Patterns of progressive atrophy vary with age in Alzheimer's disease patients

Abstract

Age is not only the greatest risk factor for Alzheimer's disease (AD) but also a key modifier of disease presentation and progression. Here, we investigate how longitudinal atrophy patterns vary with age in mild cognitive impairment (MCI) and AD. Data comprised serial longitudinal 1.5-T magnetic resonance imaging scans from 153 AD, 339 MCI, and 191 control subjects. Voxel-wise maps of longitudinal volume change were obtained and aligned across subjects. Local volume change was then modeled in terms of diagnostic group and an interaction between group and age, adjusted for total intracranial volume, white-matter hyperintensity volume, and apolipoprotein E genotype. Results were significant at p < 0.05 with family-wise error correction for multiple comparisons. An age-by-group interaction revealed that younger AD patients had significantly faster atrophy rates in the bilateral precuneus, parietal, and superior temporal lobes. These results suggest younger AD patients have predominantly posterior progressive atrophy, unexplained by white-matter hyperintensity, apolipoprotein E, or total intracranial volume. Clinical trials may benefit from adapting outcome measures for patient groups with lower average ages, to capture progressive atrophy in posterior cortices.

Keywords: Aging; Alzheimer's disease; Atrophy; Early-onset Alzheimer's disease; Hippocampus; Late-onset; Mild cognitive impairment (MCI).

Fig. 1

Flowchart showing the selection of subjects for analysis. Abbreviation: WMH, white-matter hyperintensity.

Fig. 2

Results of the F test to test the age-by-group interaction term to predict volume change. (A) Clusters in the images represent voxels in which there is a significant difference in the relationship between age and atrophy rate across the 3 groups. (B) Graphs explain these relationships; summary slopes of voxel change for each individual at the voxel of interest are plotted against baseline age in controls, MCI, and AD patients. Positive values of change in voxel volume indicate expansion, and negative values represent voxel contraction. Results are adjusted for APOE genotype and white-matter hyperintensity volume. Each voxel of interest is located within an FWE corrected p < 0.05 cluster indicated by the crosshairs in the images. Abbreviations: AD, Alzheimer's disease; MCI, mild cognitive impairment.

Fig. 3

Results of the T tests to directly compare the age-by-group interaction between controls and AD patients. Clusters indicate regions in which the relationships between age and atrophy are different between groups, that is, differences in age-by-group interaction. Red clusters signify regions in which there is greater atrophy at younger ages in AD patients, whereas for controls, there is little age–atrophy relationship. Blue clusters indicate voxels which expand more at younger ages in AD patients, whereas controls expand more at older ages. There were no differences between control and MCI patients. Analyses are corrected for multiple comparisons, FWE p < 0.05, and are also corrected for APOE genotype and WMH volume. Abbreviations: AD, Alzheimer's disease; FWE, family-wise error; MCI, mild cognitive impairment; WMH, white-matter hyperintensity. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)