We used VBM techniques to show that cognitively normal individuals with a parent with AD, especially a mother, have reduced GMV in AD-vulnerable brain regions compared with cognitively normal individuals with no family history. More specifically, individuals with a maternal family history of AD had greater GMV reductions in the prefrontal cortices (BA 45, 46, and 47) and the precuneus. These effects remained significant after accounting for potential risk factors for late-onset AD, such as age, gender, and apoE4 genotype. Although we found more frontal than temporal regional GMV decreases in the FHm group, these findings complement and extends reports of an AD endophenotype in FHm but not FHp cognitively normal individuals.7,8,19
Healthy aging is typically associated with some brain atrophy, increases in MRI white matter signal intensity, and decreases in cognitive functioning.20
Advancements in neuroimaging have improved our ability to distinguish visible markers of early transition to AD apart from normal aging. A recent report from the Alzheimer's Disease Neuroimaging Initiative showed that participants with mild cognitive impairment who later converted to AD had lower regional GMV in a number of brain regions at baseline, including temporal, parietal, and frontal cortices.21
GMV reductions in the earliest stages of AD are most often reported in the hippocampus, as well as the precuneus, a region involved in visuospatial processes.22,23
VBM is a sensitive method for identifying regional gray matter atrophy in progressing AD subjects.24
In this study, we used VBM methods and report decreased GMV in subjects with a maternal family history in regions previously shown to be affected in subjects with early AD.12
Our data are consistent with volumetric studies characterizing regions vulnerable to atrophy in the earliest stages of AD.23,25
We report atrophy in the prefrontal cortex of FHm individuals compared with both FHp and FH− groups, which complements and extends PET data showing prefrontal hypometabolism in FHm individuals over time.8
We found that subjects in the paternal family history group had reduced GMV in the prefrontal cortex and precuneus compared with FH− subjects. The paternal group, however, did not have any decreases in GMV compared with the maternal family history group, which would support data showing that FHm subjects have a stronger imaging endophenotype of AD7,8
and that there is a higher mother-to-father ratio among affected parents of subjects with AD.26
We will need to complete a longitudinal examination of our subjects to determine whether the presently reported GMV deficits predispose FHm individuals to additional atrophy in AD-vulnerable regions. It will also be crucial for future studies to analyze whether maternal family history of AD influences disease severity, rate of cognitive decline, or age at onset in subjects with a diagnosis of AD.
Accumulating literature suggests that having an AD-affected father or mother increases one's risk of late-onset, sporadic AD, although the risk is greater when the mother is the affected parent. For example, in a cohort of individuals with AD and a positive family history, the mother was more likely to be the affected parent than the father.26
Both PET and neuropsychological data suggest that FHm status has a greater impact on brain physiology and cognitive function than FHp status.6,7
Gender-specific inheritance phenomena are associated with several genetic paradigms, such as X-linked inheritance, sex-specific imprinting, and mitochondrial DNA (mtDNA) transmission. Currently, there are several lines of evidence supporting a role for mtDNA transmission in AD. Mitochondrial DNA encodes catalytic sites for the enzyme cytochrome oxidase, and cytochrome oxidase activity is reduced in AD.27
Neuronal nuclear genes influencing mitochondrial energy metabolism are underexpressed in AD, particularly in regions like the precuneus.28
Brains pathologically diagnosed with AD have significantly more abundant low-level heteroplasmic mutations in the mtDNA d-loop region,29
and higher levels of the 5-kd “common” mtDNA deletion compared with control brains.30,31
Studies of cytoplasmic hybrids (cybrids) in neuronal cell lines have demonstrated that cell lines expressing AD subject platelet mtDNA have lower mtDNA-related cytochrome oxidase activity, supporting the possibility that mtDNA might differ between AD and control subjects.32,33
Furthermore, AD-related alterations in mtDNA content are neuroanatomically specific to the hippocampus, frontal, and temporal cortices.34
While GMV differences in regions of AD-related atrophy were observed in FH+ participants, we did not find significant GMV changes in the hippocampus, a region most commonly associated with AD-related volumetric changes. AD-related hippocampal atrophy is typically associated with clinically evident cognitive changes (i.e., memory loss); however, our participants did not have dementia or evidence of cognitive or functional decline. There were no significant differences between any groups in our standardized global cognitive measure, consistent with the cross-sectional and longitudinal PET studies of family history. Larger hippocampal volume35
and hippocampal neuronal cells36
are associated with preserved cognition and function in individuals with the presence of high AD neuropathologic burden. So while these individuals may be genetically at risk of AD and demonstrate atrophy in AD-vulnerable regions, protective or compensatory mechanisms may be playing a role maintaining normal cognitive function. This is further suggested by the larger regional volumes in the left insula and prefrontal cortex in FH+ compared with FH− groups. It will be important to replicate these findings in larger community-based samples and longitudinal assessments of the relationship of family with hippocampal atrophy.
It is interesting that our FHm group had significantly more E4 allele carriers than the FHp and FH− groups, similar to another report of higher apoE
4 frequency in an FHm group.37
We and others have found reduced hippocampal GMV in cognitively normal elderly subjects with an apoE4 allele.13,38,39
In the current study, we both controlled for apoE4 and analyzed apoE4 groups separately, which demonstrated that the present findings were not accounted for by apoE4. Excluding FH+ subjects whose parents had dementia only after age 80 years may artifactually reduce the total number of FHm-eligible subjects, and thus we may have selectively enriched for apoE
4 alleles in the FHm group. Moreover, the apoE4 genotype is often overrepresented in subjects who have a family member with AD, and this family history might lead participants to seek involvement in memory studies such as ours.
Our study is limited by a lack of neuropathologic confirmation of parental AD, and it is possible that parents who developed dementia by history may have had another neurodegenerative disorder or a nondegenerative cause of dementia. If the relatives of our subjects did not have AD, it would have likely reduced our ability to detect group differences. family history questionnaires such as ours, however, have been shown to agree with neuropathologic findings.40
Moreover, it is possible that there is a censoring bias in assigning family history groups to individuals whose parents died at an earlier age. Additionally, our study is limited by a cross-sectional design, and further longitudinal evaluations will be important to confirm these findings. The small sample size may have limited our power to resolve volumetric group differences, in particular in the FHp group. Despite these limitations, the regional specificity of our findings in AD-vulnerable regions observed in individuals without dementia and with a maternal family history of AD complement and extend reports of cerebral metabolic differences in subjects with a maternal family history.