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 (FHϩ) and without (FHϪ) 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 ϭ 11), paternal history (FHp, n ϭ 10), or no parental history of AD (FHϪ, n ϭ 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 ⑀4 (APOE4) status. We also analyzed APOE4-related atrophy.Results: Cognitively normal FHϩ individuals had significantly increased whole-brain gray matter atrophy and CSF expansion compared to FHϪ. When FHϩ 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 FHϪ and FHp subjects, independent of APOE4 status, gender, and age. Individuals with an 4 allele had more regional atrophy in the frontal cortex compared to 4 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-␤ burden in FHm subjects, which may be related to a higher risk for developing AD. Late-onset Alzheimer disease (AD) is a neurodegenerative disease caused by complex genetic and environmental mechanisms.1 Age is the most significant risk factor for developing AD, followed by a family history of AD, 2 with maternal transmission significantly more frequent than paternal transmission.3 First-degree relatives of individuals with AD are at a 4-to 10-fold higher risk for AD compared to individuals with no family history.2 Since it is unknown how familial transmission of AD biologically increases susceptibility for AD, clarifying mechanisms of familial risk for AD are a step toward developing enhanced treatment and prevention strategies.Various forms of neuroimaging have attempted to characterize genetic and familial risk factors for late-onset AD by studying heritable traits in healthy individuals with no cognitive impairment.1 There are several studies showing that individuals without dementia who are

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

“…The relative consistency of these FH findings across diverse neuroimaging modalities 4,[7][8][9]11 suggests that FH is a prominent, even if nonspecific, risk factor for AD perhaps embodying an array of genetic and environmental indices that remain to be fully elucidated. 10,22 Contrary to prior reports suggesting that maternal history of AD might confer a greater risk of ADrelated cerebral abnormalities than paternal history of AD, 5,7,8,18,23 we found that pFHϩ subjects were just as likely as mFHϩ subjects to experience atrophy of the posterior hippocampus. This observation suggests that, in our cohort, the FH effect was not driven by a particular parent of origin.…”

“…For example, recent cross-sectional 18 and longitudinal 5 studies have found evidence for GM volume reductions in AD-susceptible brain regions, such as the precuneus, among cognitively intact FHϩ individuals relative to FHϪ peers. Our study extends these findings 5,18 by using a considerably larger sample, implementing a longer follow-up, and, more importantly, showing that FH-related hippocampal atrophy is present at a relatively young age (our cohort's mean baseline age was 54 years). The relative consistency of these FH findings across diverse neuroimaging modalities 4,[7][8][9]11 suggests that FH is a prominent, even if nonspecific, risk factor for AD perhaps embodying an array of genetic and environmental indices that remain to be fully elucidated.…”

“…To determine whether maternal history of AD had a differential effect on GM atrophy than paternal history of AD, 5,8 we repeated the longitudinal analysis described above but this time using a one-way ANCOVA design to assess whether there was a parent of origin effect on participants' 4-year follow-up scans, while adjusting for age, sex, baseline voxel-wise GM, and APOE4 status (see Results section for specific a priori contrasts tested). For all the imaging analyses described above, only clusters with a minimum of 188 continuous voxels and p voxel Ͻ 0.005 were deemed significant.…”

“…In the present article, we extend these prior findings by investigating the longitudinal effect of FH and APOE4 on brain morphometry within this cohort, with a particular focus on temporoparietal regions that are now known to be vulnerable to AD pathology. 16,17 In addition, because it has recently been shown that the sex of the ADaffected parent may be influential, with maternal FH being more deleterious, 5,7,8,18 we conducted supplementary analyses to determine whether any observed FH effects were possibly driven by maternal FH. In parallel analyses, we also investigated the effect of FH and APOE4 on cognitive decline.…”

Brain imaging of cognitively normal individuals with 2 parents affected by late-onset AD

“…It remains to be established whether Ab accumulation is also an early event in LOAD. 1 Previous brain imaging studies have shown that, among NL individuals who have parents with LOAD, those with maternal FH (FHm) present with increased Ab load on 11 C-Pittsburgh compound B (PiB)-PET, 11,12 progressive glucose metabolism reductions on 18 F-fluoro-2-deoxyglucose (FDG)-PET, 13,14 and gray matter volume (GMV) loss on MRI [15][16][17][18] in the same regions as those with clinical AD. In contrast, NL individuals with paternal FH (FHp) are far less likely to show biomarker abnormalities.…”