bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case report: A 50 year‐old Down syndrome man exhibiting no Alzheimer’s disease biomarker profile nor cognitive impairment. Experience from the Argentine Initiative for the Study of Down syndrome and Alzheimer’s
Authors: Clas Giulia Solange , Pertierra Lucia , Helou Belén , Tapajoz Fernanda , Guimet Nahuel Magrath , Allegri Ricardo , Marazita Mariela , Romorini Leonardo , Surace Ezequiel Ignacio 
Published: January 2025

AbstractBackgroundDown Syndrome (DS) is the most common genetic form of intellectual disability. In recent years, there has been a significant increase in the life expectancy of individuals with DS, currently reaching the age of 60 or over. However, it has been observed that as of age 40, these individuals experience higher risk of developing dementia, and almost all of them exhibit histopathological characteristics of Alzheimer's disease (AD) in their brains.As part of the first Latin American initiative for the study of Alzheimer’s disease in adults with Down syndrome (IASDA), we recruited a 50‐year‐old participant identified as SD8, who did not exhibit beta‐amyloid brain deposition and showed no signs of cognitive impairment.MethodThe absence of beta‐amyloid brain deposition was determined by positron‐emission tomography (PET) using an amyloid‐binding compound (PiB) and quantification of cerebrospinal fluid biomarkers. To explore the possibility that lack of Aβ deposition could be due to an interstitial deletion of the APP gene, we performed Array‐CGH and MLPA assays. Additionally, an exome analysis was conducted to assess the presence of Alzheimer's protective gene variants. Induced pluripotent stem cells (iPSCs) were generated from SD8 peripheral blood mononuclear cells and subsequently differentiated into neurons. This approach will enable a more in‐depth study to gain further insights into this case.ResultThese investigations revealed that SD8 possessed three copies of the APP gene, thus eliminating the possibility of an interstitial deletion. However, the exome analysis yielded no significant findings.ConclusionIn summary, in this study we present the strategies employed to delve into the possible mechanisms of SD8 being an AD “escapee” and outline our planned steps for further investigation.
Multi‐cohort analyses link plasma GDF15 with dementia, brain atrophy, and plasma biomarkers
Authors: Blew Cassandra O , Duggan Michael R , Joynes Cassandra M , Gomez Gabriela T , Tian Qu , Pilling Luke C , Chen Jingsha , Rooney Mary R , Schlosser Pascal , Herman Alison B , Tsitsipatis Dimitrios , Fornage Myriam , Gottesman Rebecca F. , Palta Priya , Lu Yifei , Ballantyne Christie M , Griswold Michael E , Coresh Josef , Walker Keenan A. 
Published: January 2025

AbstractBackgroundGrowth/differentiation factor‐15 (GDF15) has been associated with dementia risk, yet its predictive value across cohorts and sub‐population, as well as its relationship with endophenotypes relevant to dementia, remains unknown.MethodsUsing the Atherosclerosis Risk in Communities (ARIC) study as the discovery cohort, we examined the relationship between plasma GDF15 levels (SomaScan) and risk for incident all‐cause dementia (ACD) in late‐life (N=4,287, 7‐year follow‐up, Mage=75±5) and in midlife (N=11,595, 20‐year follow‐up, Mage=57±6). Utilizing the UK Biobank (UKB; replication cohort), we related plasma GDF15 (Olink) to incident ACD (N=35,673, 14‐year follow‐up, Mage=61±5), vascular dementia (VaD) and Alzheimer’s disease dementia (AD). Finally, we examined the cross‐sectional association of plasma GDF15 (SomaScan) with brain volume (N=994), white matter lesions (N=911), and plasma biomarker levels (Aβ42/40, GFAP, NfL, and pTau‐181) in cognitively normal Baltimore Longitudinal Study of Aging (BLSA) participants. Analyses were stratified by APOEε4 status, cardiometabolic diseases, education, sex, race, and obesity.ResultsLate‐life GDF15 abundance was associated with ACD risk in the full ARIC sample (HR=1.61 per log2 increase; [95% CI: 1.36‐1.90]) and in all but one subgroup – obese individuals (Figure 1A‐B). GDF15 measured during late‐life predicted 7‐year ACD risk with an AUC of 0.63 (AUC for GDF15+Age: 0.71). Midlife GDF15 was also associated with ACD risk in the full ARIC sample (HR=1.55 per log2 increase; [1.32‐1.82]) and in each subgroup (Figure 1C‐D). GDF15 measured during midlife predicted 20‐year ACD risk with an AUC of 0.65 (AUC for GDF15+Age: 0.75). We replicated GDF15’s relationship with ACD risk in the UKB sample and found that GDF15 has a much stronger association with VaD (HR=1.76 per log2 increase; [1.48‐2.10]) compared to AD (HR=1.11; [1.01‐1.23]; Figure 1E). In the BLSA, higher GDF15 was significantly associated with lower total and regional brain volume, a pattern of accelerated structural brain aging (SPARE‐BA), and elevated plasma NfL and pTau181 (Figure 2A‐G).ConclusionsPlasma GDF15 is associated with incident dementia risk across multiple cohorts, particularly vascular dementia, independent of cardiometabolic diseases and obesity. While our analyses indicate that GDF15 may play a role in dementia risk as early as midlife, GDF15, alone, provided only modest accuracy for dementia prediction.
The Knight Alzheimer Research Imaging dataset: a comprehensive multimodal resource for exploring aging, preclinical, and symptomatic Alzheimer disease pathology
Authors: Hoagey David A. , McKay Nicole S. , Gordon Brian A. , McCullough Austin A. , Schindler Suzanne E. , Xiong Chengjie , Morris John C. , Benzinger Tammie L.S. 
Published: January 2025

AbstractBackgroundThe Knight Alzheimer Research Imaging (KARI) dataset, a compilation of data from projects conducted at Washington University in St. Louis, represents a comprehensive effort to advance our understanding of Alzheimer disease (AD) through multimodal data collection. The overarching goal is to characterize normal aging and disease progression to contribute insights into the biological changes preceding AD symptom onset.MethodsThe dataset comprises cross‐sectional and longitudinal measures of magnetic resonance imaging (MRI), including T1 and T2‐weighted structural, diffusion, and resting‐state acquisitions, from over 1,600 participants aged 42 to 103 years. Additionally, a subset of participants underwent amyloid (1,100+) and tau (500+) tracer positron emission tomography (PET) acquisitions, along with cognitive, genetic, and cerebrospinal fluid (CSF) biofluid measures.ResultsIn addition to raw MRI and PET acquisitions, this dataset also includes processed output that has undergone rigorous quality assessment, anatomical segmentation, and quantification procedures using FreeSurfer, as well as post‐processing quantification of amyloid and tau burden. All data are publicly available in an online repository and can be accessed upon request.ConclusionsThe KARI dataset offers a valuable resource for investigating biomarkers, genetic factors, and imaging data in normal aging, preclinical, and symptomatic Alzheimer’s disease. Expanded use could contribute to the development of early diagnostic tools, treatment strategies, and a deeper understanding of the complexities associated with neurodegenerative diseases.
Correlation of aqueous and plasma levels of phosphorylated tau181 with age and Montreal Cognitive Assessment Scores in individuals undergoing cataract surgery
Authors: Patel Hemal , Robbins Cason B , Wisely C. Ellis , Ma Justin , Singh Pali P , Challa Pratap , Kim Terry , Grewal Dilraj S , Fekrat Sharon 
Published: January 2025

AbstractBackgroundPhosphorylated tau (p‐tau) 181 was isolated in aqueous humor and was correlated with other measures that might be consistent with Alzheimer’s disease (AD) including higher plasma p‐tau181 concentrations and lower Montreal Cognitive Assessment (MoCA blind version 7.1) scores.MethodBlood samples, aqueous humor samples, and MoCA scores were collected from patients at the time of cataract surgery. Plasma p‐tau181 concentrations and aqueous p‐tau181 concentrations were then determined using ultra‐sensitive single‐molecule assay ELISA (SiMoA) technology. Associations were tested between aqueous and plasma concentration levels, aqueous concentration levels and MoCA score, plasma concentration levels and MoCA score, aqueous concentration and age, and plasma concentration and age.Result49 eyes of 49 participants were enrolled. In this cohort, average age was 71.2 years, average MoCA score was 19.4/22, average plasma p‐tau181 concentration was 8.3 pg/mL and average aqueous p‐tau181 concentration was 3.2 pg/mL. Plasma p‐tau181 (Spearman’s rank rho=0.457, p= 0.01) and aqueous p‐tau181 (Spearman’s rank rho=0.324, p= 0.048) significantly increased with age. Higher plasma p‐tau181 was significantly associated with higher aqueous p‐tau181 (rho=0.457, p= 0.015). In 43 patients with no history of cognitive impairment, plasma p‐tau181 was negatively but not significantly associated with MoCA scores (rho= ‐0.391, p= 0.065). However, aqueous p‐tau181 was significantly negatively associated with MoCA scores (rho= ‐0.556, p= 0.009) in these patients.Conclusionp‐tau181 is measurable in aqueous humor and plasma. Its presence in the aqueous is correlated with its presence in plasma, with increasing age, and is negatively correlated with MoCA scores. Further study in individuals with mild cognitive impairment or AD confirmed by cerebrospinal fluid and volumetric MRI metrics may yield further insight.
Development of a clincally‐viable, single AAV vector for App C‐terminus CRISPR editing
Authors: Aulston Brent D , Parra‐Rivas Leonardo A , Roy Subhojit , Pizzo Donald 
Published: January 2025

AbstractBackgroundOur lab has developed a CRISPR‐based, gene‐editing strategy that targets the extreme C‐terminus (C‐term) of APP (amyloid precursor protein) – a gene with a central and indisputable role in AD. We have reported previously that APP C‐terminus CRISPRs effectively attenuate APP β‐cleavage and Alzheimer’s pathology in vivo. Here, we present new data demonstrating the feasibility and efficacy of a clinically‐viable, “all‐in‐one” therapeutic vector that has all the components needed for APP C‐terminus editing (Cas enzyme / gRNAs / regulatory elements) packaged into a single AAV.MethodAPP C‐terminus targeting gRNAs along with a SaCas9 expression cassette were cloned into AAV expression backbones and packaged into AAV‐PHP.eB capsids. Resulting AAVs were injected into APPNL‐G‐F mice and APP C‐terminus editing along with amyloid beta (Aβ) plaque pathology were evaluated.ResultAAV treated brain tissue showed wide‐spread expression of APP CRISPRs and robust APP C‐terminus editing. Both amyloid plaques and insoluble Aβ were decreased in APP CRISPR treated tissue.ConclusionThese data demonstrate in vivo feasibility of our approach and advance our long‐term goal of creating a “one‐and‐done”, single injection CRISPR therapeutic for permanent treatment of AD in human patients.
Exploring Class‐II PI3K Inhibition for the treatment of Alzheimer’s Disease: Virtual Screening for PI3KC2A Inhibitors
Authors: Jadala Chetna , Robo Michael T , Richardson Timothy I. 
Published: January 2025

AbstractBackgroundFocusing on novel AD treatments, the TREAT‐AD centers offer an array of free research tools, shared via the AD Knowledge Portal in a Target Enablement Package (TEP). This abstract showcases the research conducted by the IUSM‐Purdue TREAT‐AD Center, specifically focusing on Targeting class‐II PI3K’s as a potential breakthrough in AD therapy. Endocytosis within the brain encompasses diverse pathways for internalizing extracellular cargoes and receptors into cells. The prominent routes include clathrin‐mediated endocytosis and phagocytosis. Endocytosis plays a crucial role in processing amyloid precursor protein (APP) leading to abnormal production of Aβ peptides. Recycling endosomes are vital for delivering and eventually releasing Aβ into the brain. Recent research emphasizes the pivotal role of PI3K‐C2α, a class II PI3K member, in regulated endocytosis through its clathrin‐binding domain. Its localization spans clathrin‐coated pits, endocytic vesicles, early endosomes, and the trans‐Golgi network, generating phosphatidylinositol 3‐phosphate (PtdIns(3)P) and/or phosphatidylinositol 3,4‐bisphosphates (PtdIns(3,4)P2) in vivo. Targeting clathrin‐mediated endocytosis by inhibiting PI3K‐C2α, a key regulator in clathrin coated vesicle formation, could be a potential therapeutic strategy against Alzheimer’s disease.MethodWe conducted extensive virtual screenings of vast compound libraries to determine potent small molecules inhibiting PI3K‐C2α. Employing shape‐based screening, and clustering techniques, we identified leading compounds for subsequent in vitro kinase assays. Compounds exhibiting nanomolar activity were selected for further investigation. Leveraging these findings, we conducted Structure‐Activity Relationship (SAR) studies, optimizing analogs to enhance binding affinity and cellular pharmacology.ResultWe have identified novel PI3K‐C2α inhibitors and are in the initial stages of optimization. These compounds exhibit promising target engagement, pending further assessment for biochemical activity and cellular pharmacology. In silico assessments suggest their structures are ideal for CNS drug discovery plans.ConclusionInhibiting PI3K‐C2α stands as a promising therapeutic approach for Alzheimer’s disease. We've discovered unique molecular structures that inhibit the enzyme. Our findings suggest potential probe molecules for validating the target and developing lead compounds for clinical investigations.
Faithful Approaches: Considering Islamic Tenets in ADRD Care for Muslim Women
Authors: Irfan Bilal , Ankouni Ghadeer , Reader Jonathan M , Seraji‐Bozorgzad Navid , Giordani Bruno , Bakulski Kelly M. , Bhaumik Arijit K , Hampstead Benjamin M. , Rahman‐Filipiak Annalise 
Published: January 2025

AbstractAlzheimer’s disease and related dementias (ADRD) and its associated care pose unique challenges, particularly within minority groups such as Muslim women. This population may face higher rates of ADRD alongside barriers to accessing culturally sensitive care. This abstract emphasizes the crucial role of understanding and integrating Islamic cultural and religious practices into ADRD care. Key aspects include respecting principles of modesty and privacy, critical for women who observe hijab or niqab. There is a great heterogeneity amongst the Muslim population, spanning diverse linguistic and ethnic backgrounds, varied levels of religious observance and influence of cultural norms, and intra‐religious jurisprudential differences. Ensuring cultural sensitivity in telehealth settings, clinician‐patient interactions, and neuropsychological evaluations is paramount. Practical measures, such as providing secluded environments for virtual consultations and using educational materials featuring women in hijabs, can significantly enhance patient comfort and understanding. In clinical settings, it’s important to acknowledge some Muslim women’s preferences for female healthcare providers and minimize clothing modifications. Understanding the role of the mahram and other close family members in providing support and essential information during clinical interactions is crucial. Accommodating cultural norms during cognitive testing and other assessments is also vital for effective care. Advanced care planning for Muslim patients must be mindful of Islamic beliefs around end‐of‐life care and organ donation. The discussion of diagnostic procedures, treatment planning, and caregiving needs to be contextualized within Islamic ethics and family dynamics. Considerations such as Halal‐compliant medications and facilitating religious practices in healthcare settings are important components of patient‐centered care. This abstract highlights the necessity for healthcare providers to adopt culturally sensitive approaches that respect the values, beliefs, and practices of Muslim women with ADRD. It advocates for ongoing research and collaboration between healthcare professionals and Muslim communities to further refine these approaches. By understanding and addressing the specific needs of Muslim women, healthcare providers can offer more effective and empathetic care, thereby improving the quality of life for this underserved population in the realm of dementia care.
Understanding cognitive deficits in memory clinic patients with mixed disease by combining plasma markers and advanced diffusion MRI
Authors: Dewenter Anna , Dehsarvi Amir , Steward Anna , Biel Davina , Pescoller Julia , Zhu Zeyu , Wagner Fabian , Gross Mattes , Nuscher Brigitte , Roemer Sebastian Niclas , Buerger Katharina , Janowitz Daniel , Ewers Michael , Tiedt Steffen , Dichgans Martin , Brendel Matthias , Franzmeier Nicolai 
Published: January 2025

AbstractBackgroundMemory clinic patients typically present with Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) to varying degrees. Therefore, it is crucial to determine the etiology of cognitive deficits for facilitating patient‐centered treatment in memory clinics. Plasma biomarkers (ptau217, Glial Fibrillary Acidic Protein [GFAP], Neurofilament light chain [NfL]) and fixel‐based advanced diffusion MRI markers (fiber density, fiber‐bundle cross‐section) show potential towards disentangling AD‐ and SVD‐related brain changes (Dewenter et al., Brain, 2023). However, their predictive power in understanding heterogeneous and SVD/AD‐specific cognitive deficits in memory clinic patients remains incomplete. We assessed i) how plasma‐based and fixel markers explain AD‐typical and SVD‐typical cognitive deficits and ii) their interrelation to uncover disease‐specific mechanisms.MethodWe included n=76 in‐house memory clinic patients with Simoa‐based plasma ptau217, GFAP and NfL assessments, comprehensive neuropsychological testing (CERAD‐plus battery) and 3T MRI. Global white matter hyperintensity (WMH) volume and average skeletonized mean diffusivity (MD) were included as well‐established SVD markers. AD severity was probed through plasma ptau217 and cortical thickness of the pre‐established AD signature ROI. Advanced diffusion MRI was used to assess fiber density and fiber bundle cross‐section of key white matter tracts (Figure 1A).ResultUsing linear regression, increased ptau217, reduced cortical thickness in AD signature ROI and fiber‐bundle cross‐section were highly associated with impaired episodic memory, i.e. a typical AD‐related symptom (Figure 1B, Figure 2A). In contrast, GFAP and NfL increases and reductions in MSMD and fiber density were associated with executive dysfunction, a typical sign of SVD‐related cognitive impairment (Figure 1B, Figure 2A). Additionally, fiber density was associated with GFAP and NfL levels, while fiber bundle‐cross section, a macroscopic marker of tract atrophy, was not associated with any of the plasma markers (Figure 2B).ConclusionPtau217 displayed high sensitivity and specificity for AD‐typical memory impairment, whereas GFAP and NfL were associated with SVD‐typical processing speed and executive impairment. Additionally, fiber density, a pre‐established imaging marker for SVD, was associated with GFAP and NfL. This highlights the effectiveness of these markers in distinguishing and characterizing SVD and AD in memory clinic patients and emphasizes the importance of considering concomitant SVD in patients with elevated GFAP and NfL levels.
Differential effects of sex on hippocampal volume and cortical thickness in a racially and ethnically diverse cohort across the Alzheimer’s disease continuum
Authors: Levine Taylor F , Caldwell Jessica ZK 
Published: January 2025

AbstractBackgroundAlthough substantial literature supports sex differences in Alzheimer’s disease (AD), many research samples comprise predominantly non‐Hispanic white (NHW) participants, limiting generalizability. Work from our group in mainly‐NHW cohorts suggests a female‐specific time‐limited resilience in cortical thickness (CT; Cieri et al., 2022) and possibly hippocampal volume in the presence of amyloid (ADNI: Caldwell et al., 2017; Caldwell et al., 2018; but c.f., BioFINDER: Caldwell et al., 2019). Here, we investigated brain‐based sex differences in a racially and ethnically diverse AD cohort.MethodWe obtained data from the Health and Aging Brain Study‐Health Disparities and included 798 self‐reported NHW, 470 Black American (BA), and 713 Mexican American (MA) participants. We examined sex differences in structural resilience, as defined by stable hippocampal volume (HCV) and cortical thickness (CT; including superior and middle temporal, isthmus and posterior cingulate, precuneus, and inferior parietal) in the presence of AD pathology (plasma Aβ42/Aβ40). We hypothesized that women would show structural resilience when cognitively normal (CN; CDR=0) but not when mildly cognitively impaired (MCI; CDR=.5‐1).ResultsA significant moderation was observed for NHW individuals, such that CN women showed no relationship between HCV and Aβ42/Aβ40, whereas MCI women showed greater atrophy with increasing pathology (Right: p=.027; Left: p=.043). The same pattern was observed in BA men, who showed no relationship between HCV and Aβ42/Aβ40 when CN, but more atrophy with greater pathology when MCI (Right: p=.003; Left: p=.007). CT moderation analyses revealed a similar pattern of structural resilience in BA CN women in the left precuneus (p=.026) and left inferior parietal region (p=.026), and in MA CN men in right middle (p=.038) and left superior temporal regions (p=.028).ConclusionAs in some prior studies, CN NHW women showed time‐limited HCV resilience in the presence of amyloid; BA women also showed time‐limited CT resilience. Counter to expectations, resilience also was observed in CN BA men (HCV) and CN MA men (CT). Further work is needed to parse complex patterns of resilience and vulnerability across racial and ethnic groups, and to understand causal factors underlying these patterns.