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Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer's disease.

ABSTRACT: The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer's disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [¹⁸F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) phases GO/2 (n=678). Near genome-wide significant interaction effect was observed for rs73069071 within the IAPP (amylin) and SLCO1A2 genes (P=6.2 × 10^-8). Congruent results were found using data from participants followed up from ADNI-1 (P_one-tailed=0.028, n=165). Meta-analysis across ADNI-GO/2 and ADNI-1 revealed a genome-wide significant interaction effect (P=1.1 × 10^-8). Our results were further supported by similar interaction effects on temporal lobe cortical thickness (whole-brain voxelwise analysis: familywise error corrected P=0.013) and longitudinal changes in ADAS-cog score and left middle temporal thickness and amygdalar volume (P_one-tailed=0.026, 0.019 and 0.003, respectively). Using postmortem beta-amyloid immunohistochemistry data from 243 AD participants in the Religious Orders Study and Memory and Aging Project, we also observed similar rs73069071-by-beta-amyloid deposition interaction effect on global cognitive function (P_one-tailed=0.005). Our findings provide insight into the complexity of the relationship between beta-amyloid burden and AD-related cognitive impairment. Although functional studies are required to elucidate the role of rs73069071 in AD pathophysiology, our results support the recently growing evidence on the role of amylin in AD.

SUBMITTER: Roostaei T

PROVIDER: S-EPMC5042808 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Evidence shows that sleep dysfunction and β-amyloid (Aβ) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aβ continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective:To determine whether Aβ deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants:A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures:Sleep quality was measured via responses to sleep questionnaires, Aβ deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results:Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aβ deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aβ deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P < .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P < .001). Mediation analysis demonstrated an indirect association between Aβ deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance:Nighttime sleep disruption may mediate the association between Aβ and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aβ burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aβ accumulation.

Project description:To identify epigenetically regulated genes involved in the pathogenesis of Alzheimer's disease (AD) we analyzed global mRNA expression and methylation profiles in amyloid precursor protein (APP)-Swedish mutant-expressing AD model cells, H4-sw and selected heme oxygenase-1 (HMOX1), which is associated with pathological features of AD such as neurofibrillary tangles and senile plaques. We examined the epigenetic regulatory mechanism of HMOX1 and its application as a diagnostic and prognostic biomarker for AD. Our results show that HMOX1 mRNA and protein expression was approximately 12.2-fold and 7.9-fold increased in H4-sw cells, respectively. Increased HMOX1 expression was also detected in the brain, particularly the hippocampus, of AD model transgenic mice. However, the methylation of specific CpG sites within its promoter, particularly at CpG located -374 was significantly decreased in H4-sw cells. Treatment of neuroglioma cells with the demethylating agent 5-aza-2'-deoxycytidine resulted in reduced methylation of HMOX1 promoter accompanied by enhanced HMOX1 expression strongly supporting DNA methylation-dependent transcriptional regulation of HMOX1. Toxic Aβ-induced aberrant hypomethylation of HMOX1 at -374 promoter CpG site was correlated with increased HMOX1 expression. In addition to neuroglioma cells, we also found Aβ-induced epigenetic regulation of HMOX1 in human T lymphocyte Jurkat cells. We evaluated DNA methylation status of HMOX1 at -374 promoter CpG site in blood samples from AD patients, patients with mild cognitive impairment (MCI), and control individuals using quantitative methylation-specific polymerase chain reaction. We observed lower methylation of HMOX1 at the -374 promoter CpG site in AD patients compared to MCI and control individuals, and a correlation between Mini-Mental State Examination score and demethylation level. Receiver operating characteristics analysis revealed good discrimination of AD patients from MCI patients and control individuals. Our findings suggest that the methylation status of HMOX1 at a specific promoter CpG site is related to AD progression.

Project description:BackgroundThe increasing incidence of cognitive impairment has become a health problem in the aging society. Owing to its antioxidant and anti-inflammatory properties, Brazilian green propolis-derived from Baccharis dracunculifolia-is anticipated to possess anticognitive properties. However, the preventive effect of Brazilian green propolis on cognitive impairment remains unexplained. This study aimed to investigate the effect of Brazilian green propolis on cognitive impairment using a mouse model of Alzheimer's disease (AD) induced by intracerebroventricular injection of amyloid beta (Aβ)25‒35.MethodsFive-week-old male Slc:ddY mice were randomly divided into five groups (n = 8). The groups were pretreated with vehicle and propolis at a dose of 100, 300 and 900 mg/kg body weight for 8 days, then AD-like phenotypes were induced by intracerebroventricular (ICV) injection of Aβ25‒35. A sham operation group was set as the control. Memory and learning ability were measured at 7 to 8 days after ICV injection. Gene expression and histological studies were performed at the endpoint of the study.ResultsIn a passive avoidance test, the administration of Brazilian green propolis prevented the impairment of learning and memory function. Furthermore, comprehensive gene expression analysis in the hippocampus and forebrain cortex revealed that Brazilian green propolis suppressed Aβ25-35-induced inflammatory and immune responses. In particular, Brazilian green propolis prevented alterations in gene expressions of microglial and astrocytic markers such as Trem2 and Lcn2 induced by Aβ25‒35 injection, suggesting the suppression of excessive activation of glial cells in the brain. In addition, Brazilian green propolis suppressed the elevation of plasma interleukin (IL)-6 levels induced by Aβ25‒35 injection.ConclusionsThe results suggest that the prophylactic administration of Brazilian green propolis has a preventive effect against AD by suppressing excessive inflammation and immune response in glial cells. To our knowledge, this study is the first to demonstrate that Brazilian green propolis may inhibit the hyperactivation of microglia and astrocytes as a mechanism of action to prevent AD. Thus, it is a promising ingredient for preventing AD-type dementia.

Project description:ImportanceCerebrovascular disease (CVD) and Alzheimer disease are significant causes of cognitive impairment in the elderly. However, few studies have evaluated the relationship between CVD and β-amyloid burden in living humans or their synergistic effects on cognition. Thus, there is a need for better understanding of mild cognitive impairment (MCI) before clinical deterioration begins.ObjectiveTo determine the synergistic effects of β-amyloid burden and CVD on cognition in patients with subcortical vascular MCI (svMCI).Design, setting, and participantsA cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We prospectively recruited 95 patients with svMCI; 67 of these individuals participated in the study. Forty-five patients with amnestic MCI (aMCI) were group matched with those with svMCI by the Clinical Dementia Rating Scale Sum of Boxes.Main outcomes and measuresWe measured β-amyloid burden using positron emission tomography with carbon 11-labeled Pittsburgh Compound B (PiB). Cerebrovascular disease was quantified as white matter hyperintensity volume detected by magnetic resonance imaging fluid-attenuated inversion recovery. Detailed neuropsychological tests were performed to determine the level of patients' cognitive impairment.ResultsOn evaluation, 22 of the svMCI group (33%) and 28 of the aMCI group (62%) were found to be PiB positive. The mean PiB retention ratio was lower in patients with svMCI than in those with aMCI. In svMCI, the PiB retention ratio was associated with cognitive impairments in multiple domains, including language, visuospatial, memory, and frontal executive functions, but was associated only with memory dysfunction in aMCI. A significant interaction between PiB retention ratio and white matter hyperintensity volume was found to affect visuospatial function in patients with svMCI.Conclusions and relevanceMost patients with svMCI do not exhibit substantial amyloid burden, and CVD does not increase β-amyloid burden as measured by amyloid imaging. However, in patients with svMCI, amyloid burden and white matter hyperintensity act synergistically to impair visuospatial function. Therefore, our findings highlight the need for accurate biomarkers, including neuroimaging tools, for early diagnosis and the need to relate these biomarkers to cognitive measurements for effective use in the clinical setting.

Project description:Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-? pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-? with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-? accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-?-negative controls and -positive subjects in different diagnostic groups, and if amyloid-? had different associations with cerebral blood flow and grey matter volume. Global amyloid-? load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-? load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-?-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-? with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-? being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-? pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-? pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.

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Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer's disease.

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