Spatial patterns of white matter hyperintensities associated with Alzheimer's disease risk factors in a cognitively healthy middle-aged cohort

Abstract

Background: White matter hyperintensities (WMH) of presumed vascular origin have been associated with an increased risk of Alzheimer's disease (AD). This study aims to describe the patterns of WMH associated with dementia risk estimates and individual risk factors in a cohort of middle-aged/late middle-aged individuals (mean 58 (interquartile range 51-64) years old).

Methods: Magnetic resonance imaging and AD risk factors were collected from 575 cognitively unimpaired participants. WMH load was automatically calculated in each brain lobe and in four equidistant layers from the ventricular surface to the cortical interface. Global volumes and regional patterns of WMH load were analyzed as a function of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, as well as family history of AD and Apolipoprotein E (APOE) genotype. Additional analyses were performed after correcting for the effect of age and hypertension.

Results: The studied cohort showed very low WMH burden (median 1.94 cm³) and 20-year dementia risk estimates (median 1.47 %). Even so, higher CAIDE scores were significantly associated with increased global WMH load. The main drivers of this association were age and hypertension, with hypercholesterolemia and body mass index also displaying a minor, albeit significant, influence. Regionally, CAIDE scores were positively associated with WMH in anterior areas, mostly in the frontal lobe. Age and hypertension showed significant association with WMH in almost all regions analyzed. The APOE-ε2 allele showed a protective effect over global WMH with a pattern that comprised juxtacortical temporo-occipital and fronto-parietal deep white matter regions. Participants with maternal family history of AD had higher WMH load than those without, especially in temporal and occipital lobes.

Conclusions: WMH load is associated with AD risk factors even in cognitively unimpaired subjects with very low WMH burden and dementia risk estimates. Our results suggest that tight control of modifiable risk factors in middle-age/late middle-age could have a significant impact on late-life dementia.

Keywords: Aging; Brain; Lesions; Prevention; Vascular.

Fig. 1

Example of the brain segmentation for one participant. Different axial slices of the same participant are shown in each column. The first row shows WMH lesion segmentation in green. In the second row, lobar segmentation is shown. Finally, the last row shows the four layers in which each lobe was segmented. Of these layers, the most internal represents periventricular areas, there are two layers of DWM and finally a juxtacortical layer which is the most external

Fig. 2

Regional patterns of WMH associations with CAIDE-I and each of the individual risk factors included in the scale. The individual risks of CAIDE-I are: age, hypertension, hypercholesterolemia, body mass index, sex, education, and physical exercise. Model 1 shows direct correlations without covariates (first column). Model 2 and Model 3 show correlations against WMH correcting by age and hypertension, respectively (second and third column). Effect sizes of the correlation are colored only on regions that showed significant association (p < 0.05 FDR-corrected). Hot colors represent positive correlations between WMH and each particular condition, and cold colors negative associations. In dichotomic comparisons, hypertensive, hypercholesterolemic, men, and active participants were set as reference groups. *Model of reference due to demographic characteristics of this group. BG basal ganglia, CAIDE-I Cardiovascular Risk Factors, Aging, and Incidence of Dementia percentage risk of dementia (model without APOE), FL left frontal lobe, FR right frontal lobe, PL left parietal lobe, PR right parietal lobe, OL left occipital lobe, OR right occipital lobe, TL left temporal lobe, TR right temporal lobe

Fig. 3

Regional patterns of WMH correlation with APOE and family history of AD. These models show correlations without any covariate (Model 1), correcting for age (Model 2), and correcting for hypertension (Model 3). Effect sizes of the correlation are shown only on regions that presented significant association (p < 0.05 FDR-corrected). Hot colors represent positive correlations between WMH and each particular condition, and cold colors negative associations. APOE-ε3ε3 carriers and participants without family history of AD were set as reference group. *Model of reference due to demographic characteristics of this group. AD Alzheimer’s disease, APOE apolipoprotein E, BG basal ganglia, FL left frontal lobe, FR right frontal lobe, PL left parietal lobe, PR right parietal lobe, OL left occipital lobe, OR right occipital lobe, TL left temporal lobe, TR right temporal lobe