bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lemborexant, a Dual Orexin Receptor Antagonist, ameliorates Tau‐mediated Sleep Loss and Neurodegeneration
Authors: Parhizkar Samira , Chen Wei , Bao Xin , Gent Grace , Rensing Nicholas , Tycksen Eric , Franke Emily , Manis Melissa , Bosch Megan E. , Lee Choonghee , Serrano Javier R. , Landsness Eric , Wong Michael , Holtzman David M. 
Published: January 2025

AbstractBackgroundSleep disturbances are associated with the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD) and primary tauopathies. We have previously shown that APOE4, the strongest genetic risk factor for AD, directly influences the severity of key pathological hallmarks of neurodegeneration including tau deposition, microglial reactivity and brain atrophy. Sleep loss influences tau accumulation and microglial reactivity in both mice and humans, suggesting that sleep loss may contribute to neurodegeneration not only by influencing protein aggregation, but also through an immune mechanism. Therefore, we aimed to investigate whether promoting sleep as a therapeutic strategy could mitigate the damaging effects of chronic microglial reactivity that contribute to tau‐mediated neurodegeneration.MethodWe used lemborexant, a dual orexin receptor antagonist that promotes sleep in both mice and humans. We orally gavaged P301S/APOE4 mice, a model of tauopathy with brain atrophy, and non‐tau depositing APOE4 knock‐in mice daily with 30mg/kg lemborexant or vehicle (n = 16‐20/genotype and treatment group) at one‐hour post‐dark onset. Mice were treated from 7.5 months (M), when tau‐mediated neuroinflammation is observed without overt neuronal loss in P301S/APOE4 mice, until 9.5M.ResultIn P301S/APOE4 mice, lemborexant not only improved tau‐associated sleep loss, specifically non‐rapid eye movement sleep, but also dramatically reduced pathological tau deposition. Antagonizing orexin receptor signaling improved tau‐mediated neurodegeneration noted by a decrease in plasma neurofilament light chain levels, as well as brain atrophy compared to vehicle‐treated P301S/APOE4 controls. In support of these findings, lemborexant‐treated P301S/APOE4 mice displayed reduced microglial reactivity of disease‐associated microglia including immunostaining for CD68 and Clec7a compared to controls. Both astroglial and microglial APOE co‐localization were significantly reduced in lemborexant‐treated P301S/APOE4 mice, the latter of which is more commonly observed during elevated inflammatory and damaging conditions. Unbiased transcriptome profiling provided potential mechanistic insights into functional pathways influenced by lemborexant in P301S/APOE4 mice, including those regulating synaptic activity such as Slc17a7, Shank1, Shank2, which was further accompanied by reduced pre‐ and post‐synaptic loss.ConclusionOur study provides novel therapeutic evidence that antagonizing the orexin signaling pathway using lemborexant is neuroprotective by restoring sleep deficits as well as limiting tau‐mediated neuronal and synaptic damage, potentially by suppressing chronic neuroinflammation.
The impact of knowledge of β‐amyloid PET scan result on cognitive test performance: results of the REVEAL‐SCAN study
Authors: Karlawish Jason , Harkins Kristin , Pal Subhamoy , Welsh‐Bohmer Kathleen A. , Roberts J. Scott , Gregoire Allyson , Reader Jonathan M , Bakulski Kelly M. , Green Robert C. 
Published: January 2025

AbstractBackgroundThe impact of knowledge of β‐amyloid status on cognitively unimpaired persons' cognitive test performance is unknown.MethodCognitively unimpaired adults aged 65‐80 with a first‐degree relative with AD received a dementia risk estimate and were randomly assigned to disclosure (D+) or non‐disclosure (D‐) of their β‐amyloid PET scan result. At 6 weeks and 6 months post‐disclosure, participants completed the ADCS‐PACC, a composite of Free and Cued Selective Reminding (free portion), Logical Memory IIa test, Digit‐Symbol Substitution, and MMSE. Scores from each test are standardized to a Z‐score metric and a composite score calculated by summing the standardized Z‐scores.Result315 participants were randomized (84 elevated (41 A+D+/43 A+D‐)) and 231 not elevated (118 A‐D+, 113 A‐D‐)). After adjusting for baseline PACC scores, analyses compared PACC scores between (1.) A+D+ and A+D‐ and (2.) A‐D+ and A‐D‐ and stratified by race. A+ participants who learned their result (D+) had lower mean follow‐up PACC scores than participants who did not learn their β‐amyloid PET scan result (D‐) at 6 weeks (β = ‐0.89, 95% CI: ‐1.65, ‐0.13, p = 0.023) but not at 6 months post‐disclosure (β = ‐0.50, 95% CI ‐1.28, 0.27, p = .21). Mean follow‐up PACC scores did not differ between A‐ who did or did not learn their result at both 6 weeks (β ‐0.02, 95% CI: ‐0.42, 0.37, p = 0.91) and 6 months post‐disclosure (β ‐0.15, 95% CI ‐0.54, 0.25, p = .47). Analyses stratified by race showed Black/African American A+D+ had lower scores than A+D‐ at 6 weeks (β ‐2.01, 95% CI: ‐3.57, ‐0.45, p = 0.01) and 6 months post‐disclosure (β ‐1.63, 95% CI ‐3.19, ‐0.06, p = .04). Disclosure had no impact on scores of nonblack participants with elevated amyloid and the scores of any of not elevated participant groups.ConclusionKnowledge of an elevated amyloid result reduced cognitively unimpaired persons PACC scores. A greater impact was observed in Black/African American participants’ test performance compared to non‐Black participants. In contrast, knowledge of not‐elevated amyloid showed no impact on test performance in any of the groups. Clinical trials should consider the potential impact of AD biomarker knowledge on cognitive outcomes.
Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response
Authors: Puangmalai Nicha , Bhatt Nemil , Bittar Alice , Jerez Cynthia , Shchankin Nikita , Kayed Rakez 
Published: January 2025

AbstractBackgroundThe misfolding and aggregation of the tau protein into neurofibrillary tangles constitute a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain‐derived tau polymorphs (TBI‐BDTPs) remain elusive.MethodWe explored whether TBI‐BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild‐type mice were exposed to TBI‐BDTPs from sham, single‐blast (SB), or repeated‐blast (RB) conditions, and their memory function was assessed through behavioral assays at 2‐ and 8‐month post‐injection.ResultOur findings revealed that RB‐BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB‐BDTP‐exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers.ConclusionCollectively, our results shed light on the intricate mechanisms underlying TBI‐BDTP‐induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.
Evaluating the repurposing potential of the anti‐depressant Agomelatine for Alzheimer’s Disease
Authors: Terry Grace A , Merav Michelle , Rockwell Patricia , Serrano Peter , Xie Lei , Figueiredo‐Pereira Maria 
Published: January 2025

AbstractBackgroundThe limited treatment options for Alzheimer’s emphasizes the need to explore novel drug targets and bring new therapeutics to market. Drug repurposing is an efficient route to bring a safe and effective treatment to the clinic. Agomelatine (AGO) was identified by a high‐throughput drug screening algorithm as having mechanistic potential to treat Alzheimer’s. AGO is used as an atypical antidepressant and works as an MT1/MT2 receptor agonist and a 5HT2C serotonin receptor antagonist.MethodThe TgF344‐AD rat model was used to test AGO’s potential to reduce cognitive deficits and neuropathology. The TgF344‐AD rat model expresses human mutant “Swedish” amyloid‐precursor protein (APPsw) and a Δ exon 9 presenilin 1 (PS1ΔE9). As it presents with age‐dependent progressive Alzheimer’s pathology and cognitive decline it is an ideal model for investigating AGO’s effect on the robust presentation of Alzheimer’s. Treatment with AGO at ∼10 mg/kg body weight/day began at 5 months of age (pre‐pathology) and continued until 11 months of age when cognitive testing (active place avoidance task) and tissue collection occurred. Immunohistochemistry was used to evaluate amyloid beta plaque burden. Bulk RNAsequencing was conducted to investigate AGO’s effect on gene expression.ResultAGO treated female TgF344‐AD rats showed reduced cognitive deficits with an increased latency to first entrance in aPAT testing compared to non‐treated transgenic littermates. There were no differences between the cognitive performance of AGO treated and untreated male TgF344‐AD rats. Interestingly, this reduced cognitive deficit did not correlate with decreased amyloid beta pathology. RNA sequencing analysis showed that DDIT3 (CHOP) mRNA levels were downregulated in the AGO treated compared to untreated TgF344‐AD females. DDIT3 is a pro‐apoptotic transcription factor.ConclusionAgomelatine showed a female only reduction in cognitive deficits, which did not correlate with a decrease in amyloid beta plaque deposition. This finding paired with the decrease of DDIT3 gene expression suggests that Agomelatine has a neuroprotective mechanism that is independent of amyloid burden. Future studies will analyze neuronal loss via NeuN staining to determine if AGO prevents neuronal loss, thus supporting its ability to mitigate cognitive deficits in the TgF344‐AD rat model.
Precision Phenotyping of Mild Behavioral Impairment and the Early Detection of Dementia
Authors: Vahia Ipsit V 
Published: January 2025

AbstractThere is growing recognition of the importance of changes in behavior as an early clinical marker of the onset of Alzheimer’s disease. Behavior symptoms may precede the onset of cognitive symptoms by as many as three years. However, these symptoms are often confused for primary psychiatric pathology and there is an urgent need for markers that can help quantify behaviors with the eventual goal of helping distinguish behavior changes related to psychiatric pathology from behavior changes related to the onset of dementia.This talk will summarize the state of knowledge on mild behavioral impairment, and present data from three studies demonstrating how a range of sensor‐derived biomarkers can quantify subtle changes in behavior with precision. The talk will include case presentations around detection of apathy, agitation, pacing. It will also demonstrate how these markers can identify response to medications, which may be one way of distinguishing the presence of psychiatric versus neurodegenerative pathology.Finally, the talk will present data from ongoing clinical trials around how these biomarkers may translate into research and eventually practice.
A human induced pluripotent stem cell model of Alzheimer’s Disease‐associated fractalkine receptor polymorphism to assess AD‐related microglial dysfunction
Authors: Tutrow Kaylee , Harkin Jade , Hernandez Melody , Huang Kang‐Chieh S , Bissel Stephanie J , Puntambekar Shweta S , Lamb Bruce T. , Meyer Jason S. 
Published: January 2025

AbstractBackgroundDysfunctional microglial activity has recently been identified as a potential mechanism leading to accumulation of amyloid beta and pTau and subsequent neurodegeneration in Alzheimer’s Disease. The CX3CR1/fractalkine axis serves as a mechanism for bi‐directional communication between microglia and neurons, respectively, to promote a resting, anti‐inflammatory state in microglia. Previous studies have demonstrated that deficiency in CX3CR1 signaling leads microglia to a more pro‐inflammatory phenotype, phagocytic deficits, and increased susceptibility of neurons to cell death. Additionally, the CX3CR1‐V249I polymorphism was recently identified as a potential risk allele for Alzheimer’s Disease with worsened Braak staging in post‐mortem Alzheimer’s patients. However, the role of fractalkine dysfunction in human cells and the mechanisms by which microglia with the CX3CR1‐V249I SNP contribute to neurodegeneration remain unclear.MethodTo address this shortcoming, we utilized human induced pluripotent stem cells and CRISPR/Cas9 gene editing technology to elucidate the effects of the CX3CR1‐V249I polymorphism on human microglia‐like cells (hMGLs) compared to an isogenic control cell line. Isogenic control cells alongside both heterozygous and homozygous CX3CR1 V249I cell lines were differentiated in parallel to yield enriched populations of hMGLs. Resulting hMGLs were then assessed for uptake of amyloid beta 1‐42 using flow cytometry, cell death in response to cytokine starvation, changes in proliferation, and finally alterations to migratory behavior using a microfluidic chamber.ResultWe demonstrate the effective differentiation of hMGLS from both isogenic control and CX3CR1‐V249I backgrounds, which express characteristic microglial markers and are functionally phagocytic. Microglia bearing the homozygous CX3CR1‐V249I allele, but not heterozygous cells, demonstrated decreased uptake of amyloid beta in vitro compared to isogenic controls. Additionally, homozygous V249I microglia demonstrated increased stress‐induced cell death, as well as altered proliferation and decreased migratory capability.ConclusionThese findings suggest that the CX3CR1‐V249I polymorphism may cause a dysfunctional microglia phenotype that may contribute to neuronal dysfunction and death. Ongoing work will expand upon the transcriptome and secretome profile of CX3CR1‐V249I microglia and elucidate how this gene variant contributes to Alzheimer’s Disease‐related neurodegeneration.
The role of clusterin and the variant rs11136000_T throughout the spectrum of Alzheimer’s disease
Authors: Dauar Marina Tedeschi , Picard Cynthia , Labonte Anne , Villeneuve Sylvia , Poirier Judes , Group PREVENT‐AD Research 
Published: January 2025

AbstractBackgroundClusterin is a major cholesterol transporter in the central nervous system (CNS) and different SNPs in the CLU gene have been associated with Alzheimer’s disease (AD) risk. The rs11136000_T variant in the CLU gene has been shown to decrease the risk of AD. In this work, we investigate the role of the CLU rs11136000_T protective variant and of the clusterin protein throughout different phases of the AD spectrum.MethodLevels of clusterin, Tau, phospho(181) Tau (p‐tau), and Aß were measured using ELISA and synaptic proteins were measured using immunoprecipitation followed by mass spectroscopy in the CSF of cognitively unimpaired individuals. Flortaucipir PET was used to measure tau deposition and 18F‐NAV4694 PET was used to measure amyloid burden in the same subjects. ELISA was used to measure clusterin levels and RT‐PCR was used to measure mRNA levels in cortical areas of autopsied‐confirmed controls and AD subjects. Genotype was performed using Illumina Infinium Omni2.5M‐8 microarray.ResultThere was no effect of the protective genotype on the levels of PET biomarkers, CSF biomarkers or synaptic proteins in cognitively unimpaired individuals. CSF clusterin levels were positively associated with Aß (p = 0.021), total‐tau (p<0.001), p‐tau (p<0.001), synaptotagmin (p<0.001), SNAP 25 (p = 00006), GAP 43 (p = 0.00055) and neurogranin (p = 0.0086) in the CSF and with amyloid deposition in the hippocampus (p = 0.018) and tau retention in the entorhinal cortex (p = 0.0082) and temporal pole (p = 0.0124) in cognitively unimpaired individuals at high risk for AD. Clusterin is increased in the brain of individuals who are homozygous for the CLU_T variant (p = 0.04) and in AD patients compared to age‐matched controls (p = 0.024). mRNA levels are increased in individuals homozygous for the CLU_T variant (p = 0.003), but there are no significant differences in AD patients compared to controls (p = 0.07).ConclusionOur work shows significant correlation between CSF clusterin and the main AD biomarkers (PET and CSF) and synaptic proteins before disease onset, in subjects at high risk for the disease. In the later stage of the disease, clusterin protein and CLU mRNA levels are increased as a function of genotype and disease status, suggesting that CLU may play a protective role by increases in gene expression in the CNS.
Examining the Association Between Differences in Post Turning Driving Behavior on a Driving Simulator and Amyloid Status in Cognitively Normal Older Adults
Authors: Rose Savannah G. , Flynn Emma , Carmichael Douglas , Murphy Yi Lu , Koeppe Robert A. , Persad Carol C. , Maher Amanda Cook , Giordani Bruno 
Published: January 2025

AbstractBackgroundOlder adults diagnosed with Mild Cognitive Impairment (MCI) and dementia are at increased risk of driving impairment. As the prevalence of dementia, particularly Alzheimer’s dementia, increases, researching the link between driving behaviors and cognitive decline may aid early identification of at‐risk cognitively normal older adults. This study assesses differences in driving behavior following a left hand turn between amyloid positive and negative cognitively normal older adults.MethodSeventy‐three cognitive normal adults aged 65+ were categorized as either amyloid positive or amyloid negative based on PiB PET imaging and a centiloid scale (≥20 = positive, ≤10 = negative). Forty‐three participants were amyloid negative (CN‐) and 27 were positive (CN+). All participants completed a 20‐minute simulator drive programmed with realistic driving scenarios, including a 90 degree left turn from a stop sign at two intersecting rural two lane roads. Assessed turning behavior in the 120 meters after the left turn included the average absolute value of lane deviation, number of off‐road errors and oncoming traffic errors, number of over‐corrections, and number of total errors. Group differences were analyzed using independent samples t‐tests.ResultThere were no demographic differences between the groups. The CN‐ group had faster speed after the turn, faster average speed in the 120m post‐turn, and greater average absolute value lane offset compared to the CN+ group. The CN‐ group also made more errors, including both off‐road and oncoming‐traffic error types, compared to the CN+ group. There was no significant difference between the number of over corrections or total errors by group.ConclusionOverall, cognitively normal older adults with elevated brain amyloid displayed potentially more cautious driving behavior than their peers without elevated amyloid. It remains to be seen whether these more cautious behaviors are potentially due to decreased confidence or subconscious recognition of cognitive changes. Nonetheless, they may signal early, subtle signs of AD‐related processes differentiating individuals at‐risk for AD‐related cognitive decline.
Neuropsychiatric and behavioral markers of dementia risk
Authors: Ismail Zahinoor 
Published: January 2025

AbstractA critical need exists to find simpler approaches for early detection of Alzheimer disease (AD) and related dementias. These approaches must increase access to preventative interventions and treatments, both pharmacological and non‐pharmacological, for people in preclinical and prodromal stages of disease. This need has been amplified by the emergence of disease modifying therapies (DMTs), which require biological confirmation of amyloid‐ß positivity. Confirmation methods include positron emission tomography (PET) tracers, lumbar puncture for cerebrospinal fluid analysis, and phlebotomy for blood assays. However, given the expense, invasiveness, and lack of availability to all, these methods are not suitable for larger scale screening or case detection. Finding higher‐risk persons, enriched for biomarker positivity, can help with case detection. Digital biomarkers, delivered at scale, may have a role. Conventionally, the at‐risk group is identified based on cognitive symptoms. An underappreciated approach to help with detection of AD is to incorporate neuropsychiatric symptoms (NPS) into screening or assessment. Historically, specificity has been a limitation, with NPS manifesting due to other, non‐AD aetiologies. More recently, the construct of Mild Behavioral Impairment (MBI) has been developed to improve specificity for AD detection and prognostication when using NPS. MBI leverages risk associated with later‐life emergent and persistent NPS to improve specificity. For example, in persons with Subjective Cognitive Decline or with Mild Cognitive Impairment, stratifying by MBI status selects a subgroup with higher rates of incident cognitive decline and dementia. Even more advantageous has been the utility of MBI to predict MCI and dementia in cognitively unimpaired participants, for whom cognitive symptoms cannot easily be used to detect risk. More recently, evidence has emerged supporting the role of MBI for detection of persons with elevated AD biomarker levels, with greater specificity than NPS not meeting MBI criteria. These findings extend the epidemiological data and highlight MBI as a potential tool for sample enrichment. With MBI validated for digital delivery, there is potential to improve screening and case detection at scale. In this session, we will review the MBI construct, the role of MBI in dementia prognostication, and the most current data linking MBI to amyloid, tau, and neurodegeneration.