Journal of Alzheimer's Disease - Volume 77, issue 1

Authors: Begic, Edin | Hadzidedic, Suncica | Obradovic, Slobodan | Begic, Zijo | Causevic, Mirsada

Article Type: Research Article

Abstract: Background: Alzheimer’s disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer’s disease. Objective: To examine a relationship between factors that are part of coagulation and anticoagulation pathways with cognitive decline that develops during Alzheimer’s disease. Methods: SOMAscan …assay was used to measure levels of coagulation/anticoagulation factors V, VII, IX, X, Xa, XI, antithrombin III, protein S, protein C, and activated protein C in plasma samples obtained from three groups of subjects: 1) subjects with stable cognitively healthy function, 2) subjects with stable mild cognitive impairment, and 3) subjects diagnosed with probable Alzheimer’s disease. Results: Our results show that protein levels of coagulation factor XI are significantly increased in patients who are diagnosed with probable Alzheimer’s disease compared with cognitively healthy subjects or patients diagnosed with mild cognitive impairment. Furthermore, our results demonstrate that significant predictors of Alzheimer’s-type diagnosis are factors IX and XI—an increase in both factors is associated with a reduction in cognitive function. Conclusion: Our study justifies further investigations of biological pathways involving coagulation/anticoagulation factors in relation to dementia, including dementia resulting from Alzheimer’s-type neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, blood coagulation, blood coagulation factor xi, cognitive impairment

DOI: 10.3233/JAD-200358

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 375-386, 2020

Authors: Xu, Anping | Tang, Yinshan | Zeng, Qingtao | Wang, Xin | Tian, Huiling | Zhou, You | Li, Zhigang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease, yet there is no effective treatment. Electroacupuncture (EA) is a complementary alternative medicine approach. In clinical and animal studies, EA promotes cognition in AD and vascular dementia. It has been previously reported that cognitive decline in AD might be closely related to reduced glucose intake in the brain. It is worth mentioning that the regions of glucose hypometabolism are usually found to be associated with neuroinflammation. Objective: This study is to explore whether the protective mechanism of EA on cognition is related to the regulation of glucose metabolism and neuroinflammation. …Methods: APP/PS1 mice were randomly divided into AD group and the treatment (AD + EA) group. In the AD + EA group, EA was applied on Baihui (GV20) and Yintang (GV29) for 20 min and then pricked at Shuigou (GV26), once every alternate day for 4 weeks. Morris water maze (MWM) tests were performed to evaluate the effects of EA treatment on cognitive functions. 18 F-FDG PET, immunofluorescence, and western blot were used to examine the mechanisms underlying EA effects. Results: From MWM tests, EA treatment significantly improved cognition of APP/PS1 mice. From the 18 F-FDG PET, the levels of uptake rate of glucose in frontal lobe were higher than the AD group after EA. From immunofluorescence and western blot, amyloid-β (Aβ) and neuroinflammation were reduced after EA. Conclusion: These results suggest that EA may prevent cognitive decline in AD mouse models by enhancing glucose metabolism and inhibiting inflammation-mediated Aβ deposition in the frontal lobe. Show more

Keywords: Alzheimer’s disease, cognition, electroacupuncture, 18F-FDG PET, frontal lobe, glucose metabolism, neuroinflammation

DOI: 10.3233/JAD-200242

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 387-400, 2020

Authors: Wang, Rong-Ze | Yang, Yu-Xiang | Li, Hong-Qi | Shen, Xue-Ning | Chen, Shi-Dong | Dong, Qiang | Wang, Yi | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Hypometabolism detected by fluorodeoxyglucose F18 positron emission tomography ([18 F] FDG PET) is an early neuropathologic changes in Alzheimer’s disease (AD) and provides important pathologic staging information. Objective: This study aimed to discover genetic interactions that regulate longitudinal glucose metabolic decline in AD-related brain regions. Methods: A total of 586 non-Hispanic white individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts that met all quality control criteria were included in this study. Genome-wide association study of glucose metabolic decline in regions of interest (ROIs) was performed with linear regression under the additive genetic model. …Results: We identified two novel variants that had a strong association with longitudinal metabolic decline in different ROI. Rs4819351-A in gene 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3 ) demonstrated reduced metabolic decline in right temporal gyrus (p  = 3.97×10–8 , β= –0.016), while rs13387360-T in gene LOC101928196 demonstrated reduced metabolic decline in left angular gyrus (p  = 1.69×10–8 , β= –0.027). Conclusion: Our results suggest two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 as protective loci that modulate glucose metabolic decline. These two genes should be further investigated as potential therapeutic target for neurodegeneration diseases. Show more

Keywords: AGPAT3, Alzheimer’s disease, [18F] FDG PET, genetic variants, genome-wide association study

DOI: 10.3233/JAD-200415

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 401-409, 2020

Authors: Ma, Ya-Hui | Wu, Jia-Huan | Xu, Wei | Shen, Xue-Ning | Wang, Hui-Fu | Hou, Xiao-He | Cao, Xi-Peng | Bi, Yan-Lin | Dong, Qiang | Feng, Lei | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer’s disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. Objective: This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. Methods: Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database, …and we additionally detected the interaction effects of tea consumption with APOE ɛ 4 status and gender using a two-way analysis of covariance. Results: Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p  = 0.041) but not with the levels of CSF amyloid-β 42 (Aβ 42 ) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p  = 0.007) and CSF t-tau/Aβ 42 (p  = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ 42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOE ɛ 4 and gender. Conclusion: Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, lifestyle, pathology, tea

DOI: 10.3233/JAD-200410

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 411-421, 2020

Authors: Sharda, Nidhi | Pengo, Thomas | Wang, Zengtao | Kandimalla, Karunya K.

Article Type: Research Article

Abstract: Background: Synaptic dysfunction prevalent in Alzheimer’s disease (AD) brain is closely associated with increased accumulation of amyloid-β (Aβ) peptides in the brain parenchyma. It is widely believed that Aβ peptides trigger synaptic dysfunction by interfering with the synaptic vesicular fusion and the release of neurotransmitters, primarily facilitated by the SNARE protein complexes formed by VAMP-2, SNAP-25, and syntaxin-1. However, Aβ interactions with SNARE proteins to ultimately disrupt synaptic vesicular fusion are not well understood. Objective: Our objective is to elucidate mechanisms by which Aβ peptides perturb SNARE complexes. Methods: Intensity (qualitative) and lifetime (quantitative) based measurements …involving Forster (fluorescence) resonance energy transfer (FRET) followed by fluorescence lifetime imaging microscopy (FLIM) were employed to investigate the effect of Aβ peptides on dynamic interactions between VAMP-2, labeled with cerulean (Cer) at the N-terminus (FRET donor), and SNAP-25 labeled with citrine (Cit) on the N-terminus (FRET acceptor). The FRET and FLIM interactions at the exocytosis locations on the pre-synaptic membrane were recorded under spontaneous and high potassium evoked conditions. Moreover, cellular accumulation of fluorescein labeled Aβ (F-Aβ) peptides and their co-localization with Cer-VAMP2 was investigated by confocal microscopy. Results: The F-Aβ40 and F-Aβ42 are internalized by differentiated N2A cells, where they colocalize with Cer-VAMP2. Both Aβ40 and Aβ42 decrease interactions between the N-termini of Cer-VAMP2 and Cit-SNAP25 in N2A cells, as determined by FRET/FLIM. Conclusion: By perturbing the N-terminal interactions between VAMP-2 and SNAP-25, Aβ40 and Aβ42 , can directly interfere with the SNARE complex formation, which is critical for the docking and fusion of synaptic vesicles. Show more

Keywords: Amyloid-β peptides, Alzheimer’s disease, exocytosis, FLIM, FRET, SNAREs, SNAP-25, VAMP-2, synaptic vesicular fusion

DOI: 10.3233/JAD-200065

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 423-435, 2020

Authors: Hollinger, Kristen R. | Zhu, Xiaolei | Khoury, Elizabeth S. | Thomas, Ajit G. | Liaw, Kevin | Tallon, Carolyn | Wu, Ying | Prchalova, Eva | Kamiya, Atsushi | Rojas, Camilo | Kannan, Sujatha | Slusher, Barbara S.

Article Type: Research Article

Abstract: Background: Given the emergent aging population, the identification of effective treatments for Alzheimer’s disease (AD) is critical. Objective: We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model. Methods: Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4–5 months and cognitive performance was assessed using …the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083. Results: JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings, postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment. Conclusion: These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, APOE, glutamate, glutaminase, microglia

DOI: 10.3233/JAD-190588

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 437-447, 2020

Authors: Xu, Wei | Sun, Fu-Rong | Tan, Chen-Chen | Tan, Lan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Higher late-life body mass index (BMI) was associated with reduced risk of Alzheimer’s disease (AD), which might be explained by a reverse causal relationship. Objective: To investigate whether weight loss was a preclinical manifestation of AD pathologies and could be a predictor of cognitive impairment. Methods: A total of 1,194 participants (mean age = 73.2 [range: 54 to 91] years, female = 44.5%) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were grouped according to AD biomarker profile as indicated by amyloid (A) and tau (TN) status and clinical stage by clinical dementia rating (CDR). BMI across the biomarker-defined clinical …stages was compared with Bonferroni correction. Pearson correlation analysis was performed to test the relationship between the amyloid change by PET and the BMI change. Multiple regression models were used to explore the influences of amyloid pathologies on BMI change as well as the effects of weight loss on longitudinal changes of global cognitive function. Results: BMI was significantly decreased in AD preclinical stage (amyloid positive [A+] and CDR = 0) and dementia stage (A+/TN+ and CDR = 0.5 or 1), compared with the healthy controls (A–/TN–and CDR = 0, p  < 0.005), while no significant differences were observed between preclinical AD and AD dementia. Amyloid PET change was inversely correlated with BMI change (p  = 0.023, β= –14). Individuals in amyloid positive group exhibited faster weight loss (time×group interaction p  = 0.019, β= –0.20) compared to the amyloid negative group. Greater weight loss predicted higher risk of developing cognitive disorders. Conclusion: Elders who experienced greater weight loss might belong to preclinical stage of AD and could be targeted for primary prevention of the disease. Show more

Keywords: Alzheimer’s disease, amyloid, body mass index, longitudinal

DOI: 10.3233/JAD-200524

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 449-456, 2020

Authors: Ono, Kenjiro | Zhao, Daisy | Wu, Qingli | Simon, James | Wang, Jun | Radu, Aurelian | Pasinetti, Giulio Maria

Article Type: Correction

DOI: 10.3233/JAD-209007

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 457-457, 2020