bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein E and Apolipoprotein E receptor 2 signaling as drug targets in Alzheimer’s disease
Authors: Belaidi Abdel Ali , Bush Ashley I. , Ayton Scott 
Published: January 2025

AbstractBackgroundAllelic variation in apolipoprotein E (APOE) is by far the greatest contributor to Alzheimer’s disease (AD) after age, but the mechanisms underlying how APOE impacts on the pathology of AD remain undefined. While most research is focusing on mechanisms associated with the presence of the APOE risk allele, several aspects of APOE biology remain poorly understood. In particular, the physiological relevance of APOE receptors and their impact on disease progression have been overlooked.MethodFerroptosis was induced in N27 neurons using multiple agents (erastin, RSL3) and toxicity was evaluated using different viability assays (MTT, Propidium iodide, LDH) and ferroptosis. N27 neurons were transfected with a plasmid encoding APOER2‐GFP fusion protein or a GFP‐expressing control vector, while recombinantly expressed and purified APOE was used as an APOE source.ResultHere, we present data supporting a function of APOE in tandem with APOER2 in protecting neurons from ferroptosis. Ferroptosis is a cell death pathway characterized by the accumulation of lethal lipid hydroperoxides resulting from iron‐dependent oxidation of polyunsaturated fatty acids. APOER2 expression in neurons resulted in increase in glutathione peroxidase 4 (GPX4) expression, which functions by converting toxic lipid peroxides into non‐toxic lipid alcohol and thus increases resistance to ferroptosis. We further report that APOER2 expression potentiates APOE‐mediated protection from ferroptotic cell death in in N27 neurons. Further mechanistic studies are ongoing to validate the underlying mechanism and the involved signaling cascades.ConclusionWe present evidence for the involvement of APOE and APOER2 in neuronal protection from ferroptotic cell death. These findings represent new drug targets that can be explored to slowdown neurodegeneration in AD.Funding: This study was supported by grants from the Alzheimer’s Association and National Health & Medical Research Council of Australia.
A multi‐dimensional context‐dependent measurement framework for affective experience in preclinical AD
Authors: Turnbull Adam 
Published: January 2025

AbstractPromoting emotional well‐being (EWB) in older adults at risk for Alzheimer’s Disease (AD), for example those with mild behavioral impairment (MBI), mild cognitive impairment (MCI), or subjective cognitive decline (SCD), is important both to improve quality of life and slow the progress of cognitive decline. Understanding how the early accumulation of AD pathology affects EWB and developing interventions to improve EWB both require the precise measurement of affective experience that plays a key role in EWB. Day to day affective experiences, both positive and negative, contribute significantly to EWB, but how affective experience maps onto EWB is complex. Rather than merely reflecting a decrease in negative affect or an increase in positive affect, we propose that EWB is increased when individuals have a full affective experience, moving through the high‐dimensional space of human emotion in a context‐appropriate manner in response to internal and external triggers. Understanding affective experience through a multi‐dimensional context‐dependent lens is therefore critical to assessing changes caused by early AD pathology. For example, irritability in an individual with MCI may only emerge in specific contexts (e.g., when attempting to perform a mentally challenging task) and may be reflected as a subtle increase in arousal. To understand 1) how affective experience contributes to EWB in older adults at‐risk for AD and 2) how early AD pathology accumulation affects EWB via changes in affective experience, we therefore need measurement techniques that accurately reflect the context‐dependent, high‐dimensional nature of affective experience. We propose a multi‐dimensional context‐dependent measurement framework for quantifying affective experience in the preclinical stages of AD. We demonstrate how this framework uses experience sampling to measure multi‐dimensional affective experience across a range of experimentally induced (social scenario paradigm) and real‐world (ecological momentary assessment) contexts. We explain how this framework can be used to better characterize affective experience in MBI, MCI, and SCD with the goals of 1) better developing interventions to improve EWB and slow cognitive decline and 2) better understanding how early AD pathology affects EWB via affective experience.
Learning deficits in late middle‐aged APOE ε4 carriers: Implications for emergent Alzheimer’s disease
Authors: Lim Yen Ying , Rosenich Emily , Norfolk Maya , Maruff Paul 
Published: January 2025

AbstractBackgroundRecent studies suggest learning deficits are the earliest cognitive abnormality to emerge in Alzheimer’s disease (AD). Using the Online Repeatable Cognitive Assessment‐Language Learning Test (ORCA‐LLT), cognitively unimpaired (CU) Aβ+ older adults showed a substantial (d∼2) learning deficit compared to Aβ‐ controls. This deficit was six times greater than that observed from reduced practice effects after 9+ years of assessment with conventional neuropsychological memory tests (d∼0.3). A similar but smaller learning deficit (d∼1.2) was also observed in CU Aβ‐ ε4 carriers compared to matched non‐carriers, consistent with observations that Aβ accumulation has begun in this group. We aimed to determine the development of AD‐related learning deficits by examining the effect of age and APOE ε4 on the ORCA‐LLT in CU middle‐aged adults.MethodCU adults (n = 513) provided saliva samples for APOE genotyping, and completed the ORCA‐LLT, which required participants to learn associations between 50 Chinese characters and their English language equivalents over 5 days. Learning curves were computed for ORCA‐LLT performance accuracy across days, with learning rate defined using the exponent estimated from each power curve. The Cogstate Brief Battery was also completed and provided the Cogstate Learning/Working‐Memory Composite. All assessments were completed remotely and unsupervised on an online platform.ResultLearning curves were evident for all groups, though learning rates slowed with increasing age (Fig 1). Learning rates were slower in ε4 carriers compared to non‐carriers in the 65‐70 (d∼0.9) and 60‐64‐year age groups (d∼0.4). Learning rates were equivalent between ε4 carriers and non‐carriers in all other age groups (Fig 1, Table 1). No differences were observed between ε4 carriers and non‐carriers on the Cogstate Learning/Working‐Memory Composite for any age group (Table 1).ConclusionIn late middle‐aged adults, ε4 was associated with a large reduction in ability to learn novel information. This impairment was not evident in performance on conventional cognitive tests. It is likely that Aβ levels in this group are increasing abnormally or have reached threshold for abnormality. Placed in the context of our previous observations, these data support the hypothesis that the earliest cognitive abnormality to reflect AD pathophysiological processes is a reduced ability to benefit from new information.
A polygenic risk score contributes to identifying individuals with the potential for cognitive function improvement
Authors: Shigemizu Daichi , Fujita Kosuke , Niida Shumpei , Ozaki Kouichi , Sakurai Takashi , Arai Hidenori 
Published: January 2025

AbstractBackgroundA polygenic risk score (PRS) estimates an individual’s genetic liability for diseases based on accumulated genetic variations. While the PRS has been shown to contribute to the prediction of dementia risk, its utility in predicting the effectiveness of multifactorial interventions to reduce the risk of dementia remains unclear.MethodsA genome‐wide association study (GWAS) was conducted to identify dementia‐related traits in the Japanese population. Subsequently, PRSs were constructed based on GWAS results using PRSice‐2 software. The Japan‐multimodal intervention trial for prevention of dementia (J‐MINT) is an RCT to assess the effect of multi‐domain interventions for subjects with mild cognitive impairment. The J‐MINT samples were classified into high‐risk and low‐risk groups using the Japanese PRS. Within each risk group, cognitive function improvement due to the intervention was assessed using Fisher’s exact test.ResultsWe conducted a GWAS with 3962 AD cases and 4074 controls for 4,578,811 genetic markers that passed stringent quality control filters. The optimal PRS, composed of 12,818 SNPs and APOE status, was developed at a p‐value threshold of 0.090, selected for its highest model fit with an R2 score of 0.023. Subsequently, the PRS classified 289 J‐MINT samples into 99 high‐risk and 190 low‐risk groups. Individuals in the young‐old group (aged <75 years) showed significant cognitive improvement through the intervention in the high‐risk group; however, those in the old‐old group (aged 75 years) did not demonstrate such potential in either risk group.ConclusionsWhile we have successfully developed a Japanese PRS with high predictive ability, it is important to note that our dataset is limited and relatively small. To achieve an accurate AD PRS for the Japanese population, further validation studies are necessary, involving a larger dataset or conducting a meta‐analysis with another Japanese cohort. Additionally, our study highlights the potential utility of the PRS in screening subjects for cognitive improvement, especially for individuals with high PRS in the young‐old group.
Molecular Docking for pharmacokinetics and drug‐likeness of Naringenin and its protective effects against streptozotocin induced cognitive deficits in mice
Authors: Yadav Monu 
Published: January 2025

AbstractBackgroundThe current study aimed to investigate the chemical interaction of naringenin with the possible receptors and enzymes involved in the pathogenesis of cognitive deficits and tested their ADME and toxicity. Furthermore, in‐vivo studies have also done to evaluate the effect of naringenin and its nanoparticles on STZ‐induced cognitive decline in mice.MethodNaringenin were evaluated against the active sites of β‐secretase 1 (PDB: 3UQU), human insulin‐degrading enzyme (PDB: 4RE9), insulin receptor tyrosine kinase (PDB: 1IR3), glycogen synthase kinase‐3 β (PDB: 3L1S), phosphoprotein phosphatase 2A (PDB: 3P71), human superoxide dismutase I (PDB: 5YT0), catalase‐3 (PDB:3EJ6), and human acetylcholinesterase (PDB: 4EY7) in comparison of rivastigmine using molecular docking studies. Further, the naringenin and rivastigmine were subjected to test their pharmacokinetic and lead‐likeness properties by employing the Swiss ADME web server. Moreover, a toxicity study has been performed for both naringenin and rivastigmine with the help of a Protox‐II web server.ResultNaringenin has a better binding affinity than rivastigmine with all the potential receptors. In in‐vivo behavioral, biochemical mitochondrial and histopathological studies, naringenin nanoformulation showed more significant cognitive enhancement results as compared to pure naringenin when studied against STZ induced cognitive deficits.ConclusionThe results demonstrated that it would be worthwhile to explore more naringenin nanoformulation to expose the therapeutic effects for the treatment of cognitive deficits and neuroprotecive effects.
Modelling synaptic tau and Aβ pathology in human organotypic brain slice cultures
Authors: McGeachan Robert I. 
Published: January 2025

AbstractBackgroundMaintaining synaptic health is essential for normal neurological function, yet neurodegenerative diseases like Alzheimer’s disease and Progressive Supranuclear Palsy (PSP) exhibit synaptic loss. In these conditions, synaptic loss precedes neuronal degeneration, and the degree of synaptic loss correlates closely with the severity of clinical symptoms. Both Aβ, which accumulates in amyloid plaques in AD, and tau protein which accumulates intracellularly in tauopathies, including AD and PSP, accumulate within synaptic terminals. In model systems, the accumulation of Aβ and tau in synapses has been linked to synaptic dysfunction, synaptic loss, and the spread of pathology trans‐synaptically. However, there is currently a lack of data studying the synaptotoxic effects of these pathologic proteins in live human synapses.MethodTo address this, we usenovel human organotypic brain slice cultures derived from neurosurgical peritumoral access tissue. Employing a powerful repeated measures design to account for donor tissue variability, slices from each case were cultured with either medium, soluble protein extract (sp‐extract) from PSP (n = 6) or AD (n = 5) brain, or sp‐extracts immunodepleted for tau or Aβ respectively.ResultUsing high‐resolution array tomography, and linear mixed effect modelling of the data, our findings reveal that exogenous PSP‐derived tau (p = 0.002) and AD‐derived Aβ (p = 0.004) are taken up into living human post‐synapses, and within 72 hours AD‐derived Aβ causes a loss of synaptophysin puncta (p = 0.002). Our data further suggests that oligomeric tau has a greater propensity for synaptic uptake than phospho‐tau Ser202, Thr205 (AT8). Interestingly, PSP‐derived tau induces an astrogliosis (p = 0.001) and an associated increase in synaptic engulfment (p < 0.001) in our slice culture model.ConclusionHuman organotypic brain slice cultures can be used a valuable tool to study the effects of disease derived tau and Aβ on human synapses.
Multi‐omic cell type‐level inference of mechanisms underlying non‐coding genetic variants for Alzheimer’s disease
Authors: Kuksa Pavel P. , Carter Luke , Cifello Jeffrey , Leung Yuk Yee , Wang Li‐San 
Published: January 2025

AbstractBackgroundRecent Alzheimer’s disease (AD) genome‐wide association studies () have identified >75 risk loci, with >98% of genome‐wide significant variants residing in non‐coding genomic regions, making it more difficult to infer their functional contexts. In this study, we aim to jointly 1) fine‐map causal loci/variants, and 2) identify affected cell types and functional elements by interrogating large‐scale collections of thousands of heterogenous, cell type‐specific functional genomic (FG) datasets.MethodWe analyzed the full genome‐wide summary statistics (n = 21,101,114 variants) from the recent AD GWAS (Bellenguez et al, 2022) (Ncases = 111,326, Ncontrols = 677,663). The variants were analyzed using the recently introduced Bayesian framework (Bayesian tissue score, BTS https://bitbucket.org/wanglab‐upenn/workspace/projects/BTS) on >70,000 harmonized genome‐wide cell‐type level FG tracks (FILER; Kuksa et al, 2022), including those for FANTOM5 enhancers, Roadmap ChromHMM enhancers, ENCODE DNase hypersensitivity sites and active histone marks, and EpiMap enhancers (4,225 tracks). Using BTS, we calculated Bayesian prior odds for each of the annotation tracks overlapped with genome‐wide GWAS signals and then computed annotation‐specific causal variant and loci posteriors. With this systematic, hypothesis‐free multi‐omic approach, we jointly analyzed and ranked AD‐relevant loci, variants, and their functional contexts (affected cell types and corresponding genomic features).ResultThe BTS pipeline identified 131 non‐HLA genomic regions with 49,049 variants, across 1,294 overlapping annotation tracks on 640 cell types, with up to two distinct causal signals in each locus. BTS prioritized 152 annotations tracks with >2 prior odds (3.60 causal prior odds average) across 108 cell types belonging to the blood (57), brain (21), heart (12), digestive (12), (6) tissue categories. In total, 94 genomic loci and 119 variants prioritized in these cell types (posterior > .5).ConclusionLarge‐scale evaluation of AD GWAS data provides insights into functional contexts and potentially causal biological mechanisms of AD.
Molecular insights into the heterogeneity of depression in Alzheimer’s disease: A single‐cell transcriptomic analysis
Authors: Lutz Michael W , Man Zhaohui , Chiba‐Falek Ornit 
Published: January 2025

AbstractBackgroundPatients with Alzheimer’s Disease (AD) frequently manifest comorbid neuropsychiatric symptoms (NPS) with depression and anxiety being most prevalent. Previously we identified shared genetic risk loci between AD and major depressive disorder (MDD). In another study, we constructed a polygenic risk score (PRS) based on MDD‐GWAS data and demonstrated its performance in predicting depression onset in LOAD patients. Furthermore, using bulk brain transcriptomic data, we discovered sex‐dependent differentially expressed genes in AD comorbid with depression compared to AD only. Here we aimed to investigate in‐depth differences in gene expression on a cell‐type specific level between autopsied AD brain tissues from patients with depression compared to patients without evidence for depression.MethodSingle nucleus (sn)RNA‐seq data from the ROSMAP study (available through AMP‐AD) was analyzed, specifically, dorsolateral pre‐frontal cortex datasets from 14 brains with AD comorbid depression and from 19 brains with AD and absence of depression. Depression was determined by clinical diagnosis and CES‐D scores. Differential gene expression (DEG) was performed using Nebula with case/control status based on clinical diagnosis of depression and age, sex, PMI and subject identified included as covariates.ResultFDR‐significant DEG were found for multiple cell types with the greatest majority of DEGs for inhibitory neurons (n = 548) followed by astrocytes (n = 109). Most of the genes in these cell types were upregulated. In addition, MS4A6A gene was found to be significantly upregulated in microglia, supporting our prior results showing the pleiotropic role of MS4A6A in both MDD and AD. Pathway analysis for the inhibitory neuron DEGs showed significant enrichment for terms related to mitochondrial function including: mitochondrial electron transport and mitochondrial ATP synthesis coupled with electron transport, suggesting mitochondrial dysfunction.ConclusionThe results demonstrated numerous depression‐associated cell‐type specific DEGs in AD brains. Our single‐cell analysis provides mechanistic insight into the risk to develop comorbid depression in AD and advances our understanding of shared molecular etiologies and dysregulated pathways between AD and MDD. This knowledge has a translational impact toward the identification of actionable targets as novel therapies to treat depression earlier in disease stages as a means to delay or alleviate depression onset in AD.
Examining Methylation at the Intersection of Genetic Risk To Alzheimer’s Disease And Alcohol Use Disorder
Authors: Pathak Gita , Pietrzak Robert H , Levey Daniel , Montalvo‐Ortiz Janitza , Kranzler Henry , Gelernter Joel , Polimanti Renato A 
Published: January 2025

AbstractBackgroundAlcohol Use Disorder (AUD) affects over 15 million individuals in the United States, contributing to oxidative stress, neuroinflammation, and elevating the risk of neurodegeneration. Despite this, the connection between AUD and aging conditions, particularly Alzheimer’s disease (AD), remains unclear. AD, with a heritability of 60‐80%, is genetically linked, necessitating an exploration of the molecular implications of AUD and genetic susceptibility to AD.MethodParticipants were assessed for AUD using DSM‐5 criteria, and genotype data were imputed with the TOPMED reference panel. The polygenic score (PGS) of AD was calculated in European ancestry participants (mean±SD, 40.12 ±13.3 yrs; N = 4,915), adjusting for age, sex, and genetic ancestry. Methylation was assayed using the Illumina EPIC array using blood to conduct an epigenome‐wide association study (EWAS) on the interaction between PGS‐AD and AUD at 657,226 CpG sites in a subset of participants (N = 452). Intrinsic and extrinsic epigenetic age acceleration (IEAA, EEAA) were calculated using Hannum and Horvath’s epigenetic clocks.ResultWe observed a significant association between PGS of AD and AUD diagnosis (cases = 34%; OR = 1.44; p = 0.005). The subsequent EWAS revealed top CpG sites in genes associated with AD pathogenesis, including RLF, CD2AP, GLUL, GJA3, TRIM26, JAG2, RERE, SRRM3, COL11A2. For these top CpGs, we investigated the beta (methylation intensity) in individuals with high‐PGS of AD (top 25% quantile) and stratified them by AUD diagnosis. Briefly, the top two CpG sites in AUD cases‐cg01101221(RLF; p = 5.51E‐07) was hypomethylated (p = 0.0205); and cg05804888(CD2AP; p = 4.61E‐06) was hypermethylated (p = 0.0142). We also observed interaction of AUD and PGS of AD is associated with accelerated aging‐ IEAA and EEAA from both Horvath and Hannum’s clocks (p<8.56E‐06<0.0092).ConclusionThe identified genes have been implicated in AD pathogenesis, such as CD2AP’s association with Aβ production and GLUL’s role in brain lipid metabolism. The study also highlighted the association between AUD and PGS‐AD interaction and accelerated epigenetic aging. While the CpG associations did not reach Bonferroni significance, our ongoing research aims to extend these findings to other ancestries and cohorts to improve statistical power. Thus providing a comprehensive understanding of the complex interactions between AUD diagnosis and genetic susceptibility to AD.
Applying Digital Spatial Profiling of the Transcriptome to Elucidate Disease Mechanisms of Psychosis in Alzheimer’s disease
Authors: Thomas‐Hegarty Jacob , Lunnon Katie , Pishva Ehsan , Smith Adam , Weymouth Luke , Eyres Michael , Frost Lucy , Marshall Gayle , Platt Eleanor , Creese Byron 
Published: January 2025

AbstractBackgroundPsychosis occurs in 30‐40% of individuals with AD. New insights into disease mechanisms may lead to novel pharmacological targets and treatments. Previous studies have focused on bulk tissue analysis with limited results. Digital spatial profiling (DSP) is a new technique for spatial analysis of RNA or proteins in fixed tissue. It allows quantitative profiling with spatial complexity to be collected from samples in a non‐destructive manner. In this pilot study we used DSP to compare whole transcriptome data in amyloid beta and non‐amyloid beta regions in participants with and without psychosis (AD+P; AD‐P).MethodSix post‐mortem brain samples from prefrontal cortex were provided by the Kings College London Brains for Dementia Research (BDR) brain bank. Frozen and formalin fixed, paraffin embedded (FFPE) sections were supplied in order to test the platform on each type. Psychosis positive and negative groups were selected based on Neuropsychiatric Inventory (NPI) assessments. Samples were hematoxylin and eosin (H&E) stained as well as stained with fluorescent antibodies for AT8, NeuN, SYTO13 and Aβ. Regions of interest (ROIs) are selected based on morphology markers and tissue morphology (see Figure 1 for Amyloid ROI selection).ResultH&E staining revealed the frozen samples to be too badly degraded so the analysis was conducted on FFPE sections. AT8 staining showed widespread tau pathology to the extent that it was not possible to confidently select non‐tau ROIs. Analysis of Aβ plaque containing and Aβ plaque free regions, comparing AD+P and AD‐P groups, found 314 differentially expressed genes in plaque free regions, and 172 differentially expressed genes in plaque containing regions (Figure 2). Of these 172 genes, 28 were not differentially expressed in plaque free regions, forming a plaque‐specific signature of genes differentially expressed in AD+P.ConclusionThis pilot study demonstrates the potential of the NanoString GeoMx™ DSP platform as an innovative spatial transcriptomics methodology for investigating AD+P with the potential to uncover differentially expressed genes that may be missed by bulk RNA sequencing studies. FFPE sections appear to be optimal. Analysing earlier stage disease and more sections per subject may help with better differentiation of tau and non‐tau ROIs.