bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of tramiprosate in Alzheimer’s disease: A systematic review and meta‐analysis
Authors: Bouhuwaish Ahmad 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a common neurodegenerative disease. Tramiprosate is an amyloid protein (Aß) antagonist. It binds to soluble Aß and prevents conformational transitions that progress to plaque deposition. In this systematic review and meta‐analysis, we aim to evaluate the efficacy and safety of tramiprosate in the treatment of Alzheimer’s disease.MethodWe searched PubMed, Scopus, Web of Science, and Cochrane library on 10/6/2020 and then updated the search on 2/5/2022 for clinical trials that compare between tramiprosate and placebo in Alzheimer’s disease. We pooled data as mean difference (MD) or relative risk (RR) values using Review Manager 5.3 for windows.ResultFive studies were included in the qualitative analysis and only three of them were eligible for quantitative analysis. There was no significant difference between tramiprosate and placebo in terms of baseline‐endpoint change in Alzheimer’s disease assessment scale ‐ Cognitive subscale Score; neither in DIB 100 mg dose (MD = ‐.08, 95%CI [‐1.82, 1.65], P = 0.09) nor in DIB 150 mg (MD = ‐0.22, 95%CI [‐1.96, 1.51], P = 0.80). Also, there was no significant difference between tramiprosate and placebo in terms of baseline‐endpoint change in Clinical Dementia Rating Scale – Sum of boxes; neither in DIB 100 mg dose (MD = 0.08, 95%CI [‐0.41, 0.57], P = 0.75) nor in DIB 150 mg (MD = 0.20, 95%CI [‐0.29, 0.69], P = 0.42). Regarding safety, there was no significant difference between tramiprosate in terms of DIB 100 mg dose and placebo in side effects except in the incidence of nausea that was significantly higher in the placebo than in tramiprosate groups (RR = 1.41, 95% CI [1.02,1.94], p = 0.04). In terms of DIB 150 mg dose, there was no significant difference between tramiprosate and placebo in the incidence of side effects except in nausea (RR = 1.80, 95% CI [1.32, 2.44], p = 0.0002), vomiting (RR = 1.75, 95% CI [1.18, 2.61], p = 0.006), and decreased weight (RR = 2.28, 95% CI [1.49, 3.49], p = 0.0002) that were significantly higher in placebo than tramiprosate groups.Conclusiontramiprosate is not effective in the treatment of AD, although it may have fewer side effects. We recommend other studies to investigate mechanisms other than targeting Aß in the treatment of AD.
Microglial ADGRG1/GPR56 regulates amyloid clearance in Alzheimer’s disease
Authors: Zhu Beika , Wangzhou Andi , Yu Diankun , Li Tao , Schmidt Rachael , De Florencio Stacy L. , Chao Lauren , Seeley William W. , Piao Xianhua 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative disease with virtually no therapeutic interventions to reverse its pathology. Emerging studies emphasize the role of glial cells, particularly microglia, in brain homeostasis and AD progression. Notably, the adhesion G protein‐coupled receptor GPR56 (also known as ADGRG1) is one of the critical genes defining yolk sac‐derived microglia. Recent single‐nucleus RNA sequencing (snRNAseq) studies have shown GPR56, as one of the top five genes upregulated in microglia in individuals with early‐stage AD compared to those with no pathology or late‐stage AD. This observation suggests that individuals with upregulated microglial GPR56‐mediated pathways may have survived to an advanced age with mild AD pathology. In the present study, we test the hypothesis that microglial GPR56 is critical in modulating the microglial response in AD.MethodWe developed a novel AD mouse model with specific deletion of GPR56 in the microglia of 5xFAD mice (designated AD‐cKO and AD‐Control). Comprehensive analyses, including immunostaining, behavioral tests, and snRNAseq, were employed. The impact of GPR56 on microglial phagocytosis was evaluated using both in vitro and in vivo assays.ResultAbsence of microglial GPR56 exacerbated AD pathology, characterized by a compromised microglial response, increased plaque burden, exacerbated neuronal pathology, and cognitive deficits. snRNAseq analysis revealed a downregulation of genes associated with microglial homeostasis, phagocytosis, and lysosomal functions in AD‐cKO mice. Phagocytosis assays showed a significant reduction in phagocytic capability in AD‐cKO microglia. Extending this assay to human iPSC‐derived microglia, we observed a corresponding phenotype in GPR56 KO cells. Pearson correlation coefficient analysis using several published human sequencing databases corroborated our results in mouse models.ConclusionOur study supports that microglial GPR56 plays an indispensable role in curtailing AD progression, presenting a potential new therapeutic target in combating AD.
Correlation analysis of walking speed with executive function in patients with subjective memory decline
Authors: Chen Lei , Wang Jiayu , Li Linlin , Feng Qiansen , Wang Ziqi , Duan Mingjun 
Published: January 2025

AbstractBackgroundTo examine whether walking speed is associated with executive function in patients with subjective memory decline.MethodPatients were recruited from the Fourth People’s Hospital of Chengdu, including 63 patients with subjective cognitive decline (SCD) and 23 patients with mild cognitive impairment (MCI). Each participant assess global function by the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment‐Basic Scale (MoCA‐B). Executive function assessments using the Shape Symbol Task A (STT‐A) to evaluate visual perception and writing speed, Shape‐Tracing Test B (STT‐B) to evaluate cognitive flexibility. Animal Fluency Test (AFT) to evaluate semantic organization and retrieval strategies, Symbol Digit Modalities Test (SDMT) to assess processing speed and Digit Span Test (DST) to evaluate information processing processes. 10‐m walking test (10MWT) to evaluate walking speed, with time recorded converted to speed (m/s). SPSS 26.0 software was used to analyze the Pearson correlation between walking speed and executive function.ResultSignificant difference of MMSE, MoCA‐B, AFT, STT‐A, STT‐B and SDMT were found in both individual groups (P <0.05), and associations were independent of Gender, Age, Education and 10MWT. In the total combined group, 10MWT were significantly associated with Education (r = 0.267, p = 0.014), MMSE (r = 0.281, p = 0.009), MoCA‐B (r = 0.255, p = 0.019), AFT (r = 0.244, p = 0.024) and SDMT (r = 0.221, p = 0.043), negatively correlated with Age (r = ‐0.267, p = 0.013). In the SCD group, 10WMT were identified positive association with SDMT (r = 0.259, p = 0.042), negative correlation with Age (r = ‐0.282, p = 0.026). In the MCI group, 10WMT were identified positive association with Education (r = 0.655, p = 0.001), MMSE (r = 0.528, p = 0.01), MoCA‐B (r = 0.655, p = 0.001), AFT (r = 0.426, p = 0.043), negative correlation with STT‐A (r = ‐0.473, p = 0.023).ConclusionThere was no difference between two groups in walking speed, but were differences in global cognition and executive functions. In the SCD group, walking speed was correlated with processing speed in executive function. More associations between walking speed and executive function were found in the MCI group, mainly with the ability of organize and extract semantic strategies, visual perception and writing motor speed and also related to global cognitive function. The results revealed that impairment of executive function is a significant feature and has important relation with walking speed in the early stages of Alzheimer’s disease.
Depression, Depression Treatments, and Risk of Incident Dementia: A Prospective Cohort Study of 354,313 Participants
Authors: Yang Liu , Yu Jin‐Tai 
Published: January 2025

AbstractBackgroundTo investigate the associations between courses of depression, the application of depression treatment, and the risk of incident dementia.MethodIn this prospective cohort study, 354,313 participants aged 50 to 70 years were recruited from the UK Biobank between 2006 and 2010, and were followed‐up until 2020, with a total of 4,212,929 person‐years. We initially studied the effect of depression on dementia incidence across four subgroups characterized by courses of depressive symptoms. Then, 46,820 participants with depression diagnose were further categorized into the treated and untreated groups. We compared the risks of dementia among different depression treatments groups in all participants that depressed as well as four courses of depressive symptoms by performing survival analyses.ResultDepression was associated with a 51% higher risk of dementia, among which the increasing, chronically high and chronically low courses were associated with increased dementia risk while no association was found in the decreasing course. Compare to those who were depressed but untreated, receiving depression treatments corresponded to a hazard ratio of 0.7 (95% confidence interval = 0.62‐0.77). Among the three detrimental courses, treatments for increasing and chronically low symptoms of depression were associated with a 42% and 29% lower risk of dementia while the reduction effect for chronically high symptoms was insignificant.ConclusionThe negative association between depression treatment and incident dementia was significant in the increasing and chronically low course, highlighting the necessity of timely interventional strategies before depression progress to a chronically severe state.
AD risk alleles elevate microglial cGAS‐associated senescence and neurodegeneration in tauopathy
Authors: Gan Li , Naguib Sarah 
Published: January 2025

AbstractBackgroundThe strongest genetic risk factors for AD include the e4 allele of APOE and the R47H point mutation in the TREM2 receptor. TREM2 is required for the induction of a disease‐associated microglia (DAM) signature and microglial neurodegenerative phenotype (MGnD) in response to disease pathology, signatures which both include APOE upregulation. There is currently limited information regarding how the TREM2‐APOE pathway ultimately contributes to AD risk, and downstream mechanisms of this pathway are unknown. The combination of AD risk factors R47H and APOE4 may help highlight the mechanisms worsening disease and contributing to increased risk in humans.MethodThere are noteworthy sex differences in AD incidence and pathology, such that a greater proportion of AD patients are women, and APOE4‐associated risk is stronger in women. We accordingly focused our studies on female mice to examine the effects of combining three substantial risk factors: R47H, APOE4, and female sex. We chose to use the P301S tauopathy model for this study because tau pathology more closely aligns with cognitive decline than Ab pathology in human patientsResultOur study has found that the combination of APOE4 and R47H risk factors induces neurodegeneration in female tauopathy mice without significantly impacting hippocampal tau load. A previous study similarly found that R47H does not affect hippocampal tau load in the P301S model, suggesting that R47H risk is driven by disease‐enhancing microglial responses to tau, rather than by tau itself. Indeed, we find that APOE4‐R47H exacerbates microgliosis, amplifies microglial cGAS‐STING signaling and downstream IFN response pathways in a cell‐autonomous manner, and increases cGAS‐ and BAX‐dependent microglial senescence. Our study links the strongest AD risk factors, R47H, APOE4, and female sex, with microglial cGAS‐STING activation and associated senescence in a tauopathy model, highlighting these pathways as important therapeutic targets in the treatment of AD.ConclusionTaken together, cGAS‐STING and senescence pathways are known drivers of neurodegeneration, and our study further links upregulation of these pathways to the strongest AD risk factors. This evidence points to cGAS‐STING and senescence as vital pathological mechanisms in AD and important targets for future therapeutics.
‘Dependence’ as a meaningful patient‐focused outcome in Alzheimer’s disease: Qualitative concept elicitation and cognitive debriefing of the Dependence Scale in early symptomatic AD
Authors: Atkins Alexandra , Delbecque Laure , Elliott Emma , Heinrich Phoebe , Cano Stefan , Stern Yaakov 
Published: January 2025

AbstractBackground‘Dependence’ has been proposed as a measurable health outcome reflecting the overall impact of disease progression in Alzheimer’s disease (AD). However, the meaning and relevance of ‘dependence’ in early symptomatic AD (MCI and mild AD dementia) have not been previously investigated. Aims of the current research were to (1) explore the concept of ‘dependence’ from the perspective of caregivers of patients with early symptomatic AD, (2) assess the content validity of the Dependence Scale (DS; Stern, 1994), a 13‐item scale evaluating patient dependence based on a caregiver interview, and (3) explore the relevance of newly incorporated DS rater guidance clarifying potential ambiguities in item phrasing.MethodConcept elicitation (CE) and cognitive debriefing (CD) interviews were conducted with caregivers of patients with confirmed diagnoses of Mild Cognitive Impairment (MCI; n = 7) or mild AD dementia (mild AD; n = 18) recruited in the US. The DS was debriefed with 19 caregivers. CE interviews explored the concept of dependence, including its meaning and relevance. Transcribed interviews were analyzed thematically, with structured codes used for CD.ResultDuring CE most caregivers (n = 21) described ‘dependence’ in AD in terms of ability/lack of ability to complete tasks alone. Several (n = 16) discussed dependence in the context of concerns about leaving patients alone, citing perceived risks to physical safety or need for emotional support. Most concepts covered by the DS were discussed during interviews. During CD, some respondents (up to 42%) felt some item phrasing lacked clarity, particularly when a single response was needed to characterize functioning across multiple activities (e.g. shopping and chores); in all cases, rater guidance provides relevant clarification for use during standardized administration. Regarding content, 1 or more caregivers provided examples of patient difficulties assessed by 10 of the 13 items. Items assessing instrumental daily activities appeared most relevant, with most caregivers reporting clear examples.ConclusionFindings support patient dependence as a meaningful concept in AD and provide evidence supporting content validity of the DS. Most DS concepts were discussed during the interviews. Rater guidance is relevant and may mitigate the impact of perceived ambiguities in item phrasing.
Developing a machine learning stack model to forecast the progression of mild cognitive impairment to Alzheimer’s dementia, using the Australian Imaging, Biomarker & Lifestyle (AIBL) Study dataset
Authors: Chu Chenyin , Wang Yihan , Maruff Paul , Masters Colin L. , Goudey Benjamin , Jin Liang , Pan Yijun ,   The AIBL research group
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative condition, with considerable variation in disease progression from the mild cognitive impairment (MCI) stage. Predicting disease progression will support prognostic decisions and patient management. Here we designed a machine learning (ML) stack model, where a classifier was used to differentiate MCI progressors from non‐progressors (i.e. whether an individual with MCI progress to AD), and different regression models were then applied to each category to forecast their Mini‐Mental State Examination (MMSE) score after 3 years.MethodDemographic and neuropsychological data from 2428 participants of the AIBL study was used for model construction and validation. The model was validated via a stratified 3‐fold cross‐validation approach. Support vector machine (SVM), gradian boosting (GB), random forest (RF) was experimented, and their performance were compared. MMSE score was a predicted variable indicating cognition.ResultThe performance of RF‐stack model was superior to SVM‐ and GB‐stack models. Largest area under the receiver operating characteristic curve (0.85) when RF‐stack model was employed (compared with SVM 0.79 and GB 0.70), signifying the highest accuracy in classify MCI progressors and non‐progressors. RF‐stack model achieved the best performance in predicting MMSE score after 3 years), evidenced by the smallest median mean average error (MAE) (RF 1.51, SVM 1.52, GB 2.51). The MAE indicated how much the predicted MMSE score deviated from the AIBL record. Representative prediction results from RF‐stack model for AIBL participants were presented in Table 1.ConclusionOur RF‐stack model relies on neuropsychological test scores and demographic data to predict the probability of an individual progressing from MCI to AD and accurately forecast the MMSE score after 3 years. This model achieved is comparable if not better prediction accuracy than the existing ML models using neuroimaging data. Further model optimization and validation using data collected from other longitudinal AD cohort studies are required.
Exploring the Potential Rescue Effects of SorCS1, a Novel Amyloid Beta Competitor, on Synaptic and Cognitive Defects in an Alzheimer’s Disease Model Mouse
Authors: Yi Nayoung 
Published: January 2025

AbstractBackgroundSoluble Aβ oligomers (AβOs) induce synapse dysfunction, leading to cognitive impairment and memory deficits in Alzheimer’s disease (AD). Our laboratory and several research groups characterized neurexin family members' physiological roles, pivotal synaptic adhesion molecules for development, plasticity, and maintenance. Beyond their normal functions, we found neurexins binding to AβOs causes AβO‐induced neurexin dysregulation. Another group’s findings highlighted SorCS1’s role, regulating neurexin1β isoform (NRX1β) trafficking and surface expression. Our recent in vitro study showed SorCS1 competitively binds NRXβ, countering AβOs' effect, rescuing AβO‐induced NRXβ dysregulation and synaptic toxicity. NRXβ’s pivotal synaptic and brain function roles suggest SorCS1 mitigates AβO‐induced synaptic dysfunction and AD‐related deficits. We hypothesize SorCS1 stabilizes synaptic NRXβ by competitively inhibiting AβO‐NRXβ interaction.MethodTo explore SorCS1’s in vivo roles, we created a forebrain‐specific inducible SorCS1 transgenic mouse line, breeding it with 5xFAD, an AD mouse model overproducing AβOs. To achieve temporal and forebrain‐specific expression of SorCS1, SorCS1KI mice were crossed with CaMKIIa‐CreERT2 mice, allowing Cre recombinase expression upon tamoxifen treatment specifically in forebrain excitatory neurons. Through these crossings, we established four genetic groups: 1) non‐AD normal control(Male = 14, Female = 14, Total n = 28), 2) non‐AD with SorCS1 overexpression (OE) (Male = 12, Female = 15, Total n = 27), 3) AD model (Male = 11, Female = 12, Total = 23), 4) AD with SorCS1 OE rescue model (Male = 13, Female = 16, Total = 29). Structural, biochemical analyses such as immunoblot and immunohistochemistry, and behavioral tests (Morris water maze, Open field, Y‐maze) were conducted to determine SorCS1’s impact on synaptic impairment and memory deficits in AD mice.ResultIn mice overexpressing SorCS1 in the AD model (5xFAD), no significant differences were observed in long‐term spatial learning memory (assessed using the Morris water maze), locomotor activity, or anxiety levels (evaluated in the open field test) compared to the AD control group. However, SorCS1 overexpression notably improved weakened short‐term working memory (assessed via the y‐maze) in the AD mice. Furthermore, SorCS1 overexpression partially restored the expression levels of synaptic proteins, such as PSD95, GluA1, and β‐NRX in the cortex, as well as PSD95 and α‐NRX in the hippocampus within the crude synaptosome.ConclusionIn vivo, the overexpression of SorCS1 rescues impaired levels of synaptic proteins and improves deficits in short‐term working memory.
Proteome‐wide analyses identifies plasma immune regulators of amyloid‐beta progression
Authors: Duggan Michael R. , Gomez Gabriela T , Bilgel Murat , Chen Jingsha , Fattorelli Nicola , Hohman Timothy J. , Mancuso Renzo , Cordon Jenifer , Castellano Tonnar , Koran Mary Ellen I. , Candia Julián , Lewis Alexandria , Moghekar Abhay , Ashton Nicholas J. , Kac Przemyslaw Radoslaw , Karikari Thomas K , Blennow Kaj , Zetterberg Henrik , Martinez‐Muriana Anna , De Strooper Bart , Thambisetty Madhav , Ferrucci Luigi , Gottesman Rebecca F. , Coresh Josef , Resnick Susan M. , Walker Keenan A. 
Published: January 2025

AbstractBackgroundWhile immune function is known to play a mechanistic role in Alzheimer’s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid‐b (Aβ) progression remains unknown.MethodUsing the Baltimore Longitudinal Study of Aging (BLSA; n = 196; mean follow‐up: 5 years/4 scans), we identified immune‐related proteins in plasma (candidate proteins) related to rates of change in cortical Aβ levels, as measured by 11C‐PiB PET. Along with identifying genetic variants that contributed to candidate protein associations, characterizing their relationships with tau‐PET and changes in ADRD biomarkers (Aβ42/40, NfL, GFAP, pTau‐181), and assessing their expression patterns in human microglia, we leveraged data from the Atherosclerosis Risk in Communities (ARIC) study to determine if changes in candidate protein levels precede Ab = β onset (n = 272), and whether they predict 20‐year dementia risk during mid‐life (n = 11,596) and 8‐year dementia risk during late‐life (n = 4,288).Result32 immunological proteins in plasma (out of 942) were associated with cortical Ab = β accumulation (Figure 1A). Longitudinal changes in a subset of candidate proteins also predicted cortical Aβ accumulation (Figure 1B), and the mid‐ to late‐life trajectory of one protein, CAT, was associated with late‐life Aβ‐positive status in ARIC (Figure 1C). Genetic variants associated with the plasma abundance of CAT and two additional candidate proteins (CD36 and KRT19) predicted rates of Aβ accumulation (Figure 2A‐F). In addition to associations with other AD‐related phenotypes (tau‐PET, plasma AD biomarker changes) (Figure 2G‐H), we showed that 31% of candidate proteins were related to mid‐life (20‐year) or late‐life (8‐year) dementia risk in ARIC (Figure 2I). Single‐cell RNA‐seq showed a prominent dysregulation of candidate protein expression in homeostatic, interferon‐response and disease‐associated human microglia subtypes (Figure 3A). Candidate proteins were enriched for biological processes implicated in AD (Figure 3B), susceptible to regulation by key pro‐inflammatory cytokines (Figure 3C), displayed robust protein‐interaction networks, showed differential expression in AD brains (especially neurovascular cell types), were externally validated, and are targets of existing therapeutics (Figure 3D).ConclusionFindings provide insights into how immune proteins in peripheral circulation influence the rate of Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.