Gender Modulates the APOE  4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels

Damoiseaux, Jessica S.; Seeley, William W.; Zhou, Juan; Shirer, William R.; Coppola, Giovanni; Karydas, Anna; Rosen, Howard J.; Miller, Bruce L.; Kramer, Joel H.; Greicius, Michael D.

doi:10.1523/jneurosci.0305-12.2012

Cited by 231 publications

(204 citation statements)

References 57 publications

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“…Our findings extend these previous results by showing that with equivalent performance in episodic encoding, age is associated with decreased regional activity in posterior VA and MTL even in individuals who do not show evidence of A␤ deposition. In addition, task-independent functional connectivity was reduced in aging, consistent with reports of resting-state functional connectivity (Achard and Bullmore, 2007;Damoiseaux et al, 2008;. Considering the importance of PFC and MTL interactions in memory shown in both animal and human studies (Simons and Spiers, 2003), age effects on functional connectivity during memory have been investigated particularly between these regions (Cabeza et al, 1997;Grady et al, 2003;Daselaar et al, 2006;Dennis et al, 2008).…”

Section: Effects Of Agesupporting

confidence: 87%

“…Task-independent time course connectivity decreases with advanced age Given the age-related increases in taskdependent functional connectivity between rPHG and PFC in the present study, we examined whether task-independent functional connectivity in our sample replicates previous findings showing age-related decreases in functional connectivity mainly obtained during the resting state (Damoiseaux et al, 2008). To assess temporal synchrony between the rPHG and other brain regions independent of the task main effect (as measured by the psychological term) and interaction (as measured by the PPI term), mean time course functional connectivity maps were generated based on the time series regressor of the rPHG seeds by age group.…”

Section: Subject Characteristicssupporting

confidence: 60%

“…Connectivity maps were produced using a GLM with an initiating seed in the right parahippocampal gyrus (rPHG). We used rPHG as a seed, because of its involvement in visual episodic encoding and the relevance of PHG to visual scene processing (Epstein and Kanwisher, 1998;Prince et al, 2009). The rPHG was defined on the task-based contrast (i.e., HC-HIT Ͼ MISS).…”

Section: Methodsmentioning

confidence: 99%

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Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid

Jagust

2013

J. Neurosci.

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Approximately 30% of cognitively normal older adults harbor brain ␤-amyloid (A␤), a prominent feature of Alzheimer's disease associated with neural alterations and episodic memory decline. We examined how aging and A␤ deposition affect neural function during memory encoding of visual scenes using functional magnetic resonance imaging (fMRI) in humans. Thirty-six cognitively normal older people underwent fMRI scanning, and positron emission tomography with [ 11 C] Pittsburgh compound B to measure fibrillar brain A␤; 15 young subjects were studied with fMRI. Older adults without A␤ deposition showed reduced regional brain activation (compared with young subjects) with decreased task-independent functional connectivity between parahippocampal gyrus and prefrontal cortex. In this network, task-related connectivity was increased compared with young subjects, and the degree of connectivity was related to memory performance. In contrast, older individuals with A␤ deposition showed no such increased task-related network connectivity, but did display increased regional activity unassociated with performance. These findings suggest that network connectivity plays a significant role in compensating for reduced regional activity during successful memory encoding in aging without A␤ deposition, while in those with A␤ this network compensation fails and is accompanied by inefficient regional hyperactivation.

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Section: Effects Of Agesupporting

confidence: 87%

Section: Subject Characteristicssupporting

confidence: 60%

Section: Methodsmentioning

confidence: 99%

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Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid

Jagust

2013

J. Neurosci.

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“…This is in line with earlier findings of a change in “hub” status of these brain regions in AD patients (Buckner et al., 2009; de Haan, Mott, et al., 2012; de Haan, van der Flier, et al., 2012), and AD‐related changes in glucose metabolism (Ossenkoppele et al., 2013) and neuronal activity (Damoiseaux et al., 2012; Navas et al., 2013). …”

Section: Discussionmentioning

confidence: 99%

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

et al. 2018

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IntroductionAmyloid plaque deposition in the brain is an early pathological change in Alzheimer's disease (AD), causing disrupted synaptic connections. Brain network disruptions in AD have been demonstrated with eigenvector centrality (EC), a measure that identifies central regions within networks. Carrying an apolipoprotein (APOE)‐ε4 allele is a genetic risk for AD, associated with increased amyloid deposition. We studied whether APOE‐ε4 carriership is associated with EC disruptions in cognitively normal individuals.MethodsA total of 261 healthy middle‐aged to older adults (mean age 56.6 years) were divided into high‐risk (APOE‐ε4 carriers) and low‐risk (noncarriers) groups. EC was computed from resting‐state functional MRI data. Clusters of between‐group differences were assessed with a permutation‐based method. Correlations between cluster mean EC with brain volume, CSF biomarkers, and psychological test scores were assessed.ResultsDecreased EC in the visual cortex was associated with APOE‐ε4 carriership, a genetic risk factor for AD. EC differences were correlated with age, CSF amyloid levels, and scores on the trail‐making and 15‐object recognition tests.ConclusionOur findings suggest that the APOE‐ε4 genotype affects brain connectivity in regions previously found to be abnormal in AD as a sign of very early disease‐related pathology. These differences were too subtle in healthy elderly to use EC for single‐subject prediction of APOE genotype.

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“…Many other genetic studies have been conducted, identifying multiple common and rare variants, shedding light on pathogenic mechanisms of AD (Marei et al 2015;Saykin et al 2015). In particular, the APOEe4 allele (Metin et al 2015) and is a plausible indicator for incipient AD (Damoiseaux et al 2012;Greicius et al 2004;He et al 2009;Jones et al 2011;Balthazar et al 2014). Since there is growing evidence that genetic factors play a role in aberrant default mode connectivity (Glahn et al 2010), it may be substantially more powerful to detect genetic variants associated with the DMN, a set of multiple intermediate phenotypes, than with AD.…”

mentioning

confidence: 99%

Powerful and Adaptive Testing for Multi-trait and Multi-SNP Associations with GWAS and Sequencing Data

Kim¹,

Zhang²,

Pan

2016

Genetics

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Testing for genetic association with multiple traits has become increasingly important, not only because of its potential to boost statistical power, but also for its direct relevance to applications. For example, there is accumulating evidence showing that some complex neurodegenerative and psychiatric diseases like Alzheimer's disease are due to disrupted brain networks, for which it would be natural to identify genetic variants associated with a disrupted brain network, represented as a set of multiple traits, one for each of multiple brain regions of interest. In spite of its promise, testing for multivariate trait associations is challenging: if not appropriately used, its power can be much lower than testing on each univariate trait separately (with a proper control for multiple testing). Furthermore, differing from most existing methods for single-SNP-multiple-trait associations, we consider SNP set-based association testing to decipher complicated joint effects of multiple SNPs on multiple traits. Because the power of a test critically depends on several unknown factors such as the proportions of associated SNPs and of traits, we propose a highly adaptive test at both the SNP and trait levels, giving higher weights to those likely associated SNPs and traits, to yield high power across a wide spectrum of situations. We illuminate relationships among the proposed and some existing tests, showing that the proposed test covers several existing tests as special cases. We compare the performance of the new test with that of several existing tests, using both simulated and real data. The methods were applied to structural magnetic resonance imaging data drawn from the Alzheimer's Disease Neuroimaging Initiative to identify genes associated with gray matter atrophy in the human brain default mode network (DMN). For genomewide association studies (GWAS), genes AMOTL1 on chromosome 11 and APOE on chromosome 19 were discovered by the new test to be significantly associated with the DMN. Notably, gene AMOTL1 was not detected by single SNP-based analyses. To our knowledge, AMOTL1 has not been highlighted in other Alzheimer's disease studies before, although it was indicated to be related to cognitive impairment. The proposed method is also applicable to rare variants in sequencing data and can be extended to pathway analysis.KEYWORDS adaptive association test; ADNI; default mode network; gene-based test; imaging genetics; multiple traits A LZHEIMER'S disease (AD) (MIM 104300) is the most common neurodegenerative disease, and every 67 sec, someone in the United States develops AD (Alzheimer's Association 2015a). Currently there is no cure for AD, and most cases are diagnosed in the late stage of the disease. It is projected that the number of Americans of age 65 years and older with AD will increase from 5.1 million in 2015 to 13.5 million in 2050, a growth from an estimated 11% of the U.S. senior population in 2015 to 16% in 2050, costing .$1.1 trillion in 2050 (Alzheimer's Association 2015b). To advance our...

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Gender Modulates the APOE 4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels

Cited by 231 publications

References 57 publications

Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid

Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

Powerful and Adaptive Testing for Multi-trait and Multi-SNP Associations with GWAS and Sequencing Data

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