Anxiety correlates with cortical surface area in subjective cognitive decline: APOE ?4 carriers versus APOE ?4 non-carriers.
ABSTRACT: BACKGROUND:Subjective cognitive decline (SCD) is characterized by self-reported cognitive deficits without measurable cognitive impairment. It has been suggested that individuals with SCD exhibited brain structural alterations in widespread cortical thinning or gray matter loss in the medial temporal and frontotemporal regions. Apolipoprotein E (APOE) ?4 allele is thought to be a genetic marker associated with risk of SCD. Neuropsychiatric symptoms may provide insight in detecting higher-risk elders for early Alzheimer's disease as well. Therefore, we aim to explore the characteristics of brain morphology in SCD and to determine whether it is influenced by APOE ?4 as well as neuropsychiatric symptoms in SCD. METHODS:A total of 138 cognitively normal older individuals from the SILCODE cohort underwent a clinical interview, neuropsychological assessments, a blood test, and MRI. A two-sample t-test was used to examine the cortex volume and bilateral cortical surface area alterations between SCD (n = 65) and controls (n = 73). A general linear model analysis was used to test for both main and interaction effects of clinical phenotype (SCD vs. controls) and APOE on global and regional cortex volume and bilateral cortical surface area and thickness. A multiple linear regression analysis was conducted to determine the effects of the APOE genotype on the relationships between morphometric features and neuropsychiatric symptoms in SCD. RESULTS:Compared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area. SCD APOE ?4 carriers showed additive reduction in the right cortical surface area. The evaluation scores of anxiety symptoms were negatively associated with the right cortical surface area in SCD APOE 4 non-carriers. CONCLUSIONS:Individuals with SCD had an altered cortical surface area, and APOE genotype and anxiety symptoms are modified factors on the cortical surface area decrease in SCD. TRIAL REGISTRATION:ClinicalTrials.gov (Identifier: NCT03370744 ). Registered 15 March 2017.
Project description:OBJECTIVE:To evaluate the associative role of depression and apolipoprotein E epsilon 4 allele (APOE?4) in subjective cognitive decline (SCD) and its progression to objective cognitive decline. METHODS:After literature search in electronic databases, studies were selected by following precise eligibility criteria. Meta-analyses were performed to examine the role of APOE?4 and depression in SCD or its progression to mild cognitive impairment (MCI) or dementia. RESULTS:APOE?4 positivity was not different between SCD and normal individuals but was significantly higher in individuals with SCD plus than in normal individuals [odds ratio: 2.39 (95% CI: 1.87, 3.05); p<0.00001] and in SCD converters than in non-converters [odds ratio: 5.19 (95% CI: 2.36, 11.42); p<0.00001]. Depression was significantly higher in individuals with SCD [standardized mean difference: 0.63 (0.45, 0.82); p<0.00001] and SCD plus [standardized mean difference: 0.83 (0.43, 1.22); p<0.0001] than in normal individuals. However, depression was not different between SCD and MCI or between SCD converters and non-converters. Age of SCD converters was higher than non-converters [mean difference: 2.95 years (0.58, 5.31)]. CONCLUSION:Whereas APOE?4 positivity was higher in SCD plus and SCD converters, depression was higher in SCD and SCD plus but was not different between SCD and MCI.
Project description:Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ?4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies.
Project description:Old age and possession of the APOE-4 allele are the two main risk factors for developing later onset Alzheimer's Disease (AD). Carriers of the APOE-4 allele have known differences in intrinsic functional brain network activity across the life span. These individuals also demonstrate specific regional differences in gray and white matter gross structure. However, the relationship of these variations to whole brain structural network connectivity remains unclear. We performed diffusion tensor imaging (DTI), T1 structural imaging, and cognitive testing on aging APOE-4 noncarriers (n = 30; mean age = 63.8±8.3) and APOE-4 carriers (n = 25; mean age = 60.8 ±9.7). Fiber tractography was used to derive whole brain structural graphs, and graph theory was applied to assess structural network properties. Network communication efficiency was determined for each network by quantifying local interconnectivity, global integration, and the balance between these, the small worldness. Relative to noncarriers, APOE-4 carriers demonstrated an accelerated age-related loss of mean local interconnectivity (r = -0.64, P ? 0.01) and regional local interconnectivity decreases in the precuneus (r = -0.64), medial orbitofrontal cortex (r = -0.5), and lateral parietal cortex (r = -0.54). APOE-4 carriers also showed significant age-related loss in mean cortical thickness (r = -0.52, P < 0.05). Cognitively, APOE-4 carriers had significant negative correlations of age and performance on two episodic memory tasks (P < 0.05). This genotype-specific pattern of structural connectivity change with age thus appears related to changes in gross cortical structure and cognition, potentially affecting the rate and/or spatial distribution of AD-related pathology.
Project description:<h4>Introduction</h4>We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia.<h4>Methods</h4>We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The <i>APOE gene</i> was not included in the PRS and was analyzed separately.<h4>Results</h4>The PRS and <i>APOE</i> ε4 were associated with amyloid-positive ATN profiles, and <i>APOE</i> ε4 additionally with isolated increased tau (A-T+N-). A high PRS and <i>APOE</i> ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers.<h4>Discussion</h4>Genetic variants beyond <i>APOE</i> are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.
Project description:Apolipoprotein E (APOE) is the best-known susceptibility gene for AD. It has been well demonstrated that the ?4 allele of the APOE gene can affect brain structure/function in nondemented individuals; however, other polymorphisms in the APOE gene have been largely overlooked when assessing the effects of APOE on the neural system. Rs405509 is a newly recognized AD-related polymorphism located in the APOE promoter region that can regulate the transcriptional activity of the APOE gene. To date, it remains unknown whether and how this APOE promoter polymorphism affects the human brain in aging. Here, for the first time, we investigate the effects of the rs405509 genotype (T/T vs G-allele) on human cortical morphology using a large cohort of nondemented elderly subjects (120 subjects in total; aged 52- 81 years). High-resolution structural MRI was performed; cortical thickness and surface area were analyzed separately. Intriguingly, nondemented carriers of the rs405509 T/T genotype showed an accelerated age-related reduction of thickness in the left parahippocampal gyrus compared with the G-allele carriers. Furthermore, the cortical thickness covariance between the left parahippocampal gyrus and left medial cortex, including the left medial superior frontal gyrus, supplementary motor area, and paracentral lobule, was modulated by the interaction of the rs405509 genotype and age. These novel findings suggest an important role for the APOE promoter polymorphism in the human brain and also provide valuable insights into how the rs405509 genotype shapes the neural system to modulate the risk of developing AD.
Project description:<b>Objective:</b> This study assessed the methylation of peripheral <i>NCAPH2</i> in individuals with subjective cognitive decline (SCD), identified its correlation with the hippocampal volume, and explored whether the correlation is influenced by apolipoprotein E ?4 (APOE ?4) status. <b>Methods:</b> Cognitively normal controls (NCs, <i>n</i> = 56), individuals with SCD (<i>n</i> = 81), and patients with objective cognitive impairment (OCI, <i>n</i> = 51) were included from the Sino Longitudinal Study on Cognitive Decline (NCT03370744). All participants completed neuropsychological assessments, blood tests, and structural MRI. <i>NCAPH2</i> methylation was compared according to the diagnostic and APOE ?4 status. Partial correlation analysis was conducted to assess the correlations between the hippocampal volume, cognitive tests, and the <i>NCAPH2</i> methylation levels. <b>Results:</b> Individuals with SCD and patients with OCI showed significantly lower levels of <i>NCAPH2</i> methylation than NCs, which were independent of the APOE ?4 status. The <i>NCAPH2</i> methylation levels and the hippocampal volumes were positively correlated in the SCD <i>APOE</i> ?4 non-carriers but not in the OCI group. No association was found between the <i>NCAPH2</i> methylation levels and the cognitive function. <b>Conclusion:</b> Abnormal changes in blood <i>NCAPH2</i> methylation were found to occur in SCD, indicating its potential to be used as a useful peripheral biomarker in the early stage of Alzheimer's disease screening.
Project description:Short-term memory in middle-aged individuals with different APOE alleles was examined using a recently developed task which is sensitive to medial temporal lobe (MTL) damage. Individuals (age-range: 40-51 years) with ?3/?3, ?3/?4 and ?4/?4 APOE genotypes (N = 60) performed a delayed estimation task with a sensitive continuous measure of report. The paradigm allowed us to measure memory for items and their locations, as well as maintenance of identity-location feature binding in memory. There was a significant gene-dosage dependent effect of the ?4 allele on performance: memory decay or forgetting was slower in ?4 carriers, as measured by localization error and after controlling for misbinding errors. Furthermore ?4 carriers made less misbinding errors. These findings were specific to male carriers only. Thus, male ?4 carriers are at a behavioral advantage in midlife on a sensitive task of short-term memory. The results would be consistent with an antagonistic pleiotropy hypothesis and hightight the interaction of gender on the influence of APOE in cognition.
Project description:Objective:Apolipoprotein E (APOE) ?4 allele is a well-established risk factor in Alzheimer's disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation-related parameters in population-based cohorts. Methods:Association of cardiovascular, metabolic, and inflammation-related parameters with the APOE polymorphism in a large Finnish Metabolic Syndrome in Men (METSIM) cohort and Finnish Geriatric Intervention study to prevent cognitive impairment and disability (FINGER) were investigated. Brain-specific effects were addressed in postmortem brain samples. Results:Individuals carrying the APOE ?4 allele displayed significantly elevated serum/plasma LDL cholesterol and apolipoprotein B levels. APOE ?3?4 and ?4?4 significantly associated with lower levels of plasma high-sensitivity C-reactive protein (hs-CRP). Plasma amyloid-? 42 (A?42) and reduced hs-CRP levels showed an association independently of the APOE status. Interpretation:These data suggest that the APOE ?4 allele associates with lower levels of hs-CRP in individuals without dementia. Moreover, A?42 may encompass anti-inflammatory effects reflected by reduced hs-CRP levels.
Project description:To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ?4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ?4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ?4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3-2.03). Synergistic interactions between NPS and APOE ?4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.
Project description:Introduction:Possible joint effects of subjective cognitive decline (SCD) and apolipoprotein E (APOE) ?4 genotype on incident mild cognitive impairment (MCI) were examined for men and women separately. Methods:Cognitively normal participants with and without SCD were included from the first follow-up examination of the population-based Heinz Nixdorf Recall study. Sex-stratified logistic regression models estimated main effects and interactions (additive, multiplicative) of SCD at the first follow-up (yes+/no-) and APOE ?4 (positive+/negative-) groups for MCI 5 years later. Results:Odds for MCI 5 years later were higher in SCD/APOE ?4 group +/+ than the sum of groups +/- and -/+ in women, with a trend for positive interaction. Odds for incident MCI in men was highest in group +/-, with no interaction effect. Discussion:Our findings indicate that APOE ?4 may play an important role in the association of SCD and incident MCI, especially considering sex. Further studies need to examine these associations with larger sample sizes.