Family history of Alzheimer disease predicts hippocampal atrophy in healthy middle-aged adults

Abstract

Objective: To evaluate the longitudinal influence of family history (FH) of Alzheimer disease (AD) and apolipoprotein E ε4 allele (APOE4) on brain atrophy and cognitive decline over 4 years among asymptomatic middle-aged individuals.

Methods: Participants were cognitively healthy adults with (FH+) (n = 60) and without (FH-) (n = 48) a FH of AD (mean age at baseline 54 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention. They underwent APOE genotyping, cognitive testing, and an MRI scan at baseline and 4 years later. A covariate-adjusted voxel-based analysis interrogated gray matter (GM) modulated probability maps at the 4-year follow-up visit as a function of FH and APOE4. We also examined the influence of parent of origin on GM atrophy. Parallel analyses investigated the effects of FH and APOE4 on cognitive decline.

Results: Neither FH nor APOE4 had an effect on regional GM or cognition at baseline. Longitudinally, a FH × APOE4 interaction was found in the right posterior hippocampus, which was driven by a significant difference between the FH+ and FH- subjects who were APOE4-. In addition, a significant FH main effect was observed in the left posterior hippocampus. No significant APOE4 main effects were detected. Persons with a maternal history of AD were just as likely as those with a paternal history of AD to experience posterior hippocampal atrophy. There was no longitudinal decline in cognition within the cohort.

Conclusion: Over a 4-year interval, asymptomatic middle-aged adults with FH of AD exhibit significant atrophy in the posterior hippocampi in the absence of measurable cognitive changes. This result provides further evidence that detectable disease-related neuroanatomic changes do occur early in the AD pathologic cascade.

Figure 1. Anatomic search region examined in the study

A glass brain rendering of the a priori anatomic mask used in this study. The mask, which was constructed using the WFU_PickAtlas toolbox, included the bilateral posterior cingulate, hippocampus, parahippocampal gyrus, and amygdala. The left side of image is the left side of the brain.

Figure 2. Effects of family history (FH) and apolipoprotein E4 ϵ4 allele (APOE4) status on gray matter (GM) atrophy

A 2 × 2 analysis of covariance that examined the effects of FH and APOE4 status on GM atrophy found a significant FH × APOE4 interaction in the right posterior hippocampus (cyan color, p_voxel < 0.0001, cluster size = 201 voxels) and a significant FH effect in the left posterior hippocampus (red color, p_voxel < 0.0001, cluster size = 286 voxels). Results are displayed on the coronal view of the ICBM452 atlas, conforming to Montreal Neurological Institute space at y-plane locations −22, −18, and −14. The left side of image is the left side of the brain. The bar graph displays the adjusted mean (SE) GM modulated probability from the FH × APOE4 interaction effect, extracted from the cluster in the right posterior hippocampus.

Figure 3. Effects of parent of origin on gray matter (GM) atrophy

Contrast tests of parent of origin effects on GM atrophy found significantly greater posterior hippocampal atrophy, bilaterally, in the maternal family history−positive (mFH+) group compared with the family history-negative (FH−) group (green color, p_voxel < 0.0001, cluster size >268 voxels). The contrasts also revealed significantly greater posterior hippocampal atrophy, bilaterally, in the paternal family history−positive (pFH+) group compared with the FH− group (red color, p_voxel < 0.0001, cluster size >301 voxels). Overlapping regions are shown in yellow. There were no regions where mFH+ subjects had greater GM atrophy than pFH+ subjects or vice versa. Results and displayed on the coronal view of the ICBM452 atlas, conforming to Montreal Neurological Institute space at y-plane locations −22, −18, −14, −10, −6, and −2. The left side of the image is the left side of the brain. The bar graph displays the adjusted mean (SE) GM modulated probability from the FH− vs (mFH+ or pFH+) effect, extracted from the cluster in the right posterior hippocampus.