Effect of Alzheimer Disease Risk on Brain Function During Self-appraisal in Healthy Middle-aged Adults

Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 11/2007; 64(10):1163-71. DOI: 10.1001/archpsyc.64.10.1163
Source: PubMed


Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks.
To determine whether parental family history of AD (hereafter referred to as FH) or presence of the epsilon4 allele of the apolipoprotein E gene (APOE4) exerts independent effects on brain function during SA.
Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words.
An academic medical center with a research-dedicated 3.0-T MR imaging facility.
Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH.
Blood oxygen-dependent contrast measured using T2*-weighted echo-planar imaging.
Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype.
Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors.

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Available from: Carey Gleason, Aug 28, 2014
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    • "There were also studies reviewed which did not support the existence of a compensatory recruitment process in older cognitively intact ε4 carriers. Johnson et al. [54] found that APOE genotype alone did not impact neural activity during a self-appraisal task in middle-age adults, although APOE status did interact with a family history of AD to produce greater frontal and posterior cingulate activations in ε4 carriers without a family history of AD. Johnson et al. [55] reported similar results in an earlier study of middle-age adults using an episodic memory task. While APOE ε4 carriers with no family history of AD did show the predicted enhanced recruitment of MTL structures, ε4 carriers with a family history of AD actually showed the lowest levels of MTL recruitment of all participant groups [55]. "
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    ABSTRACT: Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.
    International Journal of Alzheimer's Disease 02/2011; 2011(5):726197. DOI:10.4061/2011/726197
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    • "In contrast to younger subjects, older APOEε4+ individuals had attenuated BOLD responses in several structures that included areas in the parietal cortex and posterior cingulate. The anatomical location of these areas are congruent with previous reports of hypometabolism in resting APOEε4+ individuals (Reiman et al. 1996), MCI patients (Nestor et al. 2003a, b) and those with a positive family history of Alzheimer's disease (Johnson et al. 2007) as well as in patients in early stages of Alzheimer's disease. Hypofunction in these same areas might be expected given the findings of resting hypometabolism leading some investigators to speculate as to whether this is the underlying mechanism for the early memory problems seen in Alzheimer's disease (Nestoret al. 2003b). "
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    ABSTRACT: How and when the known genetic risk allele, apolipoprotein E-epsilon4 (APOEepsilon4), confers risk to Alzheimer's disease has yet to be determined. We studied older adults and found that APOEepsilon4 carriers had greater neural activation in the medial frontal and parahippocampal gyrus during a memory task (cluster-corrected p < .01). When compared to a group of younger adults, interactive effects of age and APOEepsilon4 were found in the inferior frontal-anterior temporal region, one of the first areas to develop amyloid plaques in patients with Alzheimer's disease, and, in the posterior cingulate, one of the earliest areas to show decreased cerebral metabolism in Alzheimer's disease. Thus, abnormally high activation in fronto-temporal areas are present in both younger and older APOEepsilon4 carriers confronted with a working memory task when compared to non-APOEepsilon4 carriers. This effect, however, appears to diminish with age.
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    • "Sequences included diffusion-weighted imaging, and high resolution T1-weighted imaging. Many participants also received various fMRI tasks as part of other studies; the fMRI results are reported elsewhere (Johnson et al., 2004; Johnson et al., 2006; Ries et al., 2006; Schmitz, Kawahara, & Johnson, 2004; Trivedi et al., 2007). "
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    ABSTRACT: Structural brain change and concomitant cognitive decline are the seemingly unavoidable escorts of aging. Despite accumulating studies detailing the effects of age on the brain and cognition, the relationship between white matter features and cognitive function in aging have only recently received attention and remain incompletely understood. White matter microstructure can be measured with diffusion tensor imaging (DTI), but whether DTI can provide unique information on brain aging that is not explained by white matter volume is not known. In the current study, the relationship between white matter microstructure, age, and neuropsychological function was assessed using DTI in a statistical framework that employed white matter volume as a voxel-wise covariate in a sample of 120 healthy adults across a broad age range (18-83). Memory function and executive function were modestly correlated with the DTI measures while processing speed showed the greatest extent of correlation. The results suggest that age-related white matter alterations underlie age-related declines in cognitive function. Mean diffusivity and fractional anisotropy in several white matter brain regions exhibited a nonlinear relationship with age, while white matter volume showed a primarily linear relationship with age. The complex relationships between cognition, white matter microstructure, and white matter volume still require further investigation.
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