bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subtype‐specific patterns of tau pathology in Alzheimer’s and related disorders
Authors: Hobbs Diana A , Doering Stephanie , McCullough Austin A. , Millar Peter R , Flores Shaney , Keefe Sarah J. , Sotiras Aristeidis , Benzinger Tammie L.S. , Day Gregory S , Gordon Brian A. 
Published: January 2025

AbstractBackgroundAlzheimer disease (AD) involves neurodegenerative disorders with progressive cognitive decline. Atypical presentations like Posterior Cortical Atrophy (PCA) and Logopenic Variant Primary Progressive Aphasia (lvPPA) exhibit distinct clinical profiles. PCA affects the posterior parietal and occipital lobes, causing visuospatial deficits, while lvPPA manifests as language impairment in the temporoparietal region. Understanding the biological underpinnings of these variants is crucial for deciphering AD’s heterogeneity.MethodParticipants diagnosed with AD dementia (n = 54, female = 25, Age: 75.23±6.52), PCA (n = 9, female = 8, Age: 62.78±7.21), and lvPPA (n = 6, female = 2, Age: 66.33±6.38) from the Knight Alzheimer Disease Research Center (Knight ADRC) underwent 18F‐AV‐1451 tau‐PET imaging. Tau deposition, along with nine biological properties, was mapped to the cortical surface (Figure 1A): gene expression, myelin, cortical thickness, sensorimotor association axis, evolutionary expansion, cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of glucose (CMRglu) (Figure 1B). Correlation matrices and generalized linear models (GLMs) assessed relationships between tau accumulation and biological properties.ResultA correlation matrix (Figure 2A) shows significant positive associations (p<0.05) between evolutionary expansion patterns and tau accumulation in AD (r = 0.53), PCA (r = 0.29), and lvPPA (r = 0.56); and gene expression in PCA (r = 0.51). Conversely, strongest negative associations were observed in AD (r = ‐0.38, r = ‐0.15) and lvPPA (r = ‐0.18, r = ‐0.28) for CBF and myelin mapping, respectively, and in PCA (r = ‐0.25, ‐0.23) for cortical thickness and sensorimotor association axis. GLMs demonstrated significant relationships between cerebrovascular health and evolutionary expansion with tau measures across all groups. AD (r = ‐0.52) and PCA (r = ‐0.19) exhibited negative associations with gene expression and myelin mapping, respectively. Additionally, lvPPA (r = 0.39) displayed positive association with the sensorimotor association cortex.ConclusionResults elucidate distinct tau deposition patterns in AD, PCA, and lvPPA, providing insights into subtype‐specific pathophysiology. The correlation matrix and GLMs highlight the significance of evolutionary expansion and cerebrovascular health in tau accumulation. Associations underscore the complex interplay of gene expression, myelin mapping, and cortical thickness with tau pathology. Findings contribute to understanding heterogeneity within AD spectrum disorders, emphasizing the multifaceted nature of neurodegenerative processes. Further research promises refined diagnostic and therapeutic strategies tailored to distinct neurobiological profiles in AD, PCA, and lvPPA.
Mixed pathologies and cognitive outcomes in older persons ‘possibly’ eligible for anti‐amyloid treatment: a community‐based study
Authors: Kapasi Alifiya , James Bryan D , Yu Lei , Bennett David A. , Boyle Patricia A , Schneider Julie A. 
Published: January 2025

AbstractBackgroundThe recent approval of two anti‐amyloid antibodies, Aducanamab and Lecanamab, have set the stage for the next generation of anti‐amyloid treatments. Despite the capability of these treatments to lower Aβ brain levels, there is thus far limited clinical efficacy on cognitive outcomes. Because eligibility for treatment includes individuals with MCI or mild dementia, that often harbor mixed pathologies, the cognitive impact of other brain pathologies may be important. This study investigated mixed brain pathologies from autopsied persons that would be considered eligible for anti‐amyloid treatment and the association of pathologies with rate of decline in global cognition and five cognitive domains.MethodEligibility was defined based on having an MMSE score ≥ 20, a clinical diagnosis of MCI or Alzheimer’s dementia, and a level of Aβ pathology that would be indicative of having a positive amyloid PET scan (CERAD score≥moderate). We examined the number and types of co‐pathologies. Mixed‐effect models were employed to examine association of pathologies (β‐amyloid, tangles, LATE‐NC, infarcts, and LB) with rate of decline in global cognition and across 5 cognitive domains.ResultAmong 428 older autopsied persons (mean age at death = 90 years) considered possibly eligible for anti‐amyloid treatment, 58% had MCI and 42% had mild dementia. The majority (94%) had a pathologic diagnosis for AD, of which most had ≥ 1 co‐pathology; 43% had +1 co‐pathology, 22% had +2 co‐pathologies, and 3% had +3 co‐pathologies. Regarding type of co‐pathologies, 37% had AD + infarcts, 36% had AD + LATE, and 24% had AD + LB. In mixed‐effect models, tangles were associated with a faster rate of global cognitive decline, specifically in the domains of episodic (estimate = ‐0.04; SE = 0.01; p<0.001) and semantic memory (estimate = ‐0.02; SE = 0.01; p = 0.001). Independent of tangles, LATE‐NC and β‐amyloid were also associated with decline in episodic (estimate = ‐0.03, SE = 0.01; p = 0.004) and semantic memory (estimate = ‐0.02; SE = 0.01, p = 0.04), respectively. Infarcts and LB were not associated with decline in global cognition or any cognitive domains.ConclusionMixed pathologies are common in this group of community‐dwelling older persons possibly eligible for anti‐amyloid treatments. Tangles and LATE‐NC pathologies drive late‐life cognitive decline, especially episodic memory.
A comparison of cognitive factors identified by Exploratory Factor Analysis of the original ADAS‐cognitive subscale and a novel extended version in mild cognitive impairment and Alzheimer’s dementia
Authors: Overby Mark S. , McGinity Sean , Botchway Albert , Zec Ronald F. , Ala Thomas A. , Settelmyer Zachary , Ranjit Eukesh , Shah Raj C. , Hascup Erin R. , Trivedi Mehul A. 
Published: January 2025

AbstractBackgroundThe original Alzheimer’s Disease Assessment Scale – Cognitive Subscale (oADAS) is one of the most common measures of cognition used in clinical trials of Alzheimer’s dementia (AD). Despite this, the oADAS has faced criticism for lacking sensitivity to Mild Cognitive Impairment (MCI), potentially due to ceiling effects for certain subsets. Many attempts have been made to improve the sensitivity of the oADAS to MCI by including additional subtests. We previously used exploratory factor analysis (EFA) on the subtests from the oADAS and a novel extended version of the ADAS (eADAS). We identified two factors for both the oADAS (general and praxis factors) and the eADAS (memory/speed and general factors). In the present study, we examined group differences between normal controls, MCI, and AD on the four factors previously identified.MethodThis analysis included data from 680 normal controls above the age of 60 who were participants in the SIU Longitudinal Cognitive Aging Study (SIU LCAS), 63 individuals with amnestic MCI (MCI), and 51 individuals with possible/probable AD. Participants were administered the oADAS using standardized procedures along with an extended version (eADAS) that included additional measures of processing speed, language, learning/memory, and visuospatial skills. A 3‐group ANCOVA was completed between control, MCI, and AD groups and the four factor components. Age, gender, and education were included as covariates.ResultFor the oADAS, a general factor was able to discriminate between the three groups (p’s<0.001) while a praxis factor showed differences between control and AD groups and between MCI and AD groups (p’s<0.001) but not between MCI and controls (p>.90). For the eADAS, both a memory/speed factor and a general factor were able to significantly discriminate between all three groups (p’s<0.05).ConclusionThis study demonstrated that most of the identified cognitive factors were able to discriminate between the three groups with the exception of the praxis factor from the oADAS, which did not demonstrate significant differences between the MCI and control groups. More research is needed to further determine which subtests from the oADAS and eADAS are most sensitive to cognitive changes in normal and abnormal cognitive aging.
Harnessing the Potential of Human iPSC‐derived Microglia‐like Cells as Antigen Presenting Cells for MAIT Cells to Study AD Pathology
Authors: Afify Reham , Brutkiewicz Randy R 
Published: January 2025

AbstractBackgroundMicroglia are dominant immune cells residing in the brain that regulate brain homeostasis and T‐cell responses. An important immune function of microglia involves presenting microbial antigens to mucosal‐associated invariant T (MAIT) cells; MAIT cells recognize microbial vitamin B‐derived metabolites presented by the MHC class I‐like molecule, MR1. Our recent findings highlighted a detrimental role for the MR1/MAIT cell axis in Alzheimer’s disease (AD) using the 5XFAD mouse model. Here, our work is focused on how the MR1/MAIT cell innate immune axis in humans contributes to AD, using iPSC‐derived human microglia‐like cells (iMG) to provide potential mechanistic insights underlying the MR1/MAIT cell axis in AD. As an initial evaluation, we have assessed the activation of iMG and their potential as functional antigen presenting cells (APC) to MAIT cells when exposed to a microbe that can provide a MR1‐presented, MAIT cell‐specific antigen, such as from E. coli.MethodsInitially, we will generate iMG from healthy donors that will be incubated with E. coli for the assessment TNF‐α levels using ELISA as a readout of microglial activation. Subsequently, coculture experiments with human MAIT cells and E. coli‐stimulated iMG will provide an initial evaluation of microglial MR1‐dependent MAIT cell activation via MR1‐dependent antigen presentation, monitored by MAIT cell production of various cytokines measured by ELISA.ResultsWe expect that iMG will produce increased levels of TNF‐α in response to E. coli compared to the control group. Similarly, we anticipate elevated cytokine levels secreted by MAIT cells via an MR1‐dependent pathway.ConclusionsThese experiments will allow us to apply our human iPSC‐based model to studying human microglia as APC and pave the way for a broader understanding of the contributions of the MR1/MAIT cell axis in AD. To our knowledge, our proposed study will be the first of its kind to utilize iMG as APC for human MAIT cells.
Impact of age at immigration on neuropsychological assessments among older South Asian Americans
Authors: Kota Karthik , Hundal Jasdeep , Sotelo Victor , Dawson Allison , Sarkar Shromona , Hu William T. 
Published: January 2025

AbstractBackgroundSouth Asian (SA) Americans are underrepresented in US Alzheimer’s disease and related dementias (ADRD) research. Despite sharing common languages, SA Americans differ from those in South Asia in education, health‐related behaviors, and environmental exposures. NYC/NJ‐area SA communities overwhelmingly revealed English‐based neuropsychological testing preference given that many speak non‐Hindi languages. Further complicating testing is evidence of non‐cognitive/linguistic factors influencing SA adults’ performance. For example, mean performance on the language‐independent Trail Making Test A (TMT‐A) among older adults across five Indian cities was <1st percentile. We thus recruited an older SA American cohort without subjective cognitive complaints to undergo neuropsychological testing, correlating performance with immigration‐related variables.Method65 SA participants completed neuropsychological testing, assessing memory (logical memory, CERAD word list, Benson complex figure), attention/speed (forward digit span [FD], TMT‐A), executive (reversed digit span [RD], TMT‐B, symbol digit substitution test [SDST], letter‐guided fluency [FAS]), language (Multilingual Naming Test [MINT], Boston Naming Test [BNT‐60], and visuospatial functions (Judgement of Line Orientation [JOLO]). Z‐scores derived from the National Alzheimer’s Coordinating Center calculators underwent linear regression modeling to determine influence from age (first learning English, at immigration), years in the US, and education (native country vs US).ResultParticipants (30 women and 35 men) had a median age of 65 years (range 24‐86) and median education of 18 years (range 12‐20), with a median 16 in home country (range 3‐20); they were a median age of 30 (range 8‐69) years at immigration and had a median US residency of 32 years (range 4‐59). Age at immigration (story recall, TMT‐A, MINT, BNT, category fluency‐animals, JOLO) and years in the US (category fluency‐vegetables, word list learning and recall) had the greatest influence on neuropsychological performance, and two tests (story learning, letter‐guided fluency) were influenced by both. Five tests (Benson complex figure immediate and delayed recall, FD, RD, TMT B) were uninfluenced by immigration‐related factors.ConclusionIn addition to age, gender, and education, neuropsychological performance interpretation among SA Americans must account for age at immigration, years in the US, or both. Acculturation and familiarity with aptitude testing – potentially in language‐independent ways – likely influenced SA Americans’ neuropsychological analysis outcomes.
The Role of Prospective Memory in Predicting Neuropsychological Functioning in Mild Cognitive Impairment and Alzheimer’s Disease
Authors: Kozuki Jordan , Collins Andrea , Reyes Fabiola Amaya , Herrera Summer , Cruz‐Lopez Keely , Woo Ellen 
Published: January 2025

AbstractBackgroundProspective memory (PM), the ability to execute an intended action in the future (e.g., taking medications), is impaired in Alzheimer’s disease (AD). This study examines the utility of subjective and objective measures of PM in predicting neuropsychological functioning across five cognitive domains in healthy aging, mild cognitive impairment (MCI), and AD.MethodParticipants included 58 healthy older controls, 65 persons with MCI, and 18 individuals with AD. Subjective reports of PM included both participant and informant ratings on the Prospective‐Retrospective Memory Questionnaire (PRMQ). Additionally, an objective PM task was completed throughout a neuropsychological test battery. Simple objective PM was measured by asking participants to remember to execute the single action of requesting a pill after each neuropsychological test performed. Complex objective PM was measured by asking participants to request a specific number of pills depending on whether a memory or non‐memory test was completed. Composite neuropsychological test scores were used to assess the domains of language, memory, executive functioning, visuospatial skills, and attention.ResultRegression analyses revealed that in MCI, informant reports of PM predicted executive functioning. In healthy aging and MCI, both types of objective PM predicted memory performance. PM did not predict language, visuospatial skills, or attention in any group.ConclusionAmong healthy older adults and those with MCI, objective measurements of prospective memory predict episodic memory outcomes. When participants begin to exhibit cognitive decline, as seen in MCI, informant reports are additionally beneficial and predict executive functioning. This research supports previous findings that prospective memory is multifactorial and involves both memory and executive functioning. Overall, this research also suggests that the assessment of prospective memory has utility for understanding the early decline of cognitive domains traditionally evaluated in MCI.
Using proximity labelling to investigate astrocytic protein profile changes in response to amyloid pathology in a mammalian model of Alzheimer’s disease
Authors: Desai Perlina , Carcamo Lorena Arancibia , De Strooper Bart 
Published: January 2025

AbstractBackgroundAstrocytes are a numerous and diverse glial subtype specialised to carry out distinct roles involving maintaining homeostasis and effective functioning of the nervous system. To do so effectively, they respond to and secrete various proteins. In addition, astrocytes have been linked to Alzheimer’s disease (AD), where they are believed to become reactive and contribute to neuroinflammation. A key feature of this reactive gliosis is the secretion of inflammatory mediators. Although in some instances this can be protective, in others, secretion of inflammatory mediators can be harmful, thus possibly contributing to AD pathology. At present, there remains a limited understanding of global astrocytic membrane and extracellular protein profiles and potential AD‐associated changes.MethodHere, we aimed to address this using a proximity labelling‐based approach. Specifically, we used a viral construct containing TurboID targetted to the ER under a GFAP promoter in order to study astrocyte‐specific proteins trafficked through the classical secretory pathway in an AD mouse model.ResultAfter characterising the construct, we investigated changes in proteins between AD and controls over time in response to amyloid pathology. We have identified protein changes which are now being validated using mammalian biofluids such as CSF and plasma.ConclusionThis work enables a better understanding of astrocyte‐specific membrane and extracellular protein changes as the disease progresses in a mammalian model of AD. An enhanced understanding of this will not only provide insight into astrocyte biology more generally, but may ultimately be vital for identification of novel biomarkers and therapeutic targets for detecting and treating AD.
Clusters of modifiable risk factors provide resilience to the cognitive effects of β‐amyloid pathology in aging
Authors: Bhade Mohini , Pezzoli Stefania , Giorgio Joseph , Ward Tyler J. , Landau Susan M. , Jagust William J. 
Published: January 2025

AbstractBackgroundAlthough it has been estimated that modifiable risk factors account for around 40% of population variability in dementia risk, understanding how risk factors are related to one another and to brain pathology and cognition has been challenging. We used a clustering approach to examine patterns of risk factor interrelationships and to investigate how these patterns affect relationships between pathology and cognition.MethodWe collected risk factor data concerning health, lifestyle, sleep, and personality from 149 cognitively normal older adults (73±6.2 years), as well as PET‐measured amyloid (11C‐Pittsburgh compound‐B, PiB) and, in a subsample (n = 126), PET‐measured tau (18F‐Flortaucipir, FTP). All participants completed longitudinal neuropsychological testing (follow‐up 8.1±4.2 years). K‐means clustering was used to assign participants to different risk profiles that reflected how risk factors were interrelated. Linear mixed‐effects models were used to assess associations between decline in 1) episodic memory (EM) and 2) non‐memory (NM) cognition composite scores, with cluster assignment and PiB‐status (±) or entorhinal FTP uptake as predictors. Analyses were age and sex adjusted.ResultK‐means clustering generated 3 distinct risk‐related profiles, with more favorable profiles seen for participants in cluster 1 (physical/cognitive activity, education) and cluster 2 (sleep, depression, personality) than cluster 3 (Figure 1). In a model predicting NM decline with PiB‐status as a predictor, we observed a significant three‐way interaction between PiB‐status, cluster, and time (p<0.01) with an attenuated effect of Aβ on NM decline in cluster 1 (β = 3.7, p<0.01) and cluster 2 (β = 3.7, p<0.01) compared to cluster 3. A model predicting EM revealed no significant interaction between cluster, PiB‐status and time (Figure 2). While a significant entorhinal tau x time effect was observed in a model predicting EM decline, cluster assignment did not modify this relationship. Results were similar when APOE4 status was included in the models.ConclusionFavorable risk profiles (cluster 1 and 2) attenuated the effect of Aβ, but not tau, on cognitive decline. These findings suggest that different risk profiles moderate pathology‐cognition relationships, and demonstrate that different factors may operate together in reducing risk. This highlights the role of groups of modifiable resilience factors in mitigating the effects of Aβ deposition.
Relationships Between NIH Toolbox Cognitive Battery Subtests and In Vivo Amyloid and Tau in People with Amnestic Mild Cognitive Impairment and Dementia of the Alzheimer’s Type
Authors: Fox‐Fuller Joshua T , Petscavage Kenneth , Rogers Ginny , Koeppe Robert A. , Albin Roger L. , Iordan Alexandru D , Hampstead Benjamin M. , Rahman‐Filipiak Annalise 
Published: January 2025

AbstractBackgroundThe computerized NIH Toolbox Cognition Battery (NIHTB‐CB) was designed to assess cognitive functioning across the lifespan. Previous studies demonstrated that NIHTB‐CB measures discriminate between healthy controls (HCs), individuals with amnestic mild cognitive impairment (aMCI), and individuals with dementia of the Alzheimer’s type (DAT). Scores on NIHTB‐CB tasks also correspond with performance on well‐validated neuropsychological measures of the same cognitive domains. We are among the first to evaluate how NIHTB‐CB subtest performances and in vivo Alzheimer’s disease (AD) pathology are related in people with aMCI and DAT.MethodAs part of a larger clinical trial in the Research Program on Cognition and Neuromodulation Based Interventions, 139 participants with aMCI or DAT (Table 1) underwent neuropsychological assessment, including five iPad NIHTB‐CB subtests: Flanker, List Sort, Card Sort, Pattern Separation, and Picture Sequence. Participants also completed positron emission tomography (PET) scans of amyloid and tau. Amyloid PET scans were normalized to the centiloid value, and tau PET standardized uptake value ratios (SUVr) were merged into a bilateral meta‐region‐of‐interest based on Braak staging. Stepwise linear regressions were used to evaluate the relationship between age and education with NIHTB‐CB subtests (Model 1), as well as in vivo AD pathophysiology with NIHTB‐CB subtests beyond age and education (Model 2).ResultIn vivo amyloid was significantly related to List Sort (β = ‐0.31, p<.001, ΔR2 = .09) and Card Sort performance (β = ‐0.25, p = .004, ΔR2 = .06), explaining significantly more subtest variance beyond age and education. In vivo tau was significantly related to performance on all NIHTB‐CB subtests and explained significantly more subtest variance than demographic factors (Flanker: β = ‐0.25, p = .004, ΔR2 = .06; List Sort: β = ‐0.40, p<.001, ΔR2 = .15; Card Sort: β = ‐0.32, p<.001, ΔR2 = .10; Pattern Separation: β = ‐0.18, p = .04, ΔR2 = .03; Picture Sequence: β = ‐0.23, p = .01, ΔR2 = .05).ConclusionIn vivo AD pathophysiology is related to NIHTB‐CB subtest performances in individuals with aMCI or DAT and explains significantly more NIHTB‐CB subtest variance than demographic factors alone. This work adds growing support to the relationship between NIHTB‐CB subtests and in vivo AD biomarkers.