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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Jehu, Deborah A. | Pottayil, Faheem | Dong, Yanbin | Zhu, Haidong | Sams, Richard | Young, Lufei
Article Type: Research Article
Abstract: Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition : Montreal Cognitive Assessment; executive function : Trail-Making Test, Digit Span Forward Test; perception and orientation : Benton Judgement of Line Orientation Test; …language : Boston Naming Test; learning and memory : Rey Auditory Verbal Learning Test; complex attention : Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer’s disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (p s < 0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes. Show more
Keywords: Accelerometry, actigraphy, Alzheimer’s disease, cognition, cognitive domains, dementia, physical activity
DOI: 10.3233/JAD-230594
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Diaz-Asper, Catherine | Chandler, Chelsea | Elvevåg, Brita
Article Type: Short Communication
Abstract: This study surveyed 51 specialist clinicians for their views on existing cognitive screening tests for mild cognitive impairment and their opinions about a hypothetical remote screener driven by artificial intelligence (AI). Responses revealed significant concerns regarding the sensitivity, specificity, and time taken to administer current tests, along with a general willingness to consider adopting telephone-based screening driven by AI. Findings highlight the need to design screeners that address the challenges of recognizing the earliest stages of cognitive decline and that prioritize not only accuracy but also stakeholder input.
Keywords: Alzheimer’s disease, artificial intelligence, attitude of health personnel, mental status and dementia test, mild cognitive impairment
DOI: 10.3233/JAD-240293
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2024
Authors: Espay, Alberto J. | Herrup, Karl | Imbimbo, Bruno P. | Kepp, Kasper P. | Daly, Timothy
Article Type: Article Commentary
Abstract: Three recent anti-amyloid-β antibody trials for Alzheimer’s disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-β42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond …removing amyloid. Show more
Keywords: Alzheimer’s disease, ARIA, amyloid-β, Aβ42, placebo, RCT
DOI: 10.3233/JAD-240171
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2024
Authors: Tuena, Cosimo | Serino, Silvia | Goulene, Karine Marie | Pedroli, Elisa | Stramba-Badiale, Marco | Riva, Giuseppe
Article Type: Research Article
Abstract: Background: Individuals with mild cognitive impairment (MCI) syndrome often report navigation difficulties, accompanied by impairments in egocentric and allocentric spatial memory. However, studies have shown that both bodily (e.g., motor commands, proprioception, vestibular information) and visual-cognitive (e.g., maps, directional arrows, attentional markers) cues can support spatial memory in MCI. Objective: We aimed to assess navigation cues for innovative spatial training in aging. Methods: Fifteen MCI patients were recruited for this study. Their egocentric and allocentric memory recall performances were tested through a navigation task with five different virtual reality (VR) assistive encoding navigation procedures (bodily, vision …only, interactive allocentric map, reduced executive load, free navigation without cues). Bodily condition consisted of an immersive VR setup to engage self-motion cues, vision only condition consisted of passive navigation without interaction, in the interactive allocentric map condition patients could use a bird-view map, in the reduced executive load condition directional cues and attentional markers were employed, and during free navigation no aid was implemented. Results: Bodily condition improved spatial memory compared to vision only and free navigation without cues. In addition, the interactive allocentric map was superior to the free navigation without cues. Surprisingly, the reduced executive load was comparable to vison only condition. Moreover, a detrimental impact of free navigation was observed on allocentric memory across testing trials. Conclusions: These findings challenge the notion of an amodal representation of space in aging, suggesting that spatial maps can be influenced by the modality in which the environment was originally encoded. Show more
Keywords: Alzheimer’s disease, dementia, embodied cognition, mild cognitive impairment, rehabilitation, spatial cognition
DOI: 10.3233/JAD-240122
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Youssef, Hossam | Gatto, Rodolfo G. | Pham, Nha Trang Thu | Petersen, Ronald C. | Machulda, Mary M. | Reichard, R. Ross | Dickson, Dennis W. | Jack, Clifford R. | Whitwell, Jennifer L. | Josephs, Keith A.
Article Type: Research Article
Abstract: Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment …of the distribution of Aβ (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body. Show more
Keywords: Alzheimer’s disease, Cornu Ammonis 1, LATE-NC, primary age-related tauopathy, TAR DNA binding Protein 43, type-alpha
DOI: 10.3233/JAD-240136
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Zhu, Mengxin | Liu, Yang | Chen, Chen | Chen, Hao | Ni, Wanyan | Song, Yuanjian | Lv, Bingchen | Hua, Fang | Cui, Guiyun | Zhang, Zuohui
Article Type: Research Article
Abstract: Background: Neuroinflammation plays a crucial part in the initial onset and progression of Alzheimer’s disease (AD). NLRP3 inflammasome was demonstrated to get involved in amyloid-β (Aβ)-induced neuroinflammation. However, the mechanism of Aβ-triggered activation of NLRP3 inflammasome remains poorly understood. Objective: Based on our previous data, the study aimed to identify the downstream signals that bridge the activation of TLR4 and NLRP3 inflammasome associated with Aβ. Methods: BV-2 cells were transfected with TLR4siRNA or pretreated with a CLI-095 or NSC23766, followed by Aβ1–42 treatment. APP/PS1 mice were injected intraperitoneally with CLI-095 or NSC23766. NLRP3 inflammasome and …microglia activation was detected with immunostaining and western blot. G-LISA and Rac1 pull-down activation test were performed to investigate the activation of Rac1. Real-time PCR and ELISA were used to detect the inflammatory cytokines. Aβ plaques were assessed by western blotting and immunofluorescence staining. Morris water maze test was conducted to determine the spatial memory in mice. Results: Rac1 and NLRP3 inflammasome were activated by Aβ in both in vitro and in vivo experiments. Inhibition of TLR4 reduced the activity of Rac1 and NLRP3 inflammasome induced by Aβ1–42 . Furthermore, inhibition of Rac1 blocked NLRP3 inflammasome activation mediated by TLR4. Blocking the pathway by CLI095 or NSC23766 suppressed Aβ1–42 -triggered activation of microglia, reduced the expression of pro-inflammatory mediators and ameliorated the cognition deficits in APP/PS1 mice. Conclusions: Our study demonstrated that TLR4/Rac1/NLRP3 pathway mediated Aβ-induced neuroinflammation, which unveiled a novel pathway and key contributors underlying the pathogenic mechanism of Aβ. Show more
Keywords: Alzheimer’s disease, amyloid-β , microglia, neuroinflammation, NLRP3 inflammasome, Rac1, TLR4
DOI: 10.3233/JAD-240012
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Khandia, Rekha | Gurjar, Pankaj | Romashchenko, Victoria | Al-Hussain, Sami A. | Alexiou, Athanasios | Zouganelis, George | Zaki, Magdi E.A.
Article Type: Research Article
Abstract: Background: Autophagy and apoptosis are cellular processes that maintain cellular homeostasis and remove damaged or aged organelles or aggregated and misfolded proteins. Stress factors initiate the signaling pathways common to autophagy and apoptosis. An imbalance in the autophagy and apoptosis, led by cascade of molecular mechanism prior to both processes culminate into neurodegeneration. Objective: In present study, we urge to investigate the codon usage pattern of genes which are common before initiating autophagy and apoptosis. Methods: In the present study, we took up eleven genes (DAPK1, BECN1, PIK3C3 (VPS34 ), BCL2, MAPK8, …BNIP3 L (NIX ), PMAIP1 , BAD, BID, BBC3, MCL1 ) that are part of molecular signaling mechanism prior to autophagy and apoptosis. We analyzed dinucleotide odds ratio, codon bias, usage, context, and rare codon analysis. Results: CpC and GpG dinucleotides were abundant, with the dominance of G/C ending codons as preferred codons. Clustering analysis revealed that MAPK8 had a distinct codon usage pattern compared to other envisaged genes. Both positive and negative contexts were observed, and GAG-GAG followed by CTG-GCC was the most abundant codon pair. Of the six synonymous arginine codons, two codons CGT and CGA were the rarest. Conclusions: The information presented in the study may be used to manipulate the process of autophagy and apoptosis and to check the pathophysiology associated with their dysregulation. Show more
Keywords: Alzheimer’s disease, apoptosis, autophagy, codon context, codon pairs, rare codons, relative synonymous codon usage
DOI: 10.3233/JAD-240158
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Wang, Linlin | Zhang, Xuezhen | Wang, Lei | Guo, Miaomiao | Yang, Qihang | Chen, Xiaogang | Sha, Hong
Article Type: Research Article
Abstract: Background: Early recognition of dementia like Alzheimer’s disease is crucial for disease diagnosis and treatment, and existing objective tools for early screening of cognitive impairment are limited. Objective: To investigate age-related behavioral indicators of dual-task cognitive performance and gait parameters and to explore potential objective markers of early cognitive decline. Methods: The community-based cognitive screening data was analyzed. Hierarchical cluster analysis and Pearson correlation analysis were performed on the 9-item subjective cognitive decline (SCD-9) scores, walking-cognitive dual-task performance, walking speed, and gait parameters of 152 participants. The significant differences of indicators that may related to cognitive …decline were statistically analyzed across six age groups. A mathematical model with age as the independent variable and motor cognition composite score as the dependent variable was established to observe the trend of motor cognition dual-task performance with age. Results: Strong correlation was found between motor cognitive scores and SCD and age. Gait parameters like the mean value of ankle angle, the left-right difference rate of ankle angle and knee angle and the coefficient of variation of gait cycle showed an excellent correlation with age. Motor cognition scores showed a decreasing trend with age. The slope of motor cognition scores with age after 50 years (k = –1.06) was six times higher than that before 50 years (k = –0.18). Conclusions: Cognitive performance and gait parameters in the walking-cognitive dual-task state are promising objective markers that could characterize age-related cognitive decline. Show more
Keywords: Age, Alzheimer’s disease, cognitive decline, motor cognitive assessment, objective markers, walking-cognitive dual task
DOI: 10.3233/JAD-240066
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Guo, Ze-Xin | Liu, Fang | Wang, Fang-Yuan | Ou, Ya-Nan | Huang, Liang-Yu | Hu, Hao | Wang, Zhi-Bo | Fu, Yan | Gao, Pei-Yang | Tan, Lan | Yu, Jin-Tai
Article Type: Research Article
Abstract: Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual’s risk of dementia. However, studies on the link of the CAIDE score to Alzheimer’s disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. …Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p < 0.001), tTau (p < 0.001), as well as tTau/Aβ42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p < 0.001) as well as MoCA score (p < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2% . Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration. Show more
Keywords: Alzheimer’s disease, CAIDE dementia risk score, cerebrospinal fluid biomarkers, cognition, neurodegeneration
DOI: 10.3233/JAD-240005
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Rolandsson, Olov | Tornevi, Andreas | Steneberg, Pär | Edlund, Helena | Olsson, Tommy | Andreasson, Ulf | Zetterberg, Henrik | Blennow, Kaj
Article Type: Research Article
Abstract: Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer’s disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ 1–40 and Aβ 1–42 concentrations in individuals with T2D and matched controls. Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66–72 years) underwent hyperglycemic clamp and placebo clamp (saline …infusion) in a randomized order, each lasting 4 hours. Aβ 1–40 , Aβ 1–42 , and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ 1–40 and Aβ 1–42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results: At baseline, Aβ 1–40 and Aβ 1–42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ 1–40 : p = 0.034, Aβ 1–42 : p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ 40 and Aβ 42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D. Show more
Keywords: Alzheimer’s disease, amyloid-β, cognition, endocrinology and metabolism specialty, hyperglycemia, type 2 diabetes
DOI: 10.3233/JAD-230628
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
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