Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults

Abstract

The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared with ε4 non-carriers decades before the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, aged 26 to 45 years, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first- or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with covarying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades before the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late-onset AD or healthy brain aging.

Figure 1

Gray matter network subject scores and apolipoprotein E (APOE) ε4 carrier status. Multiple regression of Scaled Subprofile Model (SSM) subject scores from the network analysis of magnetic resonance imaging (MRI) voxel-based morphometry in cognitively normal, young to middle-aged carriers (n= 14) and non-carriers (n=10) of the APOE ε4 allele. The scatterplot shows that the APOE ε4 carrier group has a higher expression of the MRI network pattern than does the ε4 non-carrier group (*R² = 0.44, p ≤ 0.002, n = 24) and this difference remained significant after removing those subjects (filled circles) with a first-degree family history of dementia from the analysis (*R² = 0.55, p ≤ 0.002, n = 19). The APOE ε4-related network subject scores were derived from the linear combination of the first two SSM component patterns. 1° FHx = subjects with a first-degree family history of dementia; 2° FHx = subjects with a second-degree family history of dementia. Bars = mean network subject score for the APOE groups.

Figure 2

Regional gray matter network pattern related to apolipoprotein E (APOE) ε4 carrier status. Magnetic resonance imaging (MRI) gray matter pattern reflecting the linear combination of the first two Scaled Subprofile Model (SSM) components, whose mean subject scores differed between the APOE ε4 carriers and non-carriers in cognitively normal, young to early middle-aged adults. Voxels with Z scores ≥ +2.0 or ≤ -2.0 after bootstrap re-sampling with 500 iterations to provide robust regional pattern weights are superimposed on MRI projection maps (A) showing the right and left lateral and medial surfaces, as well as selected axial slices (B) spatially normalized with statistical parametric mapping (SPM8). The blue end of the color scale indicates brain regions showing lower gray matter volume in relation to APOE ε4 carrier status, whereas the orange end of the scale shows co-varying areas of relatively increased gray matter in relation to the presence of the ε4 allele. Regions showing greater gray matter volume reductions in the APOE ε4 carriers compared to non-carriers include areas in the vicinities of bilateral inferior frontal, middle frontal, superior frontal, superior medial frontal, anterior cingulate, inferior and middle temporal, inferior parietal, and right pre/post-central regions. Areas showing relative increases in the ε4 carriers compared to non-carriers are in the vicinities of the bilateral cerebellum, occipital cortex, thalamus, fusiform and right lingual gyri, and small bilateral areas in the vicinity of the hippocampus.