs but not in AD subjects.
White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes
Alzheimer's research & therapy, 2018
The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer's disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer's disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail. We examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-ba...
Abnormal white matter integrity in healthy apolipoprotein E epsilon4 carriers
Neuroreport, 2005
Apolipoprotein E e4 is a major genetic risk factor for Alzheimer's disease, but the neurobiological basis for this risk is unknown. We used di¡usion tensor imaging to measure di¡usion anisotropy in the parahippocampal gyrus white matter in healthy elderly apolipoprotein E e4 carriers and noncarriers. We also measured volumes of the lateral ventricles and temporal horns as proxies of cerebral atrophy. The e4 carriers (n¼14) showed signi¢cantly lower fractional anisotropy and higher radial di¡usivity in the parahippocampal white matter 15 mm below the anterior commissure^posterior commissure plane than noncarriers (n¼15). No group di¡erences in ventricular volumes were found, nor were di¡usion tensor imaging measures modulated by ventricular volumes. Di¡usion tensor imaging may be su⁄ciently sensitive to detect preclinical brain changes related to Alzheimer's disease. NeuroReport 16:1369^1372 c 2005 Lippincott Williams & Wilkins.
NeuroImage. Clinical, 2014
Little is still known about the effects of risk factors for Alzheimer's disease (AD) on white matter microstructure in cognitively healthy adults. The purpose of this cross-sectional study was to assess the effect of two well-known risk factors for AD, parental family history and APOE4 genotype. This study included 343 participants from the Wisconsin Registry for Alzheimer's Prevention, who underwent diffusion tensor imaging (DTI). A region of interest analysis was performed on fractional anisotropy maps, in addition to mean, radial, and axial diffusivity maps, aligned to a common template space using a diffeomorphic, tensor-based registration method. The analysis focused on brain regions known to be affected in AD including the corpus callosum, superior longitudinal fasciculus, fornix, cingulum, and uncinate fasciculus. Analyses assessed the impact of APOE4, parental family history of AD, age, and sex on white matter microstructure in late middle-aged participants (aged 47-...
Differential effects of the ApoE4 genotype on brain structure and function
NeuroImage, 2014
The apolipoprotein E ε4 allele is a well established genetic risk factor for sporadic Alzheimer's disease. It is associated with structural and functional brain changes in healthy young, middle-aged and elderly subjects. In the current study, we assessed the impact of the ApoE genotype on brain macro-and microstructure, cognitive functioning and brain activity in fifty healthy young subjects (25 ApoE ε4 (ε4+) carriers and 25 non-carriers (ε4−), mean age 26.4 ± 4.6 years). We used diffusion tensor imaging (DTI) and voxel based morphometry (VBM) to assess brain structure, an extensive neuropsychological battery to test cognitive functioning and event-related functional magnetic resonance imaging (fMRI) to capture brain activity during episodic memory encoding and retrieval. ApoE ε4 carriers differed from non-carriers in fMRI activations but not in cognitive performance nor in brain micro-and macrostructure. These results suggest functional alterations in the episodic memory network that are modulated by the ε4 allele and might precede clinical or structural neurodegeneration.
Age-related differences in white matter integrity and cognitive function are related to APOE status
NeuroImage, 2011
While an extensive literature is now available on age-related differences in white matter integrity measured by diffusion MRI, relatively little is known about the relationships between diffusion and cognitive functions in older adults. Even less is known about whether these relationships are influenced by the apolipoprotein (APOE) ε4 allele, despite growing evidence that ε4 increases cognitive impairment in older adults. The purpose of the present study was to examine these relationships in a group of community-dwelling cognitively normal older adults. Data were obtained from a sample of 126 individuals (ages 52-92) that included 32 ε4 heterozygotes, 6 ε4 homozygotes, and 88 non-carriers. Two measures of diffusion, the apparent diffusion coefficient (ADC) and fractional anisotropy (FA), were obtained from six brain regions-frontal white matter, lateral parietal white matter, the centrum semiovale, the genu and splenium of the corpus callosum, and the temporal stem white matter-and were used to predict composite scores of cognitive function in two domains, executive function and memory function. Results indicated that ADC and FA differed with increasing age in all six brain regions, and these differences were significantly greater for ε4 carriers compared to noncarriers. Importantly, after controlling for age, diffusion measures predicted cognitive function in a region-specific way that was also influenced by ε4 status. Regardless of APOE status, frontal ADC and FA independently predicted executive function scores for all participants, while temporal lobe ADC additionally predicted executive function for ε4 carriers, but not noncarriers. Memory scores were predicted by temporal lobe ADC but not frontal diffusion for all participants, and this relationship was significantly stronger in ε4 carriers compared to noncarriers. Taken together, age and temporal lobe ADC accounted for a striking 53% of the variance in memory scores within the ε4 carrier group. The results provide further evidence that APOE ε4 has a significant impact on the trajectory of age-related cognitive functioning in older adults. Possible mechanisms are discussed that could account for the associations between ε4, diffusion, and cognitive function, including the influence of ε4 on neural repair, oxidative stress, and the health of myelin-producing oligodendroglia.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018
Apolipoprotein E (APOE)-ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear. We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of ε4-carriers (207 heterozygotes and 65 homozygotes). We found APOE-ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. Our data indicate that APOE-ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4-carri...
ApoE influences regional white-matter axonal density loss in Alzheimer's disease
Neurobiology of aging, 2017
Mechanisms underlying phenotypic heterogeneity in young onset Alzheimer disease (YOAD) are poorly understood. We used diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI) with tract-based spatial statistics to investigate apolipoprotein (APOE) ε4 modulation of white-matter damage in 37 patients with YOAD (22, 59% APOE ε4 positive) and 23 age-matched controls. Correlation between neurite density index (NDI) and neuropsychological performance was assessed in 4 white-matter regions of interest. White-matter disruption was more widespread in ε4+ individuals but more focal (posterior predominant) in the absence of an ε4 allele. NODDI metrics indicate fractional anisotropy changes are underpinned by combinations of axonal loss and morphological change. Regional NDI in parieto-occipital white matter correlated with visual object and spatial perception battery performance (right and left, both p = 0.02), and performance (nonverbal) intelligence (WASI matri...