Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease

Abstract

Objective: Beyond age, having a family history is the most significant risk factor for Alzheimer disease (AD). This longitudinal brain imaging study examines whether there are differential patterns of regional gray matter atrophy in cognitively healthy elderly subjects with (FH+) and without (FH-) a family history of late-onset AD.

Methods: As part of the KU Brain Aging Project, cognitively intact individuals with a maternal history (FHm, n = 11), paternal history (FHp, n = 10), or no parental history of AD (FH-, n = 32) similar in age, gender, education, and Mini-Mental State Examination (MMSE) score received MRI at baseline and 2-year follow-up. A custom voxel-based morphometry processing stream was used to examine regional differences in atrophy between FH groups, controlling for age, gender, and APOE ε4 (APOE4) status. We also analyzed APOE4-related atrophy.

Results: Cognitively normal FH+ individuals had significantly increased whole-brain gray matter atrophy and CSF expansion compared to FH-. When FH+ groups were split, only FHm was associated with longitudinal measures of brain change. Moreover, our voxel-based analysis revealed that FHm subjects had significantly greater atrophy in the precuneus and parahippocampus/hippocampus regions compared to FH- and FHp subjects, independent of APOE4 status, gender, and age. Individuals with an ε4 allele had more regional atrophy in the frontal cortex compared to ε4 noncarriers.

Conclusions: We conclude that FHm individuals without dementia have progressive gray matter volume reductions in select AD-vulnerable brain regions, specifically the precuneus and parahippocampal gyrus. These data complement and extend reports of regional cerebral metabolic differences and increases in amyloid-β burden in FHm subjects, which may be related to a higher risk for developing AD.

Figure 1. Statistical parametric maps showing gray matter atrophy in cognitively healthy subjects with family history of late-onset Alzheimer disease (FH+) compared with subjects without family history of late-onset Alzheimer disease (FH−)

Areas of regional 2-year atrophy are represented on a red (FH− < FH+) and blue (FH− < FHm) color-coded scale, reflecting Z scores between 2 and 4. Overlapping regions are shown in pink. Results are displayed on the axial and sagittal views of a standard, spatially normalized MRI. Anatomic location and description of brain regions for A and B are in tables 2 and e-3.

Figure 2. Increased regional atrophy in maternal history of Alzheimer disease (FHm) group compared to subjects without family history of late-onset Alzheimer disease (FH−) and paternal history of Alzheimer disease (FHp) groups

(A) Longitudinal voxel-based results thresholded at Z >3.0, overlaid on 3-dimensional surface demonstrating precuneus and parahippocampal atrophy. (B) Mean gray matter volume loss was extracted from the clusters showing maximal statistical difference at p < 0.05 familywise error corrected for precuneus cluster (B.a) and parahippocampal cluster (B.b), organized by family history group. Line represents mean volume change within the cluster for the whole group.

Figure 3. Atrophy in APOE4 carriers compared to noncarriers, and individuals with family history of late-onset Alzheimer disease (FH+) compared to without family history of late-onset Alzheimer disease (FH−)

Blue regions indicate areas of increased atrophy in APOE4 carriers compared to noncarriers in the prefrontal, frontal, and parietal cortex. Pink regions indicate areas of increased atrophy in the medial temporal, temporal, parietal, and some frontal cortex in individuals with a family history of AD, as detailed in tables 2 and e-4. First column of images (A) are the left lateral (A.a) and medial pial surface (A.b), middle column of images (B) were the caudal (B.a) and rostral (B.b) view, right column of images (C) were the right lateral (C.a) and medial (C.b) surface. Results at p < 0.001 uncorrected, clusters >100.