bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulating dynamic brain networks and episodic memory in amnestic mild cognitive impairment using 40 Hz precuneus transcranial alternating current stimulation
Authors: Koomen Annel P. , Stam Cornelis J. , Pijnenburg Yolande A.L. , de Haan Willem 
Published: January 2025

AbstractBackgroundWorldwide, 32 million Alzheimer’s disease (AD) patients contribute to a large economic burden, making effective and safe therapies that slow or prevent the progression from pre‐dementia or mild cognitive impairment (MCI) to AD of high priority. Transcranial alternating current stimulation (tACS) is a safe and patient‐friendly non‐invasive brain stimulation technique that serves as a potential candidate for slowing and/or reducing cognitive impairment. Application of tACS in the gamma (30‐45 Hz) frequency range, specifically around 40 Hz, has been studied in patients with (pre‐dementia) AD. In these patients, a single session of 40 Hz tACS at the precuneus region showed to improve episodic memory and to increase relative power of higher frequencies such as gamma, as measured with EEG. These findings will be replicated in the current study in pre‐dementia AD patients, using magnetoencephalography (MEG) to study brain network dynamic changes with greater temporal and spatial detail.MethodIn this double‐blind, randomized, sham‐controlled, cross‐over trial, 30 pre‐dementia AD (biomarker‐confirmed amnestic MCI) patients will undergo concurrent tACS‐MEG. At two sessions separated by a week, 48 minutes of either gamma (40 Hz) or sham tACS will be applied at the precuneus region. Cognitive outcome measures assessed pre and post‐tACS are the Rey Auditory Verbal Learning (RAVL) test and Face‐Name Association Task (FNAT) score. In addition, resting‐state spectral and functional connectivity MEG measures will be extracted from the pre‐ and post‐tACS data to determine tACS‐induced network effects.ResultAn increase in RAVL test and FNAT score after 40 Hz but not sham tACS is expected, as well as an increase of relative power and global connectivity in higher frequencies (alpha [8‐13 Hz], beta [13‐30 Hz] and gamma [30‐45 Hz]). Furthermore, a positive correlation is expected between these quantitative MEG measures and cognitive outcome following 40 Hz tACS.ConclusionWe expect 40 Hz precuneus tACS to improve episodic memory and to counteract the slowing of oscillatory activity and reduction of brain communication in AD. This will support the notion that this approach can temporarily improve cognitive impairment by normalizing disturbed brain function, and encourages the use of tACS in clinical studies of AD.
Effects of BDNF and COMT variants on cognitive decline in Early‐Onset Alzheimer’s Disease
Authors: Hammers Dustin B. , Foroud Tatiana M. , Kim Hee Jin , Musema Jane , Dage Jeffrey L. , Eloyan Ani , Carrillo Maria C. , Dickerson Bradford C. , Rabinovici Gil D. , Apostolova Liana G. , Nudelman Kelly N. ,   LEADS Consortium
Published: January 2025

AbstractBackgroundEarly‐Onset Alzheimer’s Disease (EOAD) is a rare condition that affects only 5% of patients with Alzheimer’s Disease (AD). At present, only basic information is known about the impact of AD risk variants on EOAD, and the effects of more subtle genetic contributions to cognitive decline have yet to be investigated. Genetic variants for brain derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) have both been implicated in cognitive change (Fiocco et al., 2010; Ferrer et al., 2019), consequently the aim of the current study was to examine the role of these genetic variants on cognitive decline in EOAD.MethodData from 88 amyloid‐positive EOAD participants enrolled in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS; aged 40‐64) were analyzed. Exploratory multivariate analyses of covariance (MANCOVA) were conducted to investigate differences in 12‐month cognitive decline as a function of BDNF rs6265 (p.V66M) and COMT rs4680 (p.V158M) variants using dominant genetic models (Val/Val versus Val/Met or Met/Met). Cox Regression analyses were also conducted to consider the effect of genetic variants on age of onset.ResultSee Table 1 for demographic characteristics of our sample. MANCOVA, controlling for age, education, sex, and race/ethnicity, showed significant effects for BDNF p.V66M on domains of Memory (p<0.001) and Executive Functioning (p = 0.04; Table 2). Specifically, greater 12‐month cognitive decline was observed for the CRAFT Immediate and Delayed Story Memory, with worse performance associated with BDNF minor alleles (ps. = 0.007 to 0.02). Conversely, worse decline was observed for the reference group for RAVLT Immediate Memory (p<0.006) and Digit Span Backwards (p<0.02). No significant effects were evident for domains of Language, Speed/Attention, or Visuospatial skills (ps = 0.34‐0.97), nor for any analyses of COMT carrier status (ps = 0.26‐0.87). Cox Regression analyses, controlling for race and ethnicity, were not significant for BDNF or COMT carrier status (ps = 0.59‐0.64; Figure 1).ConclusionResults suggest subtle effects of BDNF p.V66M carrier status on memory decline in EOAD participants, which was not observed for disease progression/age‐of‐onset. No effects for COMT p.V158M carrier status were observed. Future investigation will replicate these effects in larger samples, permitting stratification of additional covariates including APOE genotype.
Aβ re‐wires CSF1R‐induced MAPK pathway activation in MMC microglia
Authors: Bitarafan Sara , Uhlig Zachary C. , Tobin Brendan R , Armentrout Owen S , Rangaraju Srikant , Wood Levi B 
Published: January 2025

AbstractBackgroundMitogen activated protein kinase (MAPK) signaling is a critical regulator of microglial phenotype, including phagocytic function, cytokine expression, and motility, among others. Importantly, both canonical and non‐canonical MAPK signaling is directly activated by RTKs, including Interestingly, CSF1R, is activated by two agonists, CSF1 and IL‐34, which have been shown to activate the receptor in different ways that can lead to However, little is known about how the affect microglial MAPK signaling, and whether their effects are dependent on disease state/Aβ exposure. In this study, we hypothesized that IL‐34 and CSF‐1 elicit distinct patterns of MAPK signaling activation in microglia and MAPK activation would be dependent on whether the cells were exposed to Aβ.MethodWe applied agonists of CSF1R (i.e., IL‐34, CSF1) to the mouse microglial cell (MMC) line, either pre‐treated with 500nM of Aβ1‐42 or vehicle (1% NH4OH) for 48hr. Cells were serum starved (1hr), stimulated with each agonist for 5min, then lysed for Luminex quantification of a panel of 10 MAPK phosphoproteins.ResultIn the absence of Aβ1‐42, both CSF1R and IL‐34 stimulated both canonical (ERK) and non‐canonical (p38, JNK) MAPK signaling phospho‐proteins (Wilcox test, p<0.05 vs control). While Aβ1‐42 pre‐treatment resulted in diminished activation in canonical MAPK signaling (i.e., MEK, ERK) following either CSF1 or IL‐34 stimulation, CSF1 stimulation of non‐canonical MAPK signaling through p38 and JNK was preserved with Aβ1‐42 pre‐treatment. These findings indicate that CSF1‐induced signaling is robust regardless of Aβ1‐42 exposure. Furthermore, different agonists of the same receptor distinctly activate non‐canonical MAPK pathway signaling (p38). Collectively, this finding supports the overall hypothesis that CSF‐1R‐induced signaling is dependent on Aβ and Aβ pre‐treatments shift the canonical ERK signaling to non‐canonical p38 signaling.ConclusionThese findings show that different agonists of CSF1R can provoke distinct profiles of canonical and non‐canonical MAPK pathway signaling in the presence of Aβ1‐42. Understanding differences in agonist‐specific microglial signaling in healthy and diseased microglia will be essential to designing microglial‐targeted therapeutics for treatment of AD.
snRNA‐seq analysis of human brains suggests cell type‐specific synergistic effects of APOE4 and TREM2‐R47H and potential drug targets in Alzheimer’s Disease
Authors: Zajac Diana J , Xu Jielin , Cheng Feixiong 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) risk variants APOE4 and TREM2‐R47H have been shown to impact glial cell functions and transcriptional profiles. We hypothesize that TREM2‐APOE may have synergistic effects in driving pathogenesis and disease progression of AD in a cell type‐specific manner.MethodsWe investigated cell‐type specific transcriptional changes associated with APOE4‐ and TREM2‐R47H‐carrier status. We conducted single‐nuclei RNA‐sequencing (snRNA‐seq) analysis, including cell type clustering and annotation, and identification of differentially expressed genes (DEGs). We used integrative genomic analysis for pathway enrichment and drug‐target network inference. Our investigation was between APOE‐TREM2 groups: APOE4‐carrier+TREM2‐R47H (E4‐R47H) (n = 18) vs non‐APOE4+R47H (nonE4‐R47H) (n = 6), APOE4‐carrier+TREM2‐common variant (E4‐CV) (n = 16) vs nonE4‐CV (n = 6), E4‐R47H vs nonE4‐R47H, and E4‐CV vs nonE4‐CV.ResultsWe found that APOE‐TREM2 status had synergistic effects on cell abundance in several cell types, especially in oligodendrocytes, excitatory neurons and pericytes. Pathway enrichment analysis suggests a possible APOE4‐ and TREM2‐R47H‐dependent regulation of cell type‐specific pathway signaling. Of note, preliminary analysis suggests an APOE4‐dependent regulation of TREM2‐R47H‐associated PI3K‐Akt signaling in microglia such that APOE4‐R47H carriers had significantly upregulated PI3K‐Akt signaling but nonAPOE4‐R47H carriers had comparatively downregulated PI3K‐Akt signaling. Oligodendrocyte clusters show R47H‐dependent effects of APOE4‐carrier status on relevant signaling pathways as well. Oligodendrocytic signaling pathways for long‐term depression and serotonin/anxiety events, as well as sleep regulation and circadian entrainment have R47H‐dependent regulation between APOE4 vs non‐APOE4 carriers. We employed integrative network‐based analysis of single‐nuclei transcriptomic and drug‐gene signatures and identified an FDA‐approved drug clidinium bromide, a treatment for irritable bowel syndrome and enterocolitis, to be a possible antagonist of the synergistic R47H‐APOE4 effects in microglia.ConclusionIn summary, this study suggests possible synergistic effects of APOE4‐carrier and TREM2‐R47H‐carrier status on cell type abundance and cell type‐specific specific signaling pathways. Hence, further classification of differences between joint APOE‐TREM2 genotypes will improve our understanding of glial cell alterations in AD, and could lead to novel microglia‐targeted therapeutic interventions. Such findings enhance our knowledge of druggable therapeutic targets and support the need for precision and personalized medicine. Independent cohort validation and functional observations of candidate targets and treatments are warranted.
Semantic control across different phenotypes of Alzheimer’s disease: a cognitive study
Authors: Armas Pilar , Zsadanyi Sara E , Morcillo‐Nieto Alejandra O. , Illán‐Gala Ignacio , Marques‐Kiderle Sonia Karin , Ciongoli Francesco , Rubio‐Guerra Sara , Lleo Alberto , Fortea Juan , Grasso Stephanie M , Binney Richard J , Calabria Marco , Hernando Javier , Bejanin Alexandre , Santos‐Santos Miguel A 
Published: January 2025

AbstractBackgroundWhile the functioning of semantic memory has been extensively documented in Alzheimer disease (AD), little is known about semantic control capacities that monitor and modulate semantic representations. The present study used a task to assess semantic control in typical and atypical AD patients.Method11 patients with typical AD (ADtyp), 17 patients with logopenic variant of primary progressive aphasia (lvPPA, i.e. AD language variant), and 16 cognitively unimpaired subjects performed a task (from Corbertt et al., 2011) consisting of selecting the picture of an object that could be used to complete an everyday task (e.g. “kill a fly”). Each task was performed under 4 conditions (4 trials), that manipulated the difficulty of selecting a suitable object. For each trial, the target item was either a canonical object for completing the task (e.g. “flyswat”) or a noncanonical one (e.g. “magazine”); the target picture was presented alongside 5 additional pictures of either unrelated distractors (e.g. “toothbrush”) or distractors semantically related to the target (e.g. “mousetrap”). Semantic control measures were canonicity (associated with abstraction and flexibility capacities) and relatedness (associated with inhibition). Semantic control scores were computed as the difference between canonical and noncanonical conditions (canonicity scores), and unrelated and related conditions (inhibition scores) in accuracy and reaction time (RT); higher scores indicated greater semantic control impairment.ResultLinear mixed‐model analyses showed that, across all groups, canonicity influenced RT and accuracy, whereas relatedness influenced accuracy only. Interaction analyses showed that the canonicity (but not the relatedness) manipulation resulted in slower RTs (but not lower accuracy) in both patient groups vs controls; lvPPAs unexpectedly showed faster RT in the condition theoretically demanding higher semantic control. Significant differences were found between controls and both patient groups in canonicity scores (both accuracy and RT) but not inhibition scores. No significant differences were observed between the patient groups.ConclusionOur results indicate that AD impacts semantic control capacity, with differences for canonicity and inhibition. Canonicity and inhibition semantic control abilities are similarly impaired in lvPPA and ADtyp groups. These results help us to identify different effects of semantic control capacities.
Translating Genetic Insights into Molecular Mechanisms in Alzheimer’s Disease: Innovative CRISPR Approaches Targeting Inflammasomes
Authors: Sher Falak 
Published: January 2025

AbstractBackgroundThe connection between inflammasomes and Alzheimer’s disease (AD) has garnered significant interest, with emerging evidence suggesting genetic associations and functional implications. Notably, studies have reported the upregulation of inflammasome components like NLRP1, NLRP3, and Caspase‐1 in AD patients. Moreover, genetic polymorphisms in inflammasome‐related genes are linked to increased AD risk. Inflammasome activation in microglia, key immune cells of the brain, contributes to the neuroinflammation characteristic of AD. This backdrop sets the stage for exploring inflammasomes as potential therapeutic targets using advanced genomic tools.MethodsAddressing the critical need for robust, human‐centric research models, our study developed an optimized protocol to differentiate human induced pluripotent stem cells into microglia (iMG). Validating this model through single‐cell RNA sequencing (scRNA‐Seq), proteomics, and functional assays, we employed a novel CRISPR‐based approach. We conducted comprehensive CRISPR tiling across inflammasome protein coding sequences in iMG cells, coupled with affinity chromatography‐based mass spectrometry and functional guide RNA mapping. This allowed us to investigate the essential subcomplexes within the inflammasome protein family and identify key genetic and protein interactions relevant to AD.ResultsOur CRISPR‐based investigations revealed crucial insights into the inflammasome’s role in AD. We identified specific mutations in NLRP3 that separate its impact on cell health from inflammasome activation. Additionally, our study highlighted critical amino acids in the AD‐associated protein SORL1, offering potential targets for small molecule therapeutics that alter SORL1 function with minimal side effects.ConclusionThis research marks a significant stride in translating genetic findings into a deeper understanding of molecular mechanisms in AD. By leveraging innovative CRISPR techniques on iMG models, we have elucidated the intricate roles of inflammasome pathways and their interactions with key AD‐associated proteins. Our findings pave the way for novel, targeted therapeutic strategies in Alzheimer’s disease, promising more effective interventions with higher precision.Our findings offer a generalizable approach to uncover protein or protein‐complex features suitable for rational biochemical targeting
Tau ablation rescues vascular amyloid‐related deficits in a cerebral amyloid angiopathy model
Authors: Mardones Muriel D , Jury Nur , Juarez Enrique Chimal , Patel Henika , Martinez Jonathan , Vanderbosch Katie , Perkins Abigail , Marambio Yamil , Vidal Ruben , Reeves Cristian A Lasagna 
Published: January 2025

AbstractBackgroundClose to 80 to 90% of subjects with AD also present cerebral amyloid angiopathy (CAA) a disease in which amyloid accumulation damages the vasculature an impairs blood flow. Since current AD therapies are targeting the disease focusing on amyloid, we are interested on determine how to decrease the accumulation of amyloid in the vasculature observed in CAA and our aim is to determine the impact of tau reduction in CAA pathogenesis.MethodWe crossed the Tg‐FDD mice CAA model with Mapt‐/‐ mice to decrease tau levels and analyzed the disease pathogenesis in the different genotypes though behavioral tests, histological and morphometric assays and transcriptomic analysis using the nCounter neuroimmflamation panel from Nanostring.ResultWe determined that tau ablation improved motor strength in the Tg‐FDD mice model, reduced amyloid deposition in the vasculature, decrease fibrinogen levels in the cortex, reduced astrocyte branching process associated to immunoreactivity. Nanostring analysis revealed that microglia function, oligodendrocyte and cytokine signaling are altered in the Tg‐FDD mice and that in the Tg‐FDD, Mapt‐/‐ mice there is an increase in this mechanisms restoring the values to the ones observed in wild type mice.ConclusionWe are currently evaluating the pathways observed in the distinct inflammatory profile in microglia and oligodendrocytes. Our results suggest that tau ablation decreased CAA pathology in the Tg‐FDD mice model, which shows the potential therapeutic implications of targeting tau in CAA and related neurodegenerative diseases
Objective and subjective sleep quality in Amnestic and Non‐Amnestic Elderly Patients: is a subjective report from the patient an accurate?
Authors: Gumenyuk Valentina , Roth Thomas , Korzyukov Oleg , Miller Nicholas , Jones Tristan , Rizzo Matthew , Murman Daniel L 
Published: January 2025

AbstractBackgroundSleep disturbances and cognitive impairments, especially memory deficiency are one of the most common complications affecting everyday life in patient diagnosed with neurodegenerative disorder. Clinically evaluated, specific cognitive processes can be grouped into two categories: amnestic functions (AMN, clinically memory impairments) and non‐amnestic functions (n‐AMN, cognitive impairments non‐memory related). To date, no cure treatments are available for AMN / n‐AMN patients, therefore maintaining the well‐being and an adequate sleep quality of people who are in prodromal state (i.e., AMN or n‐AMN is a high priority for society general and for the patient / family specifical. In this study, we compared objective sleep results to self‐reported sleep in AMN and n‐AMN groups with respect to healthy matched controls to investigate whether the self‐reported sleep results are accurateMethodSleep disturbances and cognitive impairments, especially memory deficiency are one of the most common complications affecting everyday life in patient diagnosed with neurodegenerative disorder. Clinically evaluated, specific cognitive processes can be grouped into two categories: amnestic functions (AMN, clinically memory impairments) and non‐amnestic functions (n‐AMN, cognitive impairments non‐memory related). To date, no cure treatments are available for AMN / n‐AMN patients, therefore maintaining the well‐being and an adequate sleep quality of people who are in prodromal state (i.e., AMN or n‐AMN is a high priority for society general and for the patient / family specifical. In this study, we compared objective sleep results to self‐reported sleep in AMN and n‐AMN groups with respect to healthy matched controls to investigate whether the self‐reported sleep results are accurateResultTable summarizes all results found in the study. AMN group showed lower score in cognitive memory related processes (Craft story and Benson figure recall), as compared to n‐AMN and Healthy groups. Both patient groups overestimated their SE in self‐report data as compared to SE in objective actigraphy data. In healthy group, the SE was accurately self‐reported (see Figure).ConclusionOur results suggest that regardless of the severity of memory impairments objective measure of sleep should be implemented for clinical evaluation.
Initial symptoms in individuals with Alzheimer’s or mixed Alzheimer’s‐Lewy body dementia are noted at an older age and are more likely to be amnestic in African Americans than Whites
Authors: Beamon Quintasha , Zhu Audrey , Bena James , Leverenz James B , Pillai Jagan A. 
Published: January 2025

AbstractBackgroundAmnestic initial symptoms are common in Alzheimer’s disease(AD). However initial non‐amnestic (language, executive or visuospatial) symptoms are seen in ∼20% and associated with faster progression. Given racial differences in clinical and biomarker characteristics in AD, we explored if initial cognitive symptoms differed by race of the participants among autopsy confirmed AD, Lewy body pathology (LBP) and mixed pathology (AD‐LBP).MethodsA retrospective cohort study conducted among 2422 participants with confirmed ADP, LBP, or mixed ADP‐LBP meeting neuropathogy diagnostic criteria in National Alzheimer Coordinating Center (NACC) data from 2005 to 2019. Participants at initial visit had a Clinical Dementia Rating‐Global (CDR‐G) scale ≤1. Due to sparse data in some minorities, analysis was limited to racial groups that had participants with both amnestic and non‐amnestic symptoms. This limited analysis to 93 African American (AA) and 2,299 White participants. Statistical methods including two‐sample t‐tests and Fisher’s Exact tests and Firth’s logistic regression examined the impact of race, age, sex and education on initial symptoms.ResultsInitial cognitive symptoms in AA were noted at an older age compared to Whites (mean[SD] (71[10] vs 69[10] yrs, p = 0.04) and their age at death was older (83[10] vs 81[10] yrs, p = 0.04) across neuropathologies. When the groups were evaluated within neuropathologies, age at onset differences were significant only in mixed ADP‐LBP (71[9]vs 68[10] yrs, p = 0.029) although a similar trend was noted for other neuropathologies. AA participants were less likely to have initial non‐amnestic symptoms than Whites (7.5% vs 23.6% p<0.0001). Similar results were noted when the groups were evaluated within ADP and AD‐LBP(Only 6 AA participants with LBP limited analysis). AA also differed from Whites on initial MMSE (22 vs 24, p = 0.003), CDR‐Sum of boxes (4.5 vs 4, p = 0.047), female% (51.6% vs 39.7%, p = 0.024) and education (14 vs 16yrs, p<0.001), but no difference in APOE ε4 carriers were noted. Despite considering age, sex and education in the regression model, AA had higher odds, 3.06(95%CI 1.51‐7.92) for amnestic initial symptoms compared to Whites.ConclusionInitial cognitive symptoms in AA were reported at an older age than Whites in the NACC. Non‐amnestic initial symptoms were less common among AA than Whites.