bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advancing Alzheimer’s disease and related dementias (ADRD) and COVID‐19 research by linking real‐world data with a standardized longitudinal ADRD data platform
Authors: Biber Sarah A , Prado Maria G , Culhane Jessica E. , Phuong Jim , Keller Ben , Lerch Melissa , Wang Sophia , Noble James M. , Moulder Krista L. , Saykin Andrew J. , Gao Sujuan , Lai Albert , Natarajan Karthik , Kukull Walter A. , Mooney Sean , Stephens Kari 
Published: January 2025

AbstractBackgroundPersons with Alzheimer’s disease and related dementias (ADRD) have been disproportionally impacted by the COVID‐19 pandemic, showing a significantly increased risk of infection and severe illness, including neurocognitive consequences. The National Alzheimer’s Coordinating Center collects rich longitudinal, standardized neurocognitive data from populations at high risk of COVID‐19 complications, including older adults who were cognitively normal prior to infection and those who had pre‐existing ADRD. These data, in combination with Electronic Health Records (EHR) clinic data, will be critical for understanding the complex pathophysiology and cognitive symptoms of COVID‐19 and the development of future therapeutics. To rapidly respond to the COVID‐19 epidemic, the present study developed a novel socio‐technical solution for the Alzheimer’s Disease Research Centers (ADRC) Program to expand longitudinal COVID‐19 data collection, integrate new data streams, and open the door to impactful new COVID‐19 and ADRD discoveries.MethodWe linked EHR, Medicare claims, and genetic data with rich standardized longitudinal cognitive assessment data collected from across the ADRC Program and housed at NACC. This project included the development and deployment of standardized IRB and consent language and a new data use agreement to provide access to all data steams within the LINKAGE enclave. It also leveraged an OMOP model to collect, harmonize, and integrate EHR data from participating ADRCs. The governance materials and technical pipelines developed will allow us to scale our solution across the heterogeneous consortium of 37 ADRCs.ResultThe new team science model we developed facilitates collaborations between informatics leaders and ADRD leaders within and across institutions. Our approach supports development and dissemination of best practices to advance data interoperability and will facilitate researchers asking and answering new questions at the intersection of COVID and ADRD. The projected cohort size for this pilot study across three ADRCs is: cognitively normal (1,109), mild cognitive impairment (214), and dementia (224).ConclusionOnce scaled to the full ADRC Program, this platform will provide one of the largest and most comprehensive longitudinal multimodal datasets in the world for an age group at high risk for COVID‐19 infection. Additionally, the dataset includes valuable cognitive, behavioral, and genetic data collected prior to COVID‐19 infection.
Human cerebrospinal fluid extracellular vesicle miRNAs identify sex‐dependent changes in synaptic proteins in postmortem Alzheimer’s disease brain
Authors: Sandau Ursula S , McFarland Trevor J. , Setthavongsack Naly , Smith Sierra J , Galasko Douglas R. , Quinn Joseph F , Woltjer Randy L , Saugstad Julie A 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the fifth leading cause of death for individuals aged 65 and older. Since FDA approved therapies have limited efficacy, there is a need to develop new treatments based on a better understand of pathological changes occurring in tissues from humans with AD. Central nervous system cells utilize extracellular vesicles (EVs) to package and secrete miRNAs where they mediate cell‐to‐cell communication. Importantly, cerebrospinal fluid (CSF) contains EVs derived from the brain whose contents – including miRNAs – reflect the originating cell’s molecular composition. Thus, we used CSF EV miRNAs to identify neurologically relevant genes and canonical pathways altered in the human AD brain.MethodHuman CSF from AD (n = 28) and controls (n = 28) was fractionated by size exclusion chromatography to separate EVs. CSF EV miRNAs were assayed by qPCR and used for target prediction and Ingenuity Pathway Analysis. Human postmortem hippocampus from AD (n = 34) and control (n = 22) were used to measure SNAP‐25, MUNC18‐1, and Reelin by immunoblot. Human hippocampal sections were co‐labeled for SNAP‐25 and miR‐16‐5p in AD (n = 4) and control (n = 3). MiR‐16‐5p puncta were analyzed using Zen Intellesis AI Segmentation software.ResultFour miRNAs (miR‐16‐5p, ‐331‐3p, ‐409‐3p, ‐454‐3p) were significantly increased in AD CSF EVs compared to control EVs. Further, the increase in miR‐16‐5p and ‐331‐3p occurred only in AD females with APOEe3/e4 genotype. Conversely in males, miR‐16‐5p and ‐331‐3p showed no group differences. The predicted targets of miR‐16‐5p include mRNAs integral to synaptic transmission (SNAP‐25, MUNC18‐1, Reelin), which were significantly decreased in the hippocampus of AD females, compared to control females. While in males these protein targets were not changed in AD. Co‐labeling of human brain sections demonstrated that miR‐16‐5p and SNAP‐25 are both expressed in cortical grey matter and preliminary analysis shows a trend of increased miR‐16‐5p in AD.ConclusionWe demonstrate that the miRNA cargo of CSF EVs is impacted by AD, sex, and APOE4 status. Also, CSF EV miRNAs have the potential to identify therapeutic targets to treat or cure AD. These data also demonstrate pathological changes in AD are sex‐ and genotype‐dependent, which may need to be considered for drug development and/or treatment strategies.
Neighborhood Disadvantage and Its Effects on Cognitive Health and Vascular Risk in Veterans
Authors: Deering Olivia , Van Hulle Carol A. , Zylstra Hannah , Cronin Kate , Cole Aleshia , Beckman Elena , Eierman Allison C , Blazel Madeleine , Lazar Karen K , Johnson Kevin M. , Rivera‐Rivera Leonardo A. , Chapell Richard , Zetterberg Henrik , Gleason Carey E. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M. 
Published: January 2025

AbstractBackgroundPrior research has highlighted the impact of neighborhood quality on health outcomes. Given veterans' unique experiences and challenges, exploring the association between neighborhood quality on cognitive measures and vascular risk scores is crucial for guiding targeted interventions, improving overall cognitive well‐being, promoting health equity, and contributing to our understanding of Alzheimer’s Disease (AD) risk factors.MethodThe Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid study (BRAVE) was an 18‐month randomized, placebo‐controlled, double‐blind, clinical trial conducted at William S. Middleton Memorial Veteran’s Hospital in Madison, Wisconsin. This analysis used cross‐sectional data on VA‐eligible Veterans between the ages of 50 and 75 with no clinical diagnosis of a memory disorder. Study analyses included N = 201 Veterans who completed pre‐study screening and N = 129 who completed a baseline visit. Cognitive outcomes were collected at the baseline visit and ASCVD scores were collected during screening. Of the Veterans who completed a pre‐study screening, live in Wisconsin (N = 164), Illinois (N = 34), Iowa (N = 2) and Minnesota (N = 1). The main outcomes are ASCVD risk score and Preclinical Alzheimer’s Cognitive Composite (PACC). The Area Deprivation Index (ADI) state decile measures neighborhood quality on 18 metrics. For this study, participants in the most disadvantaged (ADI 7‐10) were compared to participants in the least disadvantaged neighborhoods (ADI 1‐6).ResultIn the prescreening cohort, 87.7% of participants were male and 89.4% non‐Hispanic, white. In the baseline cohort, 84.5% of participants were male and 94.7% were non‐Hispanic, white. PACC scores were significantly lower (PACC; p = 0.007; Cohen’s D = 0.562) for participants living in the most disadvantaged neighborhoods (‐0.42, SD = 0.98, N = 31) compared to the least disadvantaged (0.13, SD = 0.97, N = 98). The group mean differences in ASCVD scores were not statistically significant.ConclusionOur findings reveal that Veterans in the most disadvantaged neighborhoods exhibit lower cognitive performance. We found no significant association between neighborhood disadvantage and cardiovascular risk scores. These findings emphasize the importance of implementing targeted interventions to address cognitive health disparities in disadvantaged areas. Further exploration with a larger and more representative sample is essential to gain a comprehensive understanding of the relationship between neighborhood disadvantage, cognitive health disparities, and cardiovascular risk factors among Veterans.
Genetic associations with amyloid, tau, and neurodegeneration: an ADSP neuroimaging study
Authors: Mamourian Elizabeth , Bao Jingxuan , Cui Yuhan , Huang Heng , Saykin Andrew J. , Thompson Paul M. , Moore Jason H. , Ritchie Marylyn D. , Kim Dokyoon , Davatzikos Christos , Shen Li 
Published: January 2025

AbstractBackgroundThe amyloid‐tau‐neurodegeneration (ATN) framework provides a valuable model for comprehending the pathophysiology and progression of Alzheimer’s disease (AD). However the relationship between and genetic interaction with these three characteristics are complex and not fully understood. Here, we use neuroimaging‐derived quantitative traits to evaluate the genetic risk for amyloid accumulation, tau pathology, and neurodegeneration.MethodThe Alzheimer’s Disease Sequencing Project (ADSP) collected and harmonized whole genome sequencing (WGS) and quantitative phenotype data. This study examines harmonized neuroimaging traits, including 3 Amyloid‐PET features in N = 1,217 participants (Age = 72.6±8.1 years, Sex = 48.9% female), 6 Tau‐PET features in N = 470 participants (Age = 74.0±8.6 years, Sex = 53.8% female), and 20 selected T1 MRI derived volumetric measures of neurodegeneration in N = 2,644 participants (Age = 72.6±8.3 years, Sex = 52.0% female). We conducted genome wide association studies (GWAS) using Plink on the QC'ed WGS data of over 7.1 million variants for each trait, correcting for the top 10 principal components, age, and sex; for volumetric measures, we also control for intracranial volume.ResultWe found associations at the genome‐wide significance threshold for all three characteristics, including N = 56 SNPs associated with Amyloid phenotypes, N = 53 SNPs associated with Tau phenotypes, and N = 77 SNPs associated with Neurodegeneration phenotypes (Fig. 1). The strongest associations to Amyloid phenotypes (amyloid positivity, centiloid values) overlap with Neurodegeneration phenotypes (hippocampal volume) in chromosome 19, with the lead SNPs located in APOE. We found an additional region on chromosome 6 significantly associated with Tau phenotypes (Braak staging), but not Amyloid or Neurodegenerative phenotypes (Fig. 2).ConclusionThese results provide additional evidence supporting the genetic contributions to risk of ATN pathology, confirming that variants in APOE and the surrounding region of chromosome 19 are strongly associated to amyloid positivity and hippocampal atrophy. These findings also support the genetic basis of a tau‐specific AD pathway. These results yield new insights into the genetic risk for amyloid accumulation, tau pathology, and neurodegeneration using the harmonized ADSP quantitative traits.
Association of mid‐life blood pressure status with longitudinal trajectories of blood‐based biomarkers of Alzheimer’s disease neuropathology and neurodegeneration in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Chen Jinyu , Pike James Russell , Lu Yifei , Gottesman Rebecca F. , Walker Keenan A. , Gu Zhengyi , Mielke Michelle M. , Sedaghat Sanaz , Sullivan Kevin J. , Thyagarajan Bharat , Sharrett Richey , Mosley Thomas H. , Coresh Josef , Palta Priya 
Published: January 2025

AbstractBackgroundCurrent blood biomarkers of Alzheimer’s disease (AD) neuropathology and neurodegeneration include the ratio of amyloid‐β 42 to 40 (Aβ42/Aβ40), phosphorylated tau at threonine 181 (p‐Tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Prior studies have reported that hypertension is cross‐sectionally associated with lower levels of Aβ42/Aβ40 and longitudinally associated with faster accumulation of NfL. In this longitudinal investigation, we expanded on prior research by examining whether mid‐life blood pressure status was associated with change in AD biomarkers from mid‐ to late‐life.MethodIn the Atherosclerosis in Communities Study (ARIC) cohort, 1424 participants had blood pressure measurements at Visit 3 (baseline, 1993‐95) and two or more measurements of AD blood biomarkers from Visit 3, Visit 5 (2011‐13), and Visit 6 or 7 (2016‐2019). Linear mixed effects models quantified the association of mid‐life blood pressure status (hypotension, SBP<90 or DBP<60; hypertension, SBP>130 or DBP>90; normotension) with the rate of change in each AD blood biomarker. Models were adjusted for age, sex, race, education, the presence of apolipoprotein ε4 (APOE ε4) alleles, time‐varying body mass index and estimated glomerular filtration rate, and baseline cardiovascular and lifestyle risk factors.ResultThe sample included 860 women (60.4%) and 364 Black participants (25.6%). At baseline, 143 participants (10.0%) had hypotension and 449 (31.5%) had hypertension. Compared to participants with normotension, mid‐life hypertension was associated with accelerated accumulation of NfL from mid‐ to late‐life (Table 2). Both mid‐life hypotension and hypertension were associated with accelerated accumulation of pTau‐181 from mid‐ to late‐life. In subgroup analyses, these associations were greater among women, Black participants, and individuals without APOE ε4 alleles.ConclusionMid‐life hypotension and hypertension are associated with faster changes in both AD‐specific (pTau‐181) and neurodegenerative (NfL) biomarkers from midlife to late‐life. Future investigation is needed to determine whether hypotension and hypertension are on the causal pathway relating AD neuropathology to dementia or if abnormal blood pressure and faster accumulation of pTau‐181 are shared characteristics of other comorbidities.
The effect of gantenerumab treatment on brain functional connectivity
Authors: Gobbi Susanna , Klein Gregory , van den Heuvel Martijn , Magon Stefano 
Published: January 2025

AbstractBackgroundChanges in brain functional connectivity obtained from resting state MRI (rs‐fMRI) have been found to be associated with cognitive decline and neurodegeneration in clinical trial participants with Alzheimer’s disease (AD). This study investigates whether and how this technique can be used in AD clinical trials to monitor treatment effects. Specifically, we analyzed changes in brain functional connectivity over a period of 116 weeks in participants with AD treated with gantenerumab, an investigational anti‐amyloid beta monoclonal antibody. Although this drug did not meet the primary clinical endpoints, some significant associations were found with exploratory biomarkers.MethodWe analyzed rs‐fMRI of participants with MCI due to AD and mild AD at screening and week 116 collected in a subgroup of the randomized, double‐blind, pivotal, Phase III trials GRADUATE I (273 patients, 52% female, 50% placebo) and GRADUATE II (335 patients, 59% female, 57% placebo) (NCT03444870, NCT04374253). Using group Independent Components Analysis (GIFT, Calhoun et al., 2001), we extracted 25 resting states components in each clinical trial and grouped them into 7 networks (Sensory Motor, Cerebellar, Visual, SubCortical, Auditory, Default Mode and Cognitive Control). Using a linear model, we investigated changes in between‐ and within‐networks brain connectivity at screening and week 116 in gantenerumab and placebo participants. The components‐wise Pearson’s correlation (Z‐Fisher score) was used as the dependent variable, group (gantenerumab vs placebo), visit (screening vs week 116) and the interaction term group‐by‐visit as covariates of interest, while controlling for sex, age and scanner magnetic field strength (1.5T vs 3T). This analysis was exploratory in nature and no adjustment for multiple components‐wise comparisons was applied.ResultIn both GRADUATE I and II, we found a significant group‐by‐visit effect (p < 0.05). Specifically, we found decreasing within‐ and between‐networks functional connectivity in the placebo group at week 116 compared to screening. Conversely, the gantenerumab group reported stable or higher connectivity at week 116 compared to screening (Fig. 1‐2).ConclusionThese results suggest a potential relationship between amyloid removal and changes in brain functional connectivity. Due to the exploratory nature of this study further investigation is needed to confirm these findings.
A tablet‐ and virtual reality‐based training for preventing and detecting cognitive decline: a usability study
Authors: Zuschnegg Julia , Schultz Anna , Paletta Lucas , Dini Amir , Linzer Amadeus , Berger Ursula , Kratky Wolfgang , Goldgruber Judith , Koini Marisa , Russegger Silvia , Draxler Sandra , Orgel Thomas , Schneeberger Michael , Pszeida Martin , Weiss Wolfgang , Schüssler Sandra 
Published: January 2025

AbstractBackgroundVirtual Reality (VR) is hailed as a top emerging technology for older adults in healthcare. Despite its potential, limited research exists on VR applications for individuals with cognitive decline, particularly in leisure‐based cognitive training, as opposed to traditional (instrumental) activities of daily living (I)ADL training such as shopping. The SmartAktiv project has developed immersive VR leisure experiences with (I)ADL cognitive training embedded, aiming to enhance cognition in a playful manner and detect early cognitive deficits. We assessed the usability of the SmartAktiv VR‐based intervention combined with a tablet‐based training among participants before initiating a pilot study.MethodHealthy older adults (n = 4), people with suspected mild cognitive impairment (MCI) (n = 4), people with suspected dementia (n = 4) (according Montreal Cognitive Assessment, MoCA) and healthcare professionals (n = 4) tested the combined tablet‐ and VR‐based training (hiking tour scenario). After the intervention, qualitative focus groups were held with each group to gather insights into training’s usability from participants' experiences. Furthermore, cybersickness (Simulator Sickness Questionnaire, SSQ) was measured.ResultOlder adults (MoCA, x̅ 27.00±1.41 points), people with suspected MCI (MoCA, x̅ 23.25±1.26 points) those with suspected dementia (MoCA, x̅ 16.00±0.00 points) and healthcare professionals experienced negligible cybersickness after the training (SSQ, x̅ 6.98±5.26 points). Qualitative findings indicated positive perceptions of the intervention among all participants. Participants appreciated the variety of cognitive exercises (e.g., quiz, puzzle) in the tablet‐training program, but emphasized the need for greater sensitivity of the tablet‐PC and the necessity of a tablet pen. The immersive VR hiking tour was very well‐received, evoking a longing for nature, especially among older individuals (with/without cognitive impairment). They found the interactive cognitive (I)ADL tasks enjoyable/fun, with some even reporting feeling more alert/euphoric afterwards. However, hand tracking issues arose in certain VR tasks (e.g., picking mushrooms), and low contrast made some VR elements difficult to perceive (e.g., payment for train).ConclusionThe findings offer insights into the usability of the combined tablet‐ and VR‐based (I)ADL cognitive training, to be considered for a pilot study. This pilot study will test four scenarios (hiking tour, beach vacation, city trip, winter outing) on individuals (n = 30) with and without cognitive decline.
“I’m worth saving”‐ a qualitative study of people with dementia considering treatment with lecanemab
Authors: Thacker Ayush , Parks Anna L , Dohan Daniel , Gomez Liliana A Ramirez , Ritchie Christine S , Paladino Joanna , Shah Sachin J 
Published: January 2025

AbstractBackgroundAs lecanemab becomes available to people living with dementia, there is a pressing need to understand how they weigh the potential benefits against costs. This study investigates how older adults perceive lecanemab’s risks and benefits and their approach to treatment decisions.MethodsSemi‐structured interviews of older adults undergoing evaluation in Neurology clinics for lecanemab eligibility at two academic medical centers. An interdisciplinary research team used rapid thematic analysis guided by the Ottawa Decision Support Framework.Results22 people completed interviews (mean age 70 years, 36% women, 100% white). Preliminary themes included: 1) Hopes, expected benefits, and the existential threat of dementia driving willingness and readiness to start lecanemab. Hopes included more time with family and more time feeling like themselves by stalling the progression of cognitive decline and amyloid build‐up. Some expected benefits included “getting back to where I was” and “getting better, not worse.” Some patients pursued Lecanemab because it would be doing ‘something’ (versus nothing), given the fear and stress of dementia. 2) Patients sought and obtained information from different sources, including advocacy organizations, the Internet, and clinicians. Patients desired more information about their personal risk and wanted to hear more from patients who took the medication. 3) Individual traits and preferences, family factors, and degree of trust in expertise influence how patients balance risks and benefits. Some patients were willing to accept treatment at any cost, either due to the perceived inevitability of decline without intervention or because they tend to “look past the negatives” when making decisions. Others weighed risks (e.g., brain bleeding) and financial and logistical costs carefully, but supportive families, insurance coverage, and trust in the system helped in their decision to start treatment. A small proportion of people would not get the treatment as the costs outweighed their personal benefit.ConclusionsThis group of people with mild dementia who are at the forefront of lecanemab treatment showed variation in hopes for treatment, information sought and obtained, and contextual factors in decision‐making, supporting the need for an individualized approach. These insights can guide future interventions to improve individualized decision‐making for lecanemab treatment.