bluuebunny/crossref_metadata_2025_split huggingface dataset:
APNmAb005, an anti‐tau antibody targeting synaptic tau oligomers, in Phase 1 for treatment of Alzheimer’s Disease and primary tauopathies
Authors: Tai Chin‐Yin , Ma Haou‐Tzong , Li Chung‐Lin , Fang Wu Meng‐ , Wang Silas , Wu Chia‐Lin , Lai Yen‐Ting , Serrano Geidy E , Beach Thomas G , Margolin Richard A , Zhang Lili , Jang Ming‐Kuei , Navia Bradford 
Published: December 2023

AbstractBackgroundAccumulation of tau oligomers at the synapses in Alzheimer’s disease (AD) disrupts neuronal activities and leads to neurodegeneration. Tau immunotherapy has been actively pursued as a treatment for tauopathies in the past decade. Despite several failed Phase 2 trials of N‐terminus binding antibodies a variety of tau epitopes are being investigated at different stages of clinical trials. APNmAb005 is a humanized monoclonal antibody designed to block synaptic toxicity elicited by tau oligomers.MethodAPNmAb005 was selected as a clinical candidate from APRINOIA’s antibody discovery platform based on its unique binding properties to pathological tau in vitro immunoassays as well in vivo efficacy studies in rTg4510 mice. Humanized APNmAb005 is in IgG4 backbone and the production was scaled up successfully with good stability and solubility to support preclinical and clinical development. GLP safety study was conducted in cynomolgus monkeys. A Phase 1a randomized, double‐blind, placebo‐controlled study of APNmAb005 in healthy subjects is underway.ResultEpitope‐mapping study reveals that APNmAb005 binds to a conformation‐dependent epitope in the mid‐region, which results in a preferable recognition of pathological tau in early Braak stage (III‐IV) AD brains as well as tau aggregates in astrocytes and oligodendrocytes in brains from progressive supranuclear palsy (PSP) patients but not monomeric tau in normal brains. APNmAb005 blocks in vitro tau seeding at nanomolar concentrations and rescues neuronal loss in rTG4510 mice. Four‐week repeat dosing toxicology study shows no observed adverse effects.ConclusionAPNmAb005 is a conformation selective antibody that binds to tau oligomers and aggregates preferentiually in synapses in pathological brain tissues and inhibits tau spreading. The mid‐region conformation dependent epitope is distinct from all other tau antibodies currently in clinical development. APNmAb005 offers a unique tau immunotherapy for neurodegenerative disorders and is currently in Phase 1 to evaluate its safety and tolerability.
Modulation of microglial function by neuronal expression of the Alzheimer multifactorial therapeutic agent E2F4DN is mediated by a soluble factor
Authors: Ramón‐Landreau Morgan , Lopez‐Sanchez Noelia , Frade Jose María 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder in which altered immune response is an important etiological factor (Cell Rep. 2019;27:1293.e6‐1306.e6, Nature 2019;575:669‐673). The transcription factor E2F4 regulates gene networks affected in AD (Interdiscip. Sci. 2019;11:226‐236), thus constituting a potential target for intervention. Neuronal expression of a dominant negative form of E2F4 (E2F4DN), which cannot be phosphorylated in two conserved Thr residues, can attenuate microgliosis in a mouse model of AD (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐30392), as evidenced by the reduction of area occupied by microglia (i.e. Iba1‐positive cells). Communication between neurons and microglia is essential to regulate microglial activation and neuroprotection. The loss of this communication can cause microglia overactivation and produce persistent inflammation, finally resulting in the exacerbation of the neuropathology (Neural Regen. Res. 2019;14:1499‐1502).MethodMouse cortical neurons were cultured and maintained for 9 days in vitro (DIV) for maturation. Neurons were then transfected with an E2F4DN adenoviral (Ad5) vector, or a control EGFP Ad5 vector. After 48 h, rat microglia were treated for 24 hours with the conditioned media, and then fixed and immunostained with the microglia marker Iba1. The size of these cells was analyzed as a readout of the glial inflammatory activity (Sci. Rep. 2017;7:1576).ResultMicroglial cell size was analyzed from images obtained in the fluorescence microscope. This would determine if any soluble factor secreted by neurons that express E2F4DN, but not by neurons that express EGFP, is capable of inducing morphological changes that may reflect functional changes in this cell type. A reduction in the size of microglia was observed when the conditioned medium came from neurons expressing E2F4DN. These results show the existence of a differential communication mechanism between neurons and microglia depending on the expression of E2F4DN.ConclusionWe suggest that there is an E2F4DN‐dependent neuron‐microglia communication based on soluble factors such as those described by Simon et al. (Neuroscience 2019;405:24‐34). Altogether, our data are consistent with a beneficial immune response elicited by neurons expressing E2F4DN, a molecule proposed as a multifactorial therapeutic agent against AD.
Understanding the electrochemical interaction between the hybrid bilayer lipid membranes and amyloid‐β
Authors: Hassan Qusai , Kerman Kagan 
Published: December 2023

AbstractBackgroundBiomimetic membrane systems can be deposited onto conductive metal surfaces to study the physical properties of membranes as well as the behaviour of proteins within these membranes using electrochemical and surface analytical techniques [1]. Although there are several types of biomimetic membrane, hybrid bilayer lipid membranes (HBLMs) have attracted wide interest. Traditionally, HBLMs have been developed by electrodepositing alkanethiol self‐assembled monolayers onto gold surfaces, which can then be further modified by depositing a secondary phospholipid layer to form the HBLM. Although HBLMs have been widely regarded due to them being robust, relatively straightforward to make, as well as being easy to modify according to the users needs, several concerns surround HBLMs including their reduced fluidity compared to true cell membranes. This is due to the alkanethiol layer being crystalline in nature and more densely packed, resulting in difficulty to reconstitute transmembrane proteins within them.MethodScreen‐printed carbon electrodes are modified with diazonium based phenyl alkyl groups using different protocols to evaluate the biomimetic differences of these novel HBLMs. 2,2‐diphenyl‐1‐picrylhydrazyl is used to prevent the formation of polyaryl layers on the surface of the electrode, hence limiting the electrodeposition to a monolayer. The HBLMs are formed by depositing the second layer in the form of dihexadecyl phosphate, which are analyzed using differential pulse voltammetry, ellipsometry, and X‐ray photoelectron spectroscopy.ResultThe different HBLMs presented are embedded with amyloid‐β1‐42 (Aβ42), the hallmark protein implicated in Alzheimer’s Disease, to assess the protein‐membrane interactions using HBLMs. Aβ42 is known to aggregate to form dimers, oligomers, fibrils, and plaques. Hence using electrochemical techniques, we are able to monitor the aggregation of Aβ42 in the HBLMs. The aggregation process was accelerated by the presence of the bilayer membrane.ConclusionThe electrochemical platform presented here enables us to understand how the interaction of amyloid‐β with the bilayer membrane can alter the aggregation pathways and also affect the formation of toxic oligomer species.References: [1] Fini, H., Hassan, Q., Noroozifar, M. & Kerman, K. Electrografting a Hybrid Bilayer Membrane via Diazonium Chemistry for Electrochemical Impedance Spectroscopy of Amyloid‐β Aggregation. Micromachines 13, 574 (2022).
A normative study of the Trail Making Test‐Black and White
Authors: Suh Jeewon , Baek Min Jae , Kang Yeonwook , Kim SangYun 
Published: December 2023

AbstractBackgroundThe Trail Making Test (TMT) is a neuropsychological test to measure frontal and executive function. Although it is a widely used test in identifying dementia, TMT has limited utility in cross‐culture contexts because of the use of the English alphabet in a subset of the test. TMT‐Black and white (TMT‐B&W) is a newly developed version of TMT which uses only black and white circles to overcome the performance bias among non‐English speaking and illiterate elderly. The objective of this study is to provide the initial normative data of TMT B&W and investigate the influence of age, gender and education level on the time to complete the test.MethodThe TMT‐B&W was administered to 1,012 cognitively normal participants (430 males and 582 females) from age 19 to 90 and the time in seconds taken to complete the test was measured.ResultAge, education level and gender were significantly associated with TMT‐B&W part A and part B scores. Based on these results, normative data of TMT‐B&W part A and part B for male and female were stratified for age and education level.ConclusionThis study provide normative data for the new version of TMT, the TMT‐B&W which can be used in a cross‐cultural context without language translation. TMT‐B&W could be a useful neuropsychological test for illiterate or low‐educated people without the ability to understand the written letter. Age, education level and gender had significant influences on both TMT‐B&W part A and B.
Xenografted human microglia in response to Alzheimer’s disease Aβ pathology
Authors: Martinez‐Muriana Anna , Mancuso Renzo , Fattorelli Nicola , Davis Emma , Wolfs Leen , Daele Johanna Van Den , Geric Ivana , Preman Pranav , Serneels Lutgarde , Poovathingal Suresh Kumar , Balusu Sriram , Verfaillie Catherine , Fiers Mark , De Strooper Bart 
Published: December 2023

AbstractBackgroundNeuroinflammation is a pathological hallmark of Alzheimer’s disease (AD). Murine studies have revealed that mouse microglia can adopt several cell states in response to disease insults. However, single‐nuclei RNA sequencing studies have found divergent results when recalling those cell states in human post‐mortem tissue.MethodTo overcome this limitation, we have sequenced 127,000 single cell human microglia isolated from an AD xenotransplantation model.ResultIn response to plaques, human microglia can adopt several cell states including a disease‐associated microglia (DAM) and an antigen‐presenting response (HLA). When reacting to Aβ soluble aggregates, human microglia produces a pro‐inflammatory response cytokine response (CRM). TREM2 and APOE polymorphisms affect the development of the DAM‐HLA response, suggesting an important role of this response in AD.ConclusionOverall, this multi‐faceted response to amyloid pathologies highlights a complex scenario where these distinct phenotypes might influence the outcome on the disease.
A user‐friendly calculator to estimate length of time from initial presentation to need for full‐time care or death in individual patients with Alzheimer’s disease
Authors: Stern Yaakov , Stallard Eric , Ryu Hyunnam , Kociolek Anton J , Lee Seonjoo , Cosentino Stephanie , Zhu Carolyn W , Hernandez Michelle , Kinosian Bruce , Gu Yian 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) exhibits substantial variability in its initial presentation and rate of progression. Our goal was to understand AD progression well enough to create a calculator that uses presented clinical features to estimate the length of time from initial presentation to major disease outcomes in individual patients with AD.MethodThe variability in rate of AD progression is strongly related to the variability in specific disease signs and symptoms identified at initial presentation. We developed a longitudinal Grade of Membership prediction algorithm and demonstrated its ability, based on initial presentation of six fixed covariates and 73 time‐varying clinical signs and/or symptoms, to accurately predict time to need for full‐time care (FTC) and death in two groups: a mainly white, clinic‐based group of AD patients (N = 229), and a statistically representative community‐based sample of Hispanic (N = 211) and non‐Hispanic (N = 62) older adults with MCI or AD. We then created an online calculator for use by physicians, relatives, or patients to generate these predictions.ResultThe calculator is implemented as an online, freely available R Shiny web app: https://cnd‐columbia.shinyapps.io/AD_Calc/. The user is prompted for current clinical information about the patient. Most of this information can be gleaned from patient observation, healthcare providers, or medical records. Unknown items can be skipped or sensibly approximated. The calculator generates individual‐specific survival‐probability curves, including median survival time, over the next 10 years. It also generates conditional probabilities of need for FTC in a way that allows the overall survival time to be decomposed into time free of need for FTC and time in need of FTC. The calculator does not predict which specific individuals would die before the median versus after the median; that prediction cannot be done.ConclusionGiven the substantial variability over individuals in rate of disease progression, knowing the statistics of the individual‐specific survival times as well as the times to need for FTC can be of great value to patients with AD, their caregivers, and health care providers. The new calculator meets this need. In the future, the calculator also can be extended to predict time to other important disease milestones.
Normative data on the CERAD Word List in a robustly intact sample of older adults
Authors: Duff Kevin , Hanna Elise J , Mattek Nora , DeCapo Madison , Hantke Nathan , Pierce Aimee , Kaye Jeffrey A 
Published: December 2023

AbstractBackgroundList learning and memory tests are frequently used to evaluate older adults for late life cognitive disorders, such as Alzheimer’s disease. The Word List subtest of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery has been widely‐used in clinical research, including clinical trials, to identify and track such disorders. It is also freely‐available, as it is in the public domain. However, normative data, especially in robustly intact older adults, is lacking.MethodCERAD Word List data from 897 older adults (age in years: M = 81.1, SD = 8.1, range 55‐100; 67% women; education in years: M = 14.8, SD = 2.8, range = 7‐24) deemed to be cognitively intact at two annual visits in a longitudinal observational study from the Uniform Data Set of the National Alzheimer’s Coordinating Center were used to generate predicted Word List scores based on age, sex, and education. Predicted scores were compared to observed scores to preliminarily validate these normative values.ResultFor six primary scores from the Word List subtest (Trial 1, Trial 2, Trial 3, Total Acquisition, Delay Recall, Recognition Total Correct), the three demographic variables significantly predicted test scores, with R2s ranging from 0.03 – 0.18 (p‐values<0.001). When these predicted scores were compared to observed scores, there were no significant differences (p‐values>0.40), indicating preliminary support for these prediction scores.ConclusionAlthough further validation is needed in independent intact and impaired samples, the current demographically‐based prediction scores provide normative data for the CERAD Word List subtest for older adults being evaluated for cognitive complaints. The inclusion of additional variables needs to be examined to improve the accuracy of these prediction scores. Nonetheless, normative data allows providers and researchers to be confident in using this learning and memory test in clinics and clinical trials.
Secondary School Quality and Midlife Cognition: Evidence from High School and Beyond
Authors: Chung Hyeran , Brickman Adam M. , Grodsky Eric , Manly Jennifer J. , Muller Chandra , Warren John Robert 
Published: December 2023

AbstractBackgroundResearch on the association between education and later‐life cognitive outcomes usually only considers the quantity of schooling that people complete. However, people with the same level of completed schooling are highly diverse with respect to the quality of schooling they experienced. Using a unique new data resource, we ask how secondary school quality is associated with cognitive functioning at age ∼60—net of school quantity and confounders.MethodWe use data from the High School and Beyond cohort—a large, diverse, nationally representative probability sample of American high school sophomores and seniors in 1980. HSB panelists were interviewed many times between 1980 and 2022, with high rates of participation; HSB has been supplemented with administrative data (e.g., school transcripts, mortality records) and the 2021/2022 follow‐up gathered fluid biomarkers useful for studying markers of risk for cognitive impairment. Measures from the 1980s provide extraordinarily detailed information about educational contexts, opportunities, and outcomes. We measure secondary school quality using value‐added models, which estimate each school’s contribution to student academic achievement conditional on students’ baseline achievement and family socioeconomic background. Our analyses assess the degree to which attending a high value‐added secondary school is associated with better cognitive outcomes at age ∼60 net of educational attainment. Our main dependent variables—assessed in 2021/2022—include self‐reported memory complaints and self‐reported conditions of relevance to risk of cognitive impairment (e.g., diabetes, hypertension).ResultNet of educational attainment and demographic factors, we find that individuals who attended a high value‐added secondary school experience fewer cognitive complaints (as assessed using the AD8). They are also less likely to have been diagnosed with diabetes or hypertension. In the next few months, we will have assessed heterogeneity in results across demographic and socioeconomic groups.ConclusionThe quality of the schooling that people experience matters for later‐life cognitive outcomes even net of the quantity of schooling they complete.
Survival and pharmacotherapy delay in young onset Alzheimer’s disease
Authors: Stojkovic Tanja , Stojmenovic Gorana Mandic , Šarčević Maksim , Stefanova Elka , Obradovic Dragan , Kostic Vladimir S 
Published: December 2023

AbstractIntroductionSpecific feature of young onset Alzheimer’s disease (YOAD) patients is that their diagnosis and therefore their treatment is usually delayed. Firstly, they present atypically, secondly, they have a higher cognitive reserve and symptoms are later recognized and finally at that age, the family, and the patients themselves, do not think about the possibility of dementia, which prolongs the time period to seeking medical help (on average 2‐3 years).AimTo examine the association of survival in YOAD with time elapsed from the onset of symptoms to the initiation of pharmacotherapy.Material and methodsThis is a retrospective study on 135 patients from Memory Center of Neurology Clinic, Clinical Center of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. do 01.04.2017. The association of survival with time elapsed from onset of symptoms to initiation of therapy was examined by Kaplan Meier survival analysis with log rank test.ResultsFrom 2012, when the registry was created, till 2019, 89 out of 135 included patients died. Kaplan Meier survival analysis showed that patients with lower MMSE score (from 15 points and below) and who could not dress themselves or perform personal hygiene at the time of inclusion in our registry have a shorter expected survival than those who had MMSE 16 and above (p = 0.019) and who functioned independently in terms of these activities of daily living (p = 0.041 for dressing and p = 0.018 for performing personal hygiene). Patients in whom the introduction of therapy was delayed 3 or less years survived for a year longer than patients in whom therapy was introduced 4 or more years after the onset of dementia symptoms (p = 0.004).ConclusionOur study clearly showed that certain clinical parameters (degree of cognitive and functional damage at the time of therapy introduction), but also delay in introducing therapy from symptoms onset determine the length of survival in YOAD.
Cataloging the role of brain cell types on suppressing the effect of APOE ε4 on Alzheimer’s disease risk
Authors: Ma Yiyi , Chen Kevin W , Fujita Masashi , Yu Lei , Menon Vilas , Schneider Julie A , Bennett David A. A , De Jager Philip L 
Published: December 2023

AbstractBackgroundWe have previously developed a research pipeline to identify potential suppressors of APOE ε4 risk on Alzheimer’s disease (AD), and we have successfully identified an epigenomic factor which may act as ε4 suppressor. However, it is unknown which cell type is more important to contain this ε4 suppressor on the transcriptome level.MethodWe included single‐nucleus RNA sequencing (snRNAseq) data of the postmortem human brains from 424 subjects of the Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). Based on this snRNAseq data, we have derived the estimate of the percentage and transcriptomic profiles of different types of brain cells including excitatory neurons, inhibitory neurons, endothelial cells, pericytes, oligodendrocytes, astrocytes, and microglia. Besides the main cell types, we further derived the estimates on the cell subtype level. With the generalized linear regression model, the final prioritized cell types and genes should fulfill two criteria: (1) be associated with AD pathologies (pTAU and neuritic plaque) in all subjects; and (2) reduce the effect of ε4 on AD susceptibility.ResultBased on the transcriptome‐wide association study (TWAS) of the main brain cells, almost all the brain cell types contain at least one genome‐wide significant (P≤6.5×10−6) gene which can act as the APOE ε4 suppressor on AD risk. However, the subtype cellular analysis suggested that neuronal subtypes are more important than the other cell types because almost all the subtypes of the excitatory neuronal cells (15 out of 16) contain the genome‐wide significant ε4 suppressor while this percentage for microglia is only 25% (4 out of 16). The pathway analysis suggested that the top 179 genes expressed in the neuronal cells were involved in the trans‐synaptic signaling by trans‐synaptic complex and synapse assembly.ConclusionOn the transcription level, APOE ε4 suppressor effects are present across a variety of different brain cell types but enriched in neurons where synapse pathways appear to play a predominant role in suppressing the effect of APOE ε4.