Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease

Abstract

Objective: A consistently identified risk factor for Alzheimer disease (AD) is family history of dementia, with maternal transmission significantly more frequent than paternal transmission. A history of maternal AD may be related to AD-like glucose consumption in cognitively healthy subjects. In this cross-sectional study, we tested whether cognitively healthy people with a family history of AD have less gray matter volume (GMV), an endophenotype for late-onset AD, than individuals with no family history, and whether decreases in GMV are different in subjects with a maternal family history.

Methods: As part of the Kansas University Brain Aging Project, 67 cognitively intact individuals with a maternal history of late-onset AD (FHm, n = 16), a paternal history of AD (FHp, n = 8), or no parental history of AD (FH-, n = 43), similar in age, gender, education, and Mini-Mental State Examination score, were scanned at 3 T. We used voxel-based morphometry to examine GMV differences between groups, controlling for age, gender, and apoE4.

Results: Cognitively healthy individuals with a family history of late-onset AD had significantly decreased GMV in the precuneus, middle frontal, inferior frontal, and superior frontal gyri compared with FH- individuals. FHm subjects had significantly smaller inferior frontal, middle frontal, precuneus, and lingual gyri compared with FH- and FHp subjects.

Conclusions: Overall, maternal family history of Alzheimer disease (AD) in cognitively normal individuals is associated with lower gray matter volume in AD-vulnerable brain regions. These data complement and extend reports of cerebral metabolic differences in subjects with a maternal family history.

Figure 1 Statistical parametric maps showing gray matter volume reductions in normal FH+ subjects compared with FH− subjects The first 2 rows display maps from subjects with a maternal family history of Alzheimer disease (FHm) as compared with subjects with no family history (FH−) (A) and subjects with a paternal family history (FHp) (B). Row C shows gray matter volume (GMV) reductions in apoE4-negative FHm subjects compared with apoE4-negative FH− subjects. Anatomic location and description of brain regions for A and B are in table 3. Statistical parametric maps showing GMV reductions in normal FHp subjects as compared with FH− subjects are in row D. Anatomic location and description of brain regions are in table e-1. Areas of gray matter volume decrease are represented on purple–to–yellow, blue–to–light blue, dark orange–to–yellow, and green–to–light green color-coded scales for the 4 contrasts, reflecting Z scores between 2 and 5 for the upper contrast and between 2 and 4 for the lower 3 contrasts. Areas of gray matter volume decrease are displayed on a standardized spatially normalized MRI.

Figure 2 Selected volume parameter estimates from voxel-based morphometry analyses The graphs show the corresponding parameter estimates for key regions identified in figure 1, representing group differences in family history–related gray matter volumes. Error bars are ±1 SEM. Gray matter volume (GMV) was reduced in those with a maternal family history of Alzheimer disease (FHm) vs those with a paternal family history (FHp) and no family history (FH−) in the inferior frontal gyrus (A), middle frontal gyrus (B), and precuneus (C). The FHp group demonstrated reduced GMV compared with the FH− group but not FHm in the inferior precuneus (D). See tables 3 and e-1 for statistics.