Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia

Agosta, Federica; Vossel, Keith A.; Miller, Bruce L.; Migliaccio, Raffaella; Bonasera, Stephen J.; Filippi, Massimo; Boxer, Adam L.; Karydas, Anna; Possin, Katherine L.; Gorno‐Tempini, Maria Luisa

doi:10.1073/pnas.0812697106

Cited by 160 publications

(169 citation statements)

References 42 publications

(42 reference statements)

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“…Although several studies have not found psychometric measures favoring carriers (18,20,27), a few reports accord well with the present data. For example, van der Vlies et al (25) reported remarkably similar findings in which noncarriers performed more poorly than carriers on an object naming task and parts A and B of the Trail Making Test.…”

Section: Resultssupporting

confidence: 81%

“…Conflicting results have also been reported from the limited investigations of cortical anatomy, with some studies reporting no difference and others reporting more robust regional atrophy in ε4 carriers (20,23). Finally, there are a few reports of greater atrophy in noncarriers either in select regions, such as the frontal lobe, or in global measures of brain volume (17,(19)(20)(21).…”

mentioning

confidence: 69%

“…Autopsy and amyloid imaging studies have reported greater Aβ plaque deposition in carriers of the ε4 allele, even after controlling for disease severity (16). Quantitative neuroimaging investigations have reported greater medial temporal lobe (MTL) atrophy, particularly involving the hippocampus, in AD patients who are ε4 carriers vs. noncarriers (17)(18)(19)(20)(21), although this has not been a universal finding (22,23). Conflicting results have also been reported from the limited investigations of cortical anatomy, with some studies reporting no difference and others reporting more robust regional atrophy in ε4 carriers (20,23).…”

mentioning

confidence: 99%

“…Quantitative neuroimaging investigations have reported greater medial temporal lobe (MTL) atrophy, particularly involving the hippocampus, in AD patients who are ε4 carriers vs. noncarriers (17)(18)(19)(20)(21), although this has not been a universal finding (22,23). Conflicting results have also been reported from the limited investigations of cortical anatomy, with some studies reporting no difference and others reporting more robust regional atrophy in ε4 carriers (20,23). Finally, there are a few reports of greater atrophy in noncarriers either in select regions, such as the frontal lobe, or in global measures of brain volume (17,(19)(20)(21).…”

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confidence: 99%

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Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Wolk

Dickerson²

2010

Proc. Natl. Acad. Sci. U.S.A.

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The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer's disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of ε4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer's Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.cognition | neuroimaging | dementia | cortical thickness | medial temporal lobe

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Section: Resultssupporting

confidence: 81%

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confidence: 69%

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confidence: 99%

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confidence: 99%

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Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Wolk

Dickerson²

2010

Proc. Natl. Acad. Sci. U.S.A.

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215

178

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“…In the authors' view, the changes support the idea that default networks are compromised in AD, and they could also serve as a marker to monitor disease progression or treatment. For another, Maria Gorno-Tempini and colleagues in the U.S. and Italy used MRI scans to examine the relationship between ApoE status and brain atrophy in AD and behavioral variant FTD (bvFTD) [9]. While there is an established link between the ε4 variant of ApoE and brain atrophy in AD, the researchers now extend this link to bvFTD as well, supporting the idea that ApoE4 may be a risk factor for multiple neurodegenerative diseases.…”

Section: Measuring Gross Brain Changes In Ad Ftdmentioning

confidence: 95%

Alzheimer Research Series on the Default Network

McCaffrey

Fagan

Landhuis

2010

JAD

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CORTICAL CONNECTIONS GET CLOSER LOOK IN HEALTH, DISEASEThe idea of the default mode network, an interconnected set of brain regions that are active when the brain is resting and that power down during focused mental tasks, was first proposed in 2001, but it quickly became a hot topic in cognitive neuroscience and for Alzheimer's disease (AD) researchers. The seesaw activation and deactivation of the default network and task-related brain regions appears critical for peak performance on memory tasks and deactivation and network connectivity are disrupted early in AD, perhaps as a result of amyloid deposition [1].AD is not the only disease where network activity suffers. A new study in PNAS reveals that function of the default network, as measured by fMRI, is also altered in people with schizophrenia, and their healthy first-degree relatives [2]. The changes are somewhat different from those seen in AD -network connectivity is strengthened, for one, and overall network activity is increased both at rest and during task. The study, from Susan Whitfield-Gabrieli at MIT, suggests that changes in default mode activity and alterations in the normal balance between activation and deactivation contribute to the symptoms of schizophrenia, and could be part of the genetic risk for the disease.To look at the default network in people with schizophrenia, the researchers performed fMRI scans on subjects while they were idle, and then when they engaged in a simple memory test. That allowed assessment of the basal network activity, and the extent of deactivation that occurred during a task that required concentration. The study compared 13 volunteers with early phase schizophrenia, 13 unaffected first-degree relatives and 13 healthy controls. When subjects performed the test, suppression of the default mode network was most effective in controls, and decreased in both patients and relatives. Overall, the deactivation in the default network and activation of task-related areas were strongly correlated in control subjects, but the seesaw effect was much weaker in patients and relatives. The result was a consistent hyperactivity of the default network. In addition, the patients and relatives showed stronger connectively between the medial prefrontal cortex and the precuneous and the rest of the default network, whether measured at rest or during a task.The strength of connectivity and defect in deactivation correlated with poorer performance in the working memory task and stronger schizophrenia symptoms, suggesting that the default mode network could play an important role in the cognitive and clinical symptoms of schizophrenia. In addition, the observation that unaffected relatives show similar changes suggests that aberrant network activity stems from genetic risk and is causal, rather than just a consequence of the disease, Whitfield-Gabrieli told ARF. "In the future, it may be possible to use these fMRI measures as a way of diagnosing disease, or to figure out how patients are responding to treatment," she said.In terms of the...

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