Dataset Information

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.

ABSTRACT: Apolipoprotein E (APOE) ? genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640-650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ?4 "risk" allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ?3/?4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 "short" allele showed lower white matter integrity when compared with carriers of the "long" and "very-long" alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.

SUBMITTER: Lyall DM

PROVIDER: S-EPMC3969262 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.

Lyall Donald M DM Harris Sarah E SE Bastin Mark E ME Muñoz Maniega Susana S Murray Catherine C Lutz Michael W MW Saunders Ann M AM Roses Allen D AD Valdés Hernández Maria del C Mdel C Royle Natalie A NA Starr John M JM Porteous David J DJ Wardlaw Joanna M JM Deary Ian J IJ

Neurobiology of aging 20140108 6

Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to inv ...[more]

PMID: 24508314

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Project description:Background and purposePerivascular Spaces (PVS), also known as Virchow-Robin spaces, seen on structural brain MRI, are important fluid drainage conduits and are associated with small vessel disease (SVD). Computational quantification of visible PVS may enable efficient analyses in large datasets and increase sensitivity to detect associations with brain disorders. We assessed the associations of computationally-derived PVS parameters with vascular factors and white matter hyperintensities (WMH), a marker of SVD.ParticipantsCommunity dwelling individuals (n = 700) from the Lothian Birth Cohort 1936 who had multimodal brain MRI at age 72.6 years (SD = 0.7).MethodsWe assessed PVS computationally in the centrum semiovale and deep corona radiata on T2-weighted images. The computationally calculated measures were the total PVS volume and count per subject, and the mean individual PVS length, width and size, per subject. We assessed WMH by volume and visual Fazekas scores. We compared PVS visual rating to PVS computational metrics, and tested associations between each PVS measure and vascular risk factors (hypertension, diabetes, cholesterol), vascular history (cardiovascular disease and stroke), and WMH burden, using generalized linear models, which we compared using coefficients, confidence intervals and model fit.ResultsIn 533 subjects, the computational PVS measures correlated positively with visual PVS ratings (PVS count r = 0.59; PVS volume r = 0.61; PVS mean length r = 0.55; PVS mean width r = 0.52; PVS mean size r = 0.47). PVS size and width were associated with hypertension (OR 1.22, 95% CI [1.03 to 1.46] and 1.20, 95% CI [1.01 to 1.43], respectively), and stroke (OR 1.34, 95% CI [1.08 to 1.65] and 1.36, 95% CI [1.08 to 1.71], respectively). We found no association between other PVS measures and diabetes, hypercholesterolemia or cardiovascular disease history. Computational PVS volume, length, width and size were more strongly associated with WMH (PVS mean size versus WMH Fazekas score β = 0.66, 95% CI [0.59 to 0.74] and versus WMH volume β = 0.43, 95% CI [0.38 to 0.48]) than computational PVS count (WMH Fazekas score β = 0.21, 95% CI [0.11 to 0.3]; WMH volume β = 0.14, 95% CI [0.09 to 0.19]) or visual score. Individual PVS size showed the strongest association with WMH.ConclusionsComputational measures reflecting individual PVS size, length and width were more strongly associated with WMH, stroke and hypertension than computational count or visual PVS score. Multidimensional computational PVS metrics may increase sensitivity to detect associations of PVS with risk exposures, brain lesions and neurological disease, provide greater anatomic detail and accelerate understanding of disorders of brain fluid and waste clearance.

Dataset Information

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.

Publications

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.

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