bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s disease linked amyloid beta 1‐42 exerts product feedback inhibition on gamma‐secretase impairing downstream signaling cascades
Authors: Zoltowska Katarzyna Marta , Das Utpal , Lismont Sam , Enzlein Thomas , Maesako Masato , Houser Mei CQ , Franco María Luisa , Moreira Diana Gomes , Karachentsev Dmitry , Becker Ann , Hopf Carsten , Vilar Marçal , Berezovska Oksana , Mobley William C , Chávez‐Gutiérrez Lucía 
Published: December 2023

AbstractBackgroundΓ‐secretases are proteolytic switches at the membrane regulating multiple signaling cascades. Their dysfunction, resulting in enhanced generation of longer amyloid β (Aβ) peptides from the amyloid precursor protein (APP), leads to neurodegeneration in the context of Alzheimer’s disease (AD), while their inhibition causes neurodegenerative phenotypes in mice and cognitive worsening in AD patients treated with γ‐secretase inhibitors. The accumulation of Aβ in the brain is the earliest pathological hallmark of AD. Based on the proven affinity of Aβ peptides for γ‐secretases, we hypothesized that elevations in Aβ levels would promote an inhibitory‐feedback mechanism on γ‐secretases and impair downstream cell signaling events.MethodWe conducted rigorous kinetic analyses of γ‐secretase activity in the presence of a series of Aβ and p3 peptides, by quantifying the levels of intracellular domains generated from different γ‐secretase substrates in cell‐free assays. In addition, we determined the effects of these peptides on endogenous γ‐secretase activity in living neurons, using a ratiometric FRET‐based reporter and western blot analysis of the levels of immediate γ‐secretase substrates. Furthermore, we assessed the impact of Aβ and p3 peptides on γ‐secretase‐mediated, p75‐ and TrkA‐dependent downstream signaling via immunostaining for an apoptotic marker: cleaved caspase 3. Finally, we evaluated the impact of Aβ peptides on APP processing in synaptosome fractions derived from mouse brains.ResultOur analyses showed that human Aβ42 inhibited γ‐secretase activity and accordingly caused accumulation of unprocessed γ‐secretase substrates in neuronal cells, i.e. CTFs of APP, p75 and pan‐cadherin. Remarkably, neither murine Aβ42 nor human p3 (17‐42) peptides exerted the inhibition. In TrkA signaling deficient PC12 cells and basal forebrain cholinergic neurons, Aβ1‐42‐mediated inhibition of γ‐secretase led to the accumulation of unprocessed p75‐CTFs and potentiated p75‐dependent cell death, mimicking the effects of γ‐secretase inhibitors.ConclusionWe demonstrate that the pathologically relevant human Aβ1‐42 exerts product feedback inhibition on γ‐secretases, leading to dysregulation of downstream cellular signaling. These findings provide a novel conceptual framework for investigations of Aβ toxicity in the context of γ‐secretase‐dependent homeostatic signaling and raise the possibility that Aβ42‐mediated inactivation of these enzymes contributes to AD development.
Investigating the role of mitochondrial calcium uniporter beta in Alzheimer’s disease
Authors: Jadiya Pooja , Tomar Dhanendra , Elrod John W 
Published: December 2023

AbstractBackgroundWe have recently shown that mitochondrial calcium (mCa2+) overload significantly contributes to the development of Alzheimer’s disease (AD). We found that either genetic inhibition of the neuronal mitochondrial calcium uniporter (MCU, the primary route for mCa2+ influx)1 or enhancement of mitochondrial Na+/Ca2+ exchanger (NCLX, the primary route for mCa2+ efflux)2 in the AD mouse model reduces AD‐associated phenotype and mitochondrial permeability transition pore (MPTP)‐induced cell death. However, blocking either the mCa2+ influx or enhancing mCa2+ efflux can also shut down the bioenergetics. Thus, it is vital to find a regulator of mCa2+ homeostasis that will positively impact Ca2+‐dependent physiological functions.MethodsTo define the new molecular regulatory mechanism to limit mCa2+ overload in AD that will maintain bioenergetics and prevent cell death, we have examined the role of Mitochondrial Calcium Uniporter Beta (MCUB), a paralog of MCU that acts as a negative regulator of mCa2+ uptake3. This study used AD patient samples, mice, and cell lines to examine MCUB expression. A neuroblastoma cell line stably expressing the human Swedish mutant amyloid precursor protein (N2a/APPswe) with adenovirus encoding MCUB was examined for mitochondrial alterations in: Ca2+ handling, ROS generation, permeability transition pore activation, oxidative phosphorylation (OxPHOS) and cell death.Results5xFAD mice and human AD brain samples displayed significant reductions in the expression of MCUB. Studies performed in N2a/APPswe neurons discovered that mCa2 handling, redox, and bioenergetics was severely impaired in AD cells. Rescue of MCUB via adenoviral expression enhanced the clearance of pathogenic mCa2+, enhanced OxPHOS, and prevented ROS and cell death.ConclusionsOur data suggest that MCUB modulation has the therapeutic potential to preserve bioenergetics and limit cell death in AD. This project will further utilize neuronal‐specific knockouts and overexpression of MCUB to increase or decrease mCa2+ uptake, respectively, in 5xFAD mouse models and will explore whether and how MCUB‐mediated changes in uptake are able to preserve metabolism, mCa2+ dynamics, and AD‐phenotype in vivo.
Prevalence of Depressive Symptoms in the Whole Spectrum of Cognitive Aging: Findings from the HELIAD Community Study
Authors: Georgiou Eliza (Eleni‐ Zacharoula) , Politis Antonis , Yannakoulia Mary , Dardiotis Efthimios , Hadjigeorgiou Georgios M. , Kosmidis Mary , Sakka Paraskevi , Economou Polychronis , Scarmeas Nikolaos , Alexopoulos Panagiotis 
Published: December 2023

AbstractBackgroundDepressive symptoms embody a risk factor for developing age‐related cognitive impairment, while they belong to the most common non‐cognitive symptoms of dementia. The conundrum of the prevalence of depressive symptoms in older adults in the Mediterranean region, but also worldwide is vividly reflected in reported prevalence rates ranging from 7.7% in a study from Malaysia and Australia to 81.1% in India. The present study aimed to shed light on the prevalence of mild, moderate and severe depressive symptoms in the entire spectrum of cognitive aging based on a cohort of randomly selected older adults from municipal rosters of two locations in Attica and central Greece.MethodsBased on a thorough neurological and neuropsychological assessment, the diagnoses of mild cognitive impairment, Alzheimer’s dementia (AD) or dementia caused by other diseases (non‐AD) were established in participants of the Hellenic Epidemiological Longitudinal Investigation of Aging and Diet (HELIAD). The presence of depressive symptoms was tapped with the 15‐item Geriatric Depression Scale (GDS). Scores between 0‐4 point to the absence of depression, while scores between 5‐8, 9‐11, 12‐15 are compatible with mild, moderate and severe depressive symptoms, respectively. Statistical analyses were based on Pearson’s Chi‐squared test and pairwise proportions tests.ResultsThe prevalence of depressive symptoms in the total sample (n = 1937 participants; mean age 73,84 SD: 5,427, females: 1148) was 19.5% (mild 13.1%, moderate 3.8%, severe 2.5%). The prevalence of depressive symptoms in older adults without cognitive impairment was 18%, in patients with MCI 27%, in AD 25% and in non‐AD 23.5%. The differences in the distribution of depressive symptoms of different severity across the four groups reached statistical significance (chi‐squared = 28.957, df = 9, p‐value<0.001). The prevalence of moderate to severe depressive symptoms reached its maximum in AD (11.3%) and its lowest in people without cognitive impairment (5.4%).ConclusionsAlmost one out of five older adults suffered from depressive symptoms, with the prevalence and severity increasing significantly in cases of cognitively impaired individuals. These observations highlight the urgent need for raising awareness regarding the presence of depressive symptoms in older adults and improving primary, secondary and tertiary preventive strategies.
Evidence of distinct subjective cognitive decline profiles in a community sample
Authors: Jacova Claudia , Splonskowski Moriah , Smith Samantha , Gehling Jacklyn , Dhaliwal Ravneet 
Published: December 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) refers to a self‐perceived decline in cognitive ability despite normal performance on objective tests. SCD has been conceptualized as a marker of preclinical Alzheimer’s disease (AD) but research has uncovered considerable heterogeneity in symptoms and outcomes. Therefore, it is likely that SCD encompasses distinct subtypes, similarly to Mild Cognitive Impairment (MCI). Here we sought to identify and characterize subgroups based on patterns of subjective cognitive symptoms.MethodsCommunity‐dwelling participants aged ≥50 years (n = 483), located within the United States, were recruited via a crowdsourcing website, and completed a survey consisting of the following: SCD Questionnaire‐MyCog, PROMIS depression scale, and demographic questions. The SCD‐Q includes 24 items assessing self‐perceived recent decline on memory, language, and executive functioning tasks with a yes or no format. Two‐step cluster analysis using AIC was performed on all SCD‐Q items.ResultsThe analysis yielded a 3‐cluster solution with fair cohesion and separation (silhouette measure = 0.46). Cluster 1 (No Subjective Decline) included 36% of participants reporting no decline except for sporadic endorsement (≤2%) on a few memory tasks. Cluster 2 (Mild Subjective Decline) consisted of 42% of participants who frequently (≤50%) endorsed decline on select memory and language tasks, and less frequently on executive functioning tasks (≤25%). Cluster 3 (Moderate Subjective Decline) included 22% of participants who almost unanimously (≥80%) reported decline on a wide range of memory and language tasks, and frequently (≥60%) on executive functioning tasks. Clusters differed on total SCD‐Q scores (1<2<3, M = 0.1, 3.5, 13.7), percent below the SCD cutoff of 7/24 (1 and 2<3, 0%, 8.4%, 100%), depression score (1<2<3, M = 10.9, 13.0, 16.7), gender (percent women 1<2 and 3, 58.7%, 71.0%, 704%) and AD family history (percent with history 1<2 and 3, 20%, 29%, 34.9%) but not on age.ConclusionWe identified three distinct subgroups in our community sample, defined by escalating subjective symptom burden, growing involvement of language and executive functioning domains and increasing prevalence of AD risk factors (female gender/AD family history). All Moderate‐Subjective‐Decline subgroup members but none/very few of the others, scored above the published SCD cut‐off. Longitudinal outcomes are needed to establish subgroup validity.
Interim Analysis Results of Buntanetap in Phase 3 Clinical Studies in Alzheimer’s and Parkinson’s Disease
Authors: Fang Cheng , Gaines Melissa , Damiano Eve , Nagy Anne‐Marie , Ng David , Maccecchini Maria L. 
Published: December 2023

AbstractBackgroundOverexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of neurotoxic aggregating proteins ‐ amyloid precursor protein, tau, alpha‐synuclein etc., buntanetap restores axonal transport, lowers inflammation, and protects nerve cells from dying. In phase 2a studies, buntanetap showed efficacy in two double‐blind, placebo controlled clinical studies in both AD and PD patients. These encouraging data support our further development of buntanetap into phase 3 as a potential treatment for both AD and PD.MethodWe started two double‐blind, placebo‐controlled phase 3 studies to further test buntanetap’s efficacy and safety in PD and AD patients.ResultFor the PD study, patients are dosed with either 10mg, 20mg buntanetap or placebo QD. A total of 450 early PD patients are being recruited for a 6‐month treatment. Primary endpoint is MDS‐UPDRS 2 and 3. We will present the study design and the data from the interim analysis, when 30% of the patients have been treated for 2 months.For the AD study, patients are dosed with three doses of buntanetap (placebo, 7.5, 15 and 30 mg QD). A total of 320 mild to moderate AD patients are being recruited for a 3‐month treatment. Primary endpoints are ADAS‐Cog11 and ADCS‐CGIC. We will present the study design and the data from the interim analysis, when 30% of the patients have been treated for 6 weeks.ConclusionOur phase2 data support that buntanetap is safe, well‐tolerated, and efficacious in both AD and PD population. The interim analysis will ensure we have the right sample size to test buntanetap’s efficacy in treating AD and PD.
Apheleia‐001: A novel prescreening study designed to enrich and accelerate Alzheimer’s disease clinical trials by efficiently identifying trial‐eligible participants determined to have a high probability of study inclusion, including amyloid positivity
Authors: Smith Katy , Bork Jason , Jolkovski Allison , Schillinger Rona , Batchuluun Dawn , Ng Amanda , Brown Christina M. , Kraus Lori , Matilla Inmaculada , Bernard Emmanuel G. , Hollingshead Sarah , Florian Hana , Yu Lynch Shau , Lee Christa , Bannon Anthony W. , McGeeney Danielle , Schwartzbard Julie 
Published: December 2023

AbstractBackgroundThe clinical development ecosystem cannot support the current demand for participants needed in Alzheimer’s disease clinical trials which is further disrupted by: 1) high screen fail rates (≥80‐90%); 2) lengthy screening visits constraining site resources; 3) unnecessary participant burden. The field demands a unique approach to optimize site resource utilization, participant/caregiver time, and overall development costs. Apheleia‐001 will identify patients with a high probability of meeting study‐specific eligibility criteria for a therapeutic Alzheimer’s disease clinical trial.MethodApheleia‐001 prescreens potential participants using paper and digital cognitive tests, demographic and medical information, and blood biomarkers. Apheleia‐001 procedures are completed in <2 hours and they minimize both site and participant burden. Participants eligible through Apheleia‐001 are referred to an early phase therapeutic AD trial.Apheleia‐001 will enroll ∼1600 participants across 28 clinical trial sites in both North America and Europe with an expected 24‐month enrollment period.ResultApheleia‐001 is currently open for enrollment and data is being collected. As of 18Jan2023, Apheleia‐001 has completed 300+ prescreens and has identified over 60 trial eligible participants. Of the 300+ prescreened, 35% have identified as an underrepresented minority (URM). It is projected that the Apheleia pre‐screener will ultimately reduce the screen failure rate of a specific sponsor clinical trial by up to 50%.ConclusionApheleia‐001 is projected to accelerate clinical trial enrollment and reduce the cost of an early phase therapeutic AD clinical trial. With this approach, initial screen fails will be done more efficiently (e.g., reduced speed and cost) compared to traditional clinical trial approaches. In addition, Apheleia‐001 optimizes sites for randomizations, therefore improving site resource utilization and finances. If scaled, Apheleia‐001 could significantly impact recruitment timelines across multiple studies, reducing the cost and burden of clinical trial recruitment and execution for sponsors, sites, and participants.
Advanced Diffusion MRI of White Matter in Aging and AD
Authors: Benitez Andreana 
Published: December 2023

AbstractChanges in brain white matter occur in normal aging and prior to the onset of cognitive impairment. We have shown that advanced diffusion MRI and biophysical modeling yield sensitive and specific metrics that distinguish age‐related (e.g. myelin remodeling) from amyloid‐related pathological processes (e.g. myelin repair) in the preclinical stage. In this presentation we provide an update on our ongoing observational longitudinal study to determine the extent to which these metrics can serve as predictive biomarkers of incident cognitive impairment. Cognitively unimpaired older adults completed brain MRI (including Diffusional Kurtosis Imaging) and standard clinical procedures (NACC UDS v3) at baseline and ∼2 years later, with 91.2% retention and 13.1% incident MCI (CDR = 0.5) at follow‐up. We found that in participants with preclinical AD, late‐myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. In the next 5 years of funding, we will expand our cohort in size and representativeness, incorporate complementary MRI biomarkers of myelin/gliosis (i.e. myelin water imaging [ViSTa] and 1H‐MRS of myo‐inositol and NAA) to test our inferences, and further develop diffusion MRI‐based biophysical modeling techniques (i.e. Fiber Ball Imaging‐based white matter modeling). Expected outcomes from this work include clinically feasible MRI biomarkers with which to empirically test a proposed conceptual model of white matter‐related changes in aging and AD, thereby providing translational support for trials of myelin/glia‐focused therapies which are grossly underexplored for asymptomatic AD. Our goal is to have an impact on the evolving conceptualization of how aging leads to AD and, critically, to illuminate novel mechanisms by which AD can be prevented or treated.
Saccadic latency differences in preclinical Alzheimer’s disease
Authors: Adams Sara W , Tavakoli Amir‐Vala , Molloy Cathleen , Wu Daw‐An , Hung Shao‐Min (Sean) , Minazad Yafa , Kloner Robert A , Shimojo Shinsuke , Arakaki Xianghong 
Published: December 2023

AbstractBackgroundPrevious studies indicate that individuals with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) have higher latencies on anti‐saccade tasks than healthy controls. We investigated whether this difference in latency appears even earlier, in cognitively healthy (CH) individuals at high risk of cognitive decline to MCI or AD and whether subliminal priming or task switching further impacted this latency difference.MethodWe studied CH participants whose cerebrospinal fluid (CSF) amyloid / tau ratio was normal (≥2.7132, low risk) or pathological (<2.7132, high risk) (PMID: 24260210). The testing paradigm included three blocks: (1) all saccades, (2) all anti‐saccades, and (3) patterned task switching with two saccades followed by two anti‐saccades. Trials began with a green (saccade) or red (anti‐saccade) cue appearing at a central fixation point. Then, a masked subliminal cue appeared on the right or left, followed by a target congruent or incongruent with the subliminal prime location. Trials ended 1000 ms after the participant first looked directly at the target for saccade trials or away from the target for anti‐saccade trials.ResultPreliminary results (n = 19, 3 high risk) using a 3‐way mixed ANOVA (d.f. = 3484) indicate that high risk participants perform slower across all conditions (F = 26.36, p <<< 0.001). This effect is especially pronounced when task switching (F = 3.41, p < 0.05), with high risk participants performing 70.9 ms slower in the task switching block (Bonferroni‐corrected p = 6.62×10−6, 95% CI = [29.8, 112]). During the block with all anti‐saccades, however, the difference in performance is not significant (Bonferroni‐corrected p = 0.78), unlike the effects previously observed in individuals with MCI or AD. Additionally, subliminal cues do not show a significant overall effect on behavioral data (F = 2.32, p = 0.13).ConclusionPilot results indicate that latency differences when task switching between saccade and anti‐saccade tasks exist in CH people at high risk of cognitive decline. Because eye tracking tasks are much less invasive and expensive than spinal taps, they could provide a potential screening tool for those at risk of cognitive decline.
Deep Learning‐based Integration of neuroimaging and genetic data for classification of Alzheimer’s Disease
Authors: Jo Taeho , Nho Kwangsik , Risacher Shannon L , Saykin Andrew J. 
Published: December 2023

AbstractBackgroundThe progression of Alzheimer’s disease(AD) is intricately linked to the accumulation of abnormal tau protein. Identifying single nucleotide polymorphisms(SNPs) associated with AD is crucial as it provides a deeper understanding of the underlying mechanisms of AD pathogenesis. Our goal is to develop a novel deep learning‐based approach that integrates neuroimage and genetic data to identify key features of tau protein accumulation in AD and identify potential genetic markers associated with the disease.MethodTo identify the morphological endophenotypes of tau deposition in tau‐PET images, we applied a deep learning framework utilizing convolutional neural networks(CNNs) and Layer‐wise Relevance Propagation(LRP) to data from a total of 300 ADNI participants(N = 300; 66 CN, 66 AD, 97 EMCI, and 71 LMCI) with tau PET scans(Fig.1A). This approach was used to classify AD in cognitively normal elderly individuals(CN) and to identify AD‐related morphological phenotypes of tau deposition. To identify informative SNPs associated with AD, we employed the Sliding Window Association Test(SWAT) method to GWAS data from ADNI (N = 981; 650 CN, 331 AD)(Fig.1B). We used stacking ensemble to integrate results from both analyses for AD classification.ResultThe proposed framework on tau PET identified the AD‐related morphological phenotype of tau deposition in tau‐PET images and yielded a classification accuracy of 90.8% as determined by 5‐fold cross‐validation. The LRP results were consistent with those from the traditional voxel‐wise analysis in SPM12, showing significant focal AD‐associated regional tau deposition in the bilateral temporal lobes, including the entorhinal cortex. The SWAT method effectively identified known APOE regions as the most critical genetic loci for AD and revealed the association of previously unreported SNPs with an AUC of 0.82.ConclusionThis study developed a deep learning framework that uses CNNs and LRP to identify the morphological phenotypes of tau deposition in tau‐PET images for classifying AD. Additionally, the study examined the use of the SWAT method for identifying SNPs associated with AD. Combining these two deep learning frameworks resulted in a better classification model. The proposed method offers a promising approach for understanding the genetic factors that contribute to the development and progression of AD.