Influence of APOE genotype on whole-brain functional networks in cognitively normal elderly.
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ABSTRACT:
SUBMITTER: Seo EH
PROVIDER: S-EPMC3859658 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Project description:As the Apolipoprotein E (APOE) ɛ4 allele is a major genetic risk factor for sporadic Alzheimer's disease (AD), which has been suggested as a disconnection syndrome manifested by the disruption of white matter (WM) integrity and functional connectivity (FC), elucidating the subtle brain structural and functional network changes in cognitively normal ɛ4 carriers is essential for identifying sensitive neuroimaging based biomarkers and understanding the preclinical AD-related abnormality development. We first constructed functional network on the basis of resting-state functional magnetic resonance imaging and a structural network on the basis of diffusion tensor image. Using global, local and nodal efficiencies of these two networks, we then examined (i) the differences of functional and WM structural network between cognitively normal ɛ4 carriers and non-carriers simultaneously, (ii) the sensitivity of these indices as biomarkers, and (iii) their relationship to behavior measurements, as well as to cholesterol level. For ɛ4 carriers, we found reduced global efficiency significantly in WM and marginally in FC, regional FC dysfunctions mainly in medial temporal areas, and more widespread for WM network. Importantly, the right parahippocampal gyrus (PHG.R) was the only region with simultaneous functional and structural damage, and the nodal efficiency of PHG.R in WM network mediates the APOE ɛ4 effect on memory function. Finally, the cholesterol level correlated with WM network differently than with the functional network in ɛ4 carriers. Our results demonstrated ɛ4-specific abnormal structural and functional patterns, which may potentially serve as biomarkers for early detection before the onset of the disease.
| S-EPMC4367462 | biostudies-literature
Project description:The conceptual significance of understanding functional brain alterations and cognitive deficits associated with Alzheimer's disease (AD) process has been widely established. However, the whole-brain functional networks of AD and its prodromal stage, mild cognitive impairment (MCI), are not well clarified yet. In this study, we compared the characteristics of the whole-brain functional networks among cognitively normal (CN), MCI, and AD individuals by applying graph theoretical analyses to [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) data. Ninety-four CN elderly, 183 with MCI, and 216 with AD underwent clinical evaluation and FDG-PET scan. The overall small-world property as seen in the CN whole-brain network was preserved in MCI and AD. In contrast, individual parameters of the network were altered with the following patterns of changes: local clustering of networks was lower in both MCI and AD compared to CN, while path length was not different among the three groups. Then, MCI had a lower level of local clustering than AD. Subgroup analyses for AD also revealed that very mild AD had lower local clustering and shorter path length compared to mild AD. Regarding the local properties of the whole-brain networks, MCI and AD had significantly decreased normalized betweenness centrality in several hubs regionally associated with the default mode network compared to CN. Our results suggest that the functional integration in whole-brain network progressively declines due to the AD process. On the other hand, functional relatedness between neighboring brain regions may not gradually decrease, but be the most severely altered in MCI stage and gradually re-increase in clinical AD stages.
| S-EPMC3545923 | biostudies-literature
Project description:IntroductionLate onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women.HypothesisWe hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women.MethodsWe studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed.ResultWomen had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men.ConclusionWomen overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD.Significance statementTwo thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes.
| S-EPMC9252274 | biostudies-literature
Project description:AimEarly prediction using cognitive evaluation tools that are less influenced by education level is beneficial for dementia screening. This study investigated the relationship between Word List Memory Immediate Recall (WLM IR) and the Saving Score (SS) with having the APOE ε4 risk allele in the elderly with normal global cognitive assessment.MethodsA cross-sectional study on 105 subjects ≥60 years with normal MMSE scores who met inclusion criteria. Memory impairment (MI) if: WLM IR score on the third trial <8 or an SS score <80%.ResultsThe majority of the subjects were female (68.6%), 65 ± 7.1 years, had undertaken formal education for <6 years (56.2%), had MI (81%), and the APOE ε4 genotype was detected in 24.8% of subjects. There was a significant relationship between APOE ε4 and lower WLMIR (p = 0.02, OR 7.92, CI 95% (1.00-62.38)).ConclusionsWLM IR score is lower in elderly people with the APOE ε4 despite their normal global cognitive assessment results, and these scores were not influenced by education level. Further research needs to confirm that the WLM IR can be used to screen for early dementia.
| S-EPMC4728477 | biostudies-literature
Project description:We investigated the influence of the apolipoprotein E-ɛ4 allele (APOE-ɛ4) on longitudinal age-related changes in brain functional connectivity (FC) and cognition, in view of mixed cross-sectional findings. One hundred and twenty-two healthy older adults (aged 58-79; 25 APOE-ɛ4 carriers) underwent task-free fMRI scans at baseline. Seventy-eight (16 carriers) had at least one follow-up (every 2 years). Changes in intra- and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross-sectionally, APOE-ɛ4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age-dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter-ECN-DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE-ɛ4 genotype, but the brain-cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE-ɛ4 may alter aging by accelerating the change in segregation between high-level cognitive systems. Its modulation on the longitudinal brain-cognition relationship was age-dependent.
| S-EPMC6866329 | biostudies-literature
Project description:Mild behavioral impairment (MBI), characterized by the late-life onset of sustained and meaningful neuropsychiatric symptoms, is increasingly recognized as a prodromal stage of dementia. However, the underlying neural mechanisms of MBI remain unclear. Here, we examined alterations in the topological organization of the structural covariance networks of patients with MBI (N = 32) compared with normal controls (N = 38). We found that the gray matter structural covariance networks of both the patients with MBI and controls exhibited a small-world topology evidenced by sigma value larger than one. The patients with MBI had significantly decreased clustering coefficients at several network densities and local efficiency at densities ranging from 0.05 to 0.26, indicating decreased local segregation. No significant differences in the characteristic path length, gamma value, sigma value, or global efficiency were detected. Locally, the patients with MBI showed significantly decreased nodal betweenness centrality in the left middle frontal gyrus, right inferior frontal gyrus (opercular part), and left Heschl gyrus and increased betweenness centrality in the left gyrus rectus, right insula, bilateral precuneus, and left thalamus. Moreover, the difference in the bilateral precuneus survived after correcting for multiple comparisons. In addition, a different number and distribution of hubs was identified in patients with MBI, showing more paralimbic hubs than observed in the normal controls. In conclusion, we revealed abnormal topological patterns of the structural covariance networks in patients with MBI and offer new insights into the network dysfunctional mechanisms of MBI.
| S-EPMC8511486 | biostudies-literature
Project description:The apolipoprotein E (APOE) Ɛ4 allele increases Alzheimer's disease (AD) risk and has been linked to a greater risk of sleep-disordered breathing. We investigated the association of APOE genotype with nonrespiratory sleep parameters. We studied 1264 cognitively normal participants in the Baltimore Longitudinal Study of Aging (mean = 57.5 ± 16.1 years, range 19.9-92.0, 48.2% women, 19.8% African American) with APOE genotyping and self-reported sleep duration (≥9, 7 or 8, ≤6 hours), difficulty falling/staying asleep, and napping. We compared Ɛ4 carriers with all noncarriers and compared persons at reduced (Ɛ2/Ɛ2 or Ɛ2/Ɛ3) or elevated AD risk (≥1 Ɛ4 allele) with those neutral for AD risk (Ɛ3/Ɛ3). In fully adjusted models, those with ≥1 Ɛ4 allele had a greater odds of being in a shorter sleep duration category compared to all noncarriers (odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.06, 1.88) and Ɛ3/Ɛ3 carriers (OR = 1.43, 95% CI 1.06, 1.92). Compared to Ɛ3/Ɛ3 carriers, Ɛ2/Ɛ2 or Ɛ2/Ɛ3 carriers had a lower odds of reporting napping (OR = 0.64, 95% CI 0.43, 0.96). Among participants aged ≥50 years, sleep duration findings remained and Ɛ4 carriers had a greater odds of trouble falling/staying asleep than noncarriers (OR = 1.49, 95% CI 1.02, 2.17). We found some evidence for stronger associations of Ɛ4 with sleep duration among African Americans. Self-reported sleep duration, napping, and trouble falling/staying asleep differ by APOE genotype. Studies are needed to examine whether APOE promotes AD by degrading sleep and to clarify the role of race in these associations.
| S-EPMC5804995 | biostudies-literature
Project description:Age-related changes in functional brain network have been well documented. However, recent studies have suggested the nonstationary properties of the functional connectivity of the brain, and little is known about the changes of functional connectivity dynamics during aging. In this study, a two-step singular value decomposition was introduced to capture the dynamic patterns of the time-varying functional connectivity in different frequency intervals, and the whole-brain and regional brain diversity were quantified by using Shannon entropy. The relationships between age and functional connectivity dynamics were investigated in a relatively large sample cohort of cognitively healthy elderly (N = 188, ages 65-80). The results showed an age-related decreased diversity in the whole brain as well as in the right inferior frontal gyrus, right amygdala, right hippocampus, left parahippocampal, and left inferior parietal gyrus in the frequency interval of 0.06-0.12 Hz. In addition, the whole-brain diversity during resting state could also reflect the general mental flexibility. This study provided the first evidence of frequency-specific age effects on the functional connectivity dynamics in cognitively healthy elderly, and may shed new light on the dynamic functional connectivity analysis of aging and neurodegenerative diseases.
| S-EPMC6865413 | biostudies-literature
Project description:Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.
| S-EPMC8793109 | biostudies-literature
Project description:IntroductionAmyloid plaque has been reported in brain biopsies from patients with idiopathic normal-pressure hydrocephalus (iNPH) and proposed as a significant feature of the pathophysiology. Presence of the apolipoprotein E ε4 (APOE ε4) allele is associated with increased risk of Alzheimer's disease (AD).AimsTo compare the distribution of APOE genotype in iNPH patients with an age-matched population-based control group and with Alzheimer's disease (AD) patients.MethodsAPOE genotype frequencies were determined in 77 iNPH patients (50 men and 27 women, mean age 71.7 years) diagnosed with iNPH, a sample of 691 AD patients and 638 age-matched population controls (299 men and 339 women) from the INTERGENE cohort.ResultsThe APOE distribution did not differ significantly between the iNPH patients and the control population. The per e4-allele odds-ratio (OR) of iNPH was given by OR = 0.90, 95% confidence interval (CI) = (0.50, 1.60) that was considerably smaller than the per-allele OR of AD, OR = 5.34 (4.10, 7.00).ConclusionThe results suggest that the APOE-related risk of AD in patients with iNPH is not higher than in the general population.
| S-EPMC4956274 | biostudies-literature