Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ε4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance

Foster, C. M.; Kennedy, James L.; Rodrigue, Karen M.

doi:10.1523/jneurosci.3900-16.2017

Cited by 12 publications

(13 citation statements)

References 48 publications

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“…We then matched these 15 APOE ε4+ individuals (ε4/ε4: n = 2; ε2/ε4: n = 3; ε3/ε4: n = 10) with 15 individuals who were APOE ε4- (ε2/ε3: n = 2; ε2/ε3: n = 3; ε3/ε3: n = 10) based on age and years of education. Similar to the methodology of Foster et al (2017), we retained all ε4+ heterozygotes, including ε2/ε4 individuals, as any individual with an ε4 allele is at greater risk of AD than individuals without ε4 alleles (Liu et al, 2013). Therefore, the current study included 30 healthy adults, aged 60 to 90 years, with an average age of 69 years (Table 1).…”

Section: Methodsmentioning

confidence: 99%

APOE ε4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation

Sinha

Berg

Tustison

et al. 2018

Neurobiology of Aging

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African Americans are 1.4 times more likely than European Americans to carry the apolipoprotein E (APOE) ε4 allele, a risk factor for Alzheimer's disease (AD). However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to genetic risk for AD. In particular, no past study on African Americans has examined the effect of APOE ε4 status on pattern separation-mnemonic discrimination performance and its corresponding neural computations in the hippocampus. Previous work using the mnemonic discrimination paradigm has localized increased activation in the DG/CA3 hippocampal subregions as being correlated with discrimination deficits. In a case-control high-resolution functional magnetic resonance imaging study of 30 healthy African Americans, aged 60 years and older, we observed APOE ε4-related impairments in mnemonic discrimination, coincident with dysfunctional hyperactivation in the DG/CA3, and CA1 regions, despite no evidence of structural differences in the hippocampus between carriers and noncarriers. Our results add to the growing body of evidence that deficits in pattern separation may be an early marker for AD-related neuronal dysfunction.

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Section: Methodsmentioning

confidence: 99%

APOE ε4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation

Sinha

Berg

Tustison

et al. 2018

Neurobiology of Aging

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“…With the help of BrainAGE, we were able to better stratify these findings by revealing a further association of IFG recruitment with BrainAGE: Not only do APOE ε4 carriers show a need for compensation, but especially do APOE ε4 carriers with older-appearing brains, i.e., individuals with maximal pathological burden. Recent work suggests that APOE ε4 is associated with a different lifespan trajectory regarding the modulation of brain activation under cognitive load (Foster et al, 2017 ). This corroborates our findings of APOE variant as a strong moderator with high impact on neuronal recruitment.…”

Section: Discussionmentioning

confidence: 99%

Brain Aging and APOE ε4 Interact to Reveal Potential Neuronal Compensation in Healthy Older Adults

Scheller

Schumacher

Peter

et al. 2018

Front. Aging Neurosci.

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Compensation implies the recruitment of additional neuronal resources to prevent the detrimental effect of age-related neuronal decline on cognition. Recently suggested statistical models comprise behavioral performance, brain activation, and measures related to aging- or disease-specific pathological burden to characterize compensation. Higher chronological age as well as the APOE ε4 allele are risk factors for Alzheimer's disease. A more biological approach to characterize aging compared with chronological age is the brain age gap estimation (BrainAGE), taking into account structural brain characteristics. We utilized this estimate in an fMRI experiment together with APOE variant as measures related to pathological burden and aimed at identifying compensatory regions during working memory (WM) processing in a group of 34 healthy older adults. According to published compensation criteria, better performance along with increased brain activation would indicate successful compensation. We examined the moderating effects of BrainAGE on the relationship between task performance and brain activation in prefrontal cortex, as previous studies suggest predominantly frontal compensatory activation. Then we statistically compared them to the effects of chronological age (CA) tested in a previous study. Moreover, we examined the effects of adding APOE variant as a further moderator. Herewith, we strived to uncover neuronal compensation in healthy older adults at risk for neurodegenerative disease. Higher BrainAGE alone was not associated with an increased recruitment in prefrontal cortex. When adding APOE variant as a second moderator, we found an interaction of BrainAGE and APOE variant, such that ε4 carriers recruited right inferior frontal gyrus with higher BrainAGE to maintain WM performance, thus showing a pattern compatible with successful neuronal compensation. Exploratory analyses yielded similar patterns in left inferior and bilateral middle frontal gyrus. These results contrast those from a previous study, where we found no indication of compensation in prefrontal cortex in ε4 carriers with increasing CA. We conclude that BrainAGE together with APOE variant can help to reveal potential neuronal compensation in healthy older adults. Previous results on neuronal compensation in frontal areas corroborate our findings. Compensatory brain regions could be targeted in affected individuals by training or stimulation protocols to maintain cognitive functioning as long as possible.

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“…Carriers of the ε4 allele are not only at an increased risk of AD but also are prone to early onset.2 Additionally, the probability of remaining unaffected over time will also decrease in an apoE4 gene dose-dependent manner.3 However, the prevalence of APOE ε4 among people with AD varies across geographic regions and is significantly lower in Asia than in North America and Europe.4 It has been demonstrated that APOE ε4 contributes to the biological modulation of β-amyloid (Aβ) clearance.5 Genome-wide association studies (GWASs) evaluating the cerebral amyloid burden endophenotype have also reinforced APOE ε4’s role in amyloid accumulation.6 And previous longitudinal studies find that there is only a marginal joint effect of AD genes (such as CLU, PICALM, BIN1, CR1, ABCA7, MS4A6A, MS4A4E, CD2AP, EPHA1, and CD33) on memory independent from APOE in nondemented people 5,6. What is more, patients with APOE ε4 often show some defects in the repair of nerve injury7 as well as exhibit an altered lifespan trajectory in the ability of the brain to dynamically modulate function to cognitive challenge.8…”

Section: Introductionmentioning

confidence: 99%

<p>Short-term adverse effects of the apolipoprotein E ϵ4 allele over language function and executive function in healthy older adults</p>

Li¹,

Qiu²,

Sun³

et al. 2019

NDT

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Background: The 4 allele of the apolipoprotein E (APOE) gene is known as a risk factor for cognitive impairment. How APOE ε polymorphism affects the language and executive functions of healthy aging subjects remains less clear. Purpose: In this follow-up study, the relationship between APOE status and cognitive performance across various cognitive domains in healthy individuals (without dementia or mild cognitive impairment (MCI)) over 60 years old was investigated. Patients and methods: Based on multiplex amplification refractory mutation system polymerase chain reaction (PCR), 228 subjects (n=228; mean age: 70.59±8.07 years old; male %=40.8%) were divided into three groups, e2 (ε2/ε2 and ε2/ε3, n=35), e3 (ε3/ε3, n=152), and e4 (ε2/ε4, ε3/ε4, and ε4/ε4, n=41). Results: There was no statistical difference ( p >0.05) in the general demographic data and neuropsychological tests among the three groups on the baseline; however, e4 group showed a greater drop rate ( p <0.05) versus non-carriers on verbal fluency (e2: −0.043±0.221; e3: -0.081±0.239; e4: 0.069±0.329) and Webster picture completion (e2: 0.055±0.281; e3: 0.083±0.428; e4: 0.438±1.280) over the subsequent one year. Conclusion: The findings suggest that possession of the APOE ε 4 allele predicted a higher decline on tasks of language function and executive function in healthy elderly. And further research is required to determine whether strengthening the training of language function and executive function will delay the occurrence of cognitive impairment.

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Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ε4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance

Cited by 12 publications

References 48 publications

APOE ε4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation

APOE ε4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation

Brain Aging and APOE ε4 Interact to Reveal Potential Neuronal Compensation in Healthy Older Adults

<p>Short-term adverse effects of the apolipoprotein E ϵ4 allele over language function and executive function in healthy older adults</p>

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