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

Authors: Wang, Xin | Liu, En-Jie | Liu, Qian | Li, Shi-Hong | Li, Ting | Zhou, Qiu-Zhi | Liu, Yan-Chao | Zhang, Huaqiu | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Background: Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer’s disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive. Objective: To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory. Methods: Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used. Results: We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal …cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls. Conclusion: Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits. Show more

Keywords: Acetylation, Alzheimer’s disease, neuroglia, propagation, tau

DOI: 10.3233/JAD-200529

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 241-255, 2020

Authors: Breuza, Lionel | Arighi, Cecilia N. | Argoud-Puy, Ghislaine | Casals-Casas, Cristina | Estreicher, Anne | Famiglietti, Maria Livia | Georghiou, George | Gos, Arnaud | Gruaz-Gumowski, Nadine | Hinz, Ursula | Hyka-Nouspikel, Nevila | Kramarz, Barbara | Lovering, Ruth C. | Lussi, Yvonne | Magrane, Michele | Masson, Patrick | Perfetto, Livia | Poux, Sylvain | Rodriguez-Lopez, Milagros | Stoeckert, Christian | Sundaram, Shyamala | Wang, Li-San | Wu, Elizabeth | Orchard, Sandra | IMEx Consortium, UniProt Consortium

Article Type: Research Article

Abstract: Background: The analysis and interpretation of data generated from patient-derived clinical samples relies on access to high-quality bioinformatics resources. These are maintained and updated by expert curators extracting knowledge from unstructured biological data described in free-text journal articles and converting this into more structured, computationally-accessible forms. This enables analyses such as functional enrichment of sets of genes/proteins using the Gene Ontology, and makes the searching of data more productive by managing issues such as gene/protein name synonyms, identifier mapping, and data quality. Objective: To undertake a coordinated annotation update of key public-domain resources to better support Alzheimer’s disease …research. Methods: We have systematically identified target proteins critical to disease process, in part by accessing informed input from the clinical research community. Results: Data from 954 papers have been added to the UniProtKB, Gene Ontology, and the International Molecular Exchange Consortium (IMEx) databases, with 299 human proteins and 279 orthologs updated in UniProtKB. 745 binary interactions were added to the IMEx human molecular interaction dataset. Conclusion: This represents a significant enhancement in the expert curated data pertinent to Alzheimer’s disease available in a number of biomedical databases. Relevant protein entries have been updated in UniProtKB and concomitantly in the Gene Ontology. Molecular interaction networks have been significantly extended in the IMEx Consortium dataset and a set of reference protein complexes created. All the resources described are open-source and freely available to the research community and we provide examples of how these data could be exploited by researchers. Show more

Keywords: Alzheimer’s disease, Cytoscape network analysis, data curation, database, neurobiology, protein

DOI: 10.3233/JAD-200206

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 257-273, 2020

Authors: Caligiore, Daniele | Silvetti, Massimo | D’Amelio, Marcello | Puglisi-Allegra, Stefano | Baldassarre, Gianluca

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and …neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions. Show more

Keywords: Alzheimer’s disease, anterior cingulate cortex, apathy, decision-making, dopamine, effort, locus coeruleus, meta-learning, norepinephrine, pre-plaque stage, reinforcement learning, reinforcement meta-learner, ventral tegmental area

DOI: 10.3233/JAD-200276

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 275-290, 2020

Authors: Brice, Sandrine | Jabouley, Aude | Reyes, Sonia | Machado, Carla | Rogan, Christina | Dias-Gastellier, Nathalie | Chabriat, Hugues | du Montcel, Sophie Tezenas

Article Type: Research Article

Abstract: Background: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. Objective: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. Methods: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory …of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. Results: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. Conclusion: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies. Show more

Keywords: Aging, Alzheimer’s disease, behavior, CADASIL, cognitive decline, latent variable modeling, longitudinal studies, neuropsychological tests, patient outcome assessment

DOI: 10.3233/JAD-200310

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 291-300, 2020

Authors: Ciminelli, Bianca Maria | Menduti, Giovanna | Benussi, Luisa | Ghidoni, Roberta | Binetti, Giuliano | Squitti, Rosanna | Rongioletti, Mauro | Nica, Sabrina | Novelletto, Andrea | Rossi, Luisa | Malaspina, Patrizia

Article Type: Research Article

Abstract: Background: The compilation of a list of genetic modifiers in Alzheimer’s disease (AD) is an open research field. The GABAergic system is affected in several neurological disorders but its role in AD is largely understudied. Objective/Methods: As an explorative study, we considered variants in genes of GABA catabolism (ABAT , ALDH5A1 , AKR7A2 ), and APOE in 300 Italian patients and 299 controls. We introduce a recent multivariate method to take into account the individual APOE genotype, thus controlling for the effect of the discrepant allele distributions in cases versus controls. We add a genotype-phenotype analysis …based on age at onset and the Mini-Mental State Evaluation score. Results: On the background of strongly divergent APOE allele distributions in AD versus controls, two genotypic interactions that represented a subtle but significant peculiarity of the AD cohort emerged. The first is between ABAT and APOE, and the second between some ALDH5A1 genotypes and APOE . Decreased SSADH activity is predicted in AD carriers of APOE ɛ 4, representing an additional suggestion for increased oxidative damage. Conclusion: We identified a difference between AD and controls, not in a shift of the allele frequencies at genes of the GABA catabolism pathway, but rather in gene interactions peculiar of the AD cohort. The emerging view is that of a multifactorial contribution to the disease, with a main risk factor (APOE ), and additional contributions by the variants here considered. We consider genes of the GABA degradation pathway good candidates as modifiers of AD, contributing to energy impairment in AD brain. Show more

Keywords: ABAT, AKR7A2, ALDH5A1, Alzheimer’s disease, association studies, GABA, single nucleotide polymorphisms

DOI: 10.3233/JAD-200429

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 301-311, 2020

Authors: Zhang, Min | Zhong, Xiaomei | Shi, Haishan | Vanmechelen, Eugeen | De Vos, Ann | Liu, Sen | Chen, Ben | Mai, Naikeng | Peng, Qi | Chen, Xinru | Wu, Zhangying | Hou, Le | Zhou, Huarong | Ouyang, Cong | Zhang, Weiru | Liang, Wanyuan | Dai, Chunying | Ning, Yuping

Article Type: Research Article

Abstract: Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer’s disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1–40 (Aβ40 ), Aβ42 , and total tau in …the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. Conclusion: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations. Show more

Keywords: Alzheimer’s disease, BACE1, general paresis of insane, neurogranin, neurosyphilis

DOI: 10.3233/JAD-200362

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 313-322, 2020

Authors: Sheng, Can | Sun, Yu | Wang, Min | Wang, Xiaoni | Liu, Yi | Pang, Dongqing | Liu, Jiaqi | Bi, Xiaoxia | Du, Wenying | Zhao, Mingyan | Li, Yuxia | Li, Xiaobo | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Visual rating scales for medial temporal lobe atrophy (MTA) and posterior atrophy (PA) have been reported to be useful for Alzheimer’s disease diagnosis in routine clinical practice. Objective: To investigate the efficacy of combined MTA and PA visual rating scales to discriminate amnestic mild cognitive impairment (aMCI) patients from healthy controls. Methods: This study included T1-weighted MRI images from two different cohorts. In the first cohort, we recruited 73 patients with aMCI and 48 group-matched cognitively normal controls for training and validation. Visual assessments of MTA and PA were carried out for each participant. Global …gray matter volume and density were estimated using voxel-based morphometry analysis as the objective reference. We investigated the discriminative power of a single visual rating scale and the combination of the MTA and PA rating scales for identifying aMCI. The second cohort, consisting of 33 aMCI patients and 45 controls, was used to verify the reliability of the visual assessments. Results: Compared with the single visual rating scale, the combination of the MTA and PA exhibited the best discriminative power, with an AUC of 0.818±0.041, which was similar to the diagnostic accuracy of the gray matter volumetric measures. The discriminative power of the combined MTA and PA was verified in the second cohort (AUC 0.824±0.058). Conclusion: The combined MTA and PA rating scales demonstrated practical diagnostic value for distinguishing aMCI patients from controls, suggesting its potential to serve as a convenient and reproducible method to assess the degree of atrophy in clinical settings. Show more

Keywords: Magnetic resonance imaging, medial temporal lobe atrophy, mild cognitive impairment, posterior atrophy, visual rating scales

DOI: 10.3233/JAD-200016

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 323-337, 2020

Authors: McKeown, Alex | Turner, Andrew | Angehrn, Zuzanna | Gove, Dianne | Ly, Amanda | Nordon, Clementine | Nelson, Mia | Tochel, Claire | Mittelstadt, Brent | Keenan, Alex | Smith, Michael | Singh, Ilina

Article Type: Research Article

Abstract: Background: Dementia has been described as the greatest global health challenge in the 21st Century on account of longevity gains increasing its incidence, escalating health and social care pressures. These pressures highlight ethical, social, and political challenges about healthcare resource allocation, what health improvements matter to patients, and how they are measured. This study highlights the complexity of the ethical landscape, relating particularly to the balances that need to be struck when allocating resources; when measuring and prioritizing outcomes; and when individual preferences are sought. Objective: Health outcome prioritization is the ranking in order of desirability or importance …of a set of disease-related objectives and their associated cost or risk. We analyze the complex ethical landscape in which this takes place in the most common dementia, Alzheimer’s disease. Methods: Narrative review of literature published since 2007, incorporating snowball sampling where necessary. We identified, thematized, and discussed key issues of ethical salience. Results: Eight areas of ethical salience for outcome prioritization emerged: 1) Public health and distributive justice, 2) Scarcity of resources, 3) Heterogeneity and changing circumstances, 4) Knowledge of treatment, 5) Values and circumstances, 6) Conflicting priorities, 7) Communication, autonomy and caregiver issues, and 8) Disclosure of risk. Conclusion: These areas highlight the difficult balance to be struck when allocating resources, when measuring and prioritizing outcomes, and when individual preferences are sought. We conclude by reflecting on how tools in social sciences and ethics can help address challenges posed by resource allocation, measuring and prioritizing outcomes, and eliciting stakeholder preferences. Show more

Keywords: Alzheimer’s disease, dementia, ethics, health priorities

DOI: 10.3233/JAD-191300

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 339-353, 2020

Authors: Schneider, Julia | Schönstein, Anton | Teschauer, Winfried | Kruse, Andreas | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: The outcomes of hospitalized People with Dementia (PwD) are likely to be negative due to, among other key causes, negative staff attitudes and limited staff knowledge regarding dementia. Targeted interventions have been shown to positively change the attitudes of the hospital staff while also increasing their overall knowledge of dementia. However, training effects are often short-lived and frequently long-term effects are not examined in studies. Objective: To examine whether attending a dementia training program changes the attitudes of hospital staff toward PwD and/or increases their knowledge levels about dementia, and whether or not these changes are stable. …Methods: The training program lasted two days and N  = 60 attending hospital staff members agreed to participate in the study. Data were assessed with questionnaires prior to the training, 3 months, and 6 months after the training. German versions of the Dementia Attitude Scale (DAS-D) and the Knowledge in Dementia (KIDE) scale were used. Additionally, data about perception of PwD and confidence in dealing with challenging behavior were collected and analyzed. Results: After the training program, participants showed a significantly better attitude toward PwD as measured by DAS-D. These time-effects occurred in both DAS-D subscales (“dementia knowledge” and “social comfort”). Although a positive trend could be seen in the KIDE scale, no statistically significant increase occurred over time. Conclusion: Specialist training programs seem to be promising in positively changing attitudes toward and increasing knowledge about PwD with long-term effects. Further research should address the effects of attitude change in patient care. Show more

Keywords: Education, health facilities, health personnel, neurocognitive disorders, staff development

DOI: 10.3233/JAD-200268

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 355-365, 2020

Authors: Yu, Zi-Wei | Li, Xin | Wang, Ying | Fu, Yu-Hong | Gao, Xin-Yuan

Article Type: Research Article

Abstract: Background: Diabetes may increase the risk of conversion of mild cognitive impairment (MCI) to dementia. Lipid accumulation product (LAP), an index of visceral obesity, has been shown to be a powerful predictor of insulin resistance and type 2 diabetes (T2D). However, little attention has been paid to the relationship between LAP and MCI in T2D. Objective: We aimed to investigate the association between the LAP index and MCI in patients with T2D. Methods: In total, 220 hospitalized patients with T2D, including 113 MCI patients and 107 patients with normal cognition, were enrolled in this cross-sectional study. …We collected demographic, anthropometric, and biochemical data on each subject. The LAP index was calculated according to the following formulas: [waist circumference (WC) (cm) – 65]×triglyceride (TG) (mmol/L) for males and [WC (cm) – 58] ×TG (mmol/L) for females. Results: Compared with patients with normal cognition, MCI patients were older and had a higher LAP index, WC, body mass index, and glycosylated hemoglobin A1c level, as well as a lower Montreal Cognitive Assessment score and education level (p  < 0.05). After adjusting for confounding factors, LAP index was associated with MCI (OR = 1.047, 95% CI = 1.031–1.063, p  < 0.01). The area under the ROC curve (AUC) for the LAP index was higher than that for WC and BMI. Conclusion: A high LAP index is associated with an increased risk of MCI in T2D patients. The LAP index appears to be a good indicator of risk of MCI in patients with T2D. Show more

Keywords: Lipid accumulation product, mild cognitive impairment, type 2 diabetes, visceral obesity

DOI: 10.3233/JAD-200332

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 367-374, 2020

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