bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of life course adiposity with risk of incident dementia: a prospective cohort study of 322,336 participants
Authors: Yue‐Ting Deng 
Published: January 2025

AbstractBackgroundCohort studies report inconsistent associations between body mass index (BMI) and all‐cause incident dementia. Furthermore, evidence on fat distribution and body composition measures are scarce and few studies estimated the association between early life adiposity and dementia risk.Method322,336 individuals of European ancestry were included in the main analysis after exluding people with baseline dementia, who are younger than 50 years old and who are non‐white. All participants joined the UK Biobank study from 2006 to 2010 and were followed up until December 31, 2020. Overall adiposity was comprised of birthweight (BW), childhood body size and adulthood body mass index (BMI). Other adiposity measures included central adiposity, body composition and fat distribution. Incident all‐cause dementia, ascertained through hospital inpatient, death records, and primary care.ResultAmong the 322,336 individuals (mean [SD] age, 62.24 [5.41] years; 53.9% women) in the study, during a median 8.74 years of follow‐up, 5083 all‐cause incident dementia events occurred. The risk of dementia was 22% higher with plumper childhood body size (P < 0.001). A strong U‐shaped association was observed between adult BMI and dementia. More fat and less fat‐free mass distribution on arms were associated with a higher risk of dementia. Interestingly, similar U‐shaped associations were found between BMI and four metabolites (i.e., 3‐hydroxybutrate, acetone, citrate and poly unsaturated fatty acids), four inflammatory cells (i.e., neutrophil, lymphocyte, monocyte and leukocyte) and abnormalities in brain structure that were also related to dementia.ConclusionIn this large cohort study, adiposity in both childhood and adulthood were significantly associated with risk of dementia and a strong U‐shaped association existed between BMI and dementia. The findings that adiposity is associated with metabolites, inflammatory cells and abnormalities in brain structure that were related to dementia risk might provide clues to underlying biological mechanisms. Interventions to prevent dementia should begin early in life and include not only BMI control but fat distribution and body composition.
A framework for concepts of reserve and resilience in aging
Authors: Stern Yaakov 
Published: January 2025

AbstractBackgroundThis talk will review the Framework and discuss how it can be used to help conceive of and design research studies into cognitive reserve, brain maintenance and brain reserve. It will also highlight several funded pilot awards that emerged to implement the operational definitions. Finally, the talk will highlight the fourth Collaboratory workshop at which a set of collaborative research projects were initiated that make use of the Framework and address both human and nonhuman cognition.MethodThe Framework offers consensus operational definitions for three aspects of an overall concept of “resilience:” cognitive reserve, brain maintenance and brain reserve.ResultCognitive reserve is defined as a property of the brain that allows for cognitive performance that is better than expected given the degree of life‐course related brain changes and brain injury or disease. Brain maintenance was defined as the relative absence of changes in neural resources or neuropathologic change over time as a determinant of preserved cognition in older age. Finally, we define the concept of brain reserve to reflect the neurobiological status of the brain at any point in time. The Collaboratory funded 12 pilot awards that utilize these definitions. These awards are summarized in the supplement to the published Framework. At a fourth Collaboratory meeting, investigators gathered to initiate new collaborative research based on the framework. These include several projects that will be discussed at this talk. Additional projects will be described including evaluation of the interaction of physical activity and stress on cognitive performance, sociocultural factors and cognitive resilience, the contribution of molecular measures such as astrocytes and glia to cognitive reserve.ConclusionThe framework defines three concepts developed to guide research. These operational definitions are also of use if researchers choose to use alternate names for concepts. The use of a common vocabulary and operational definitions will facilitate even greater progress in understanding the factors that are associated with successful aging. The studies we discuss demonstrate that the Framework can underline a broad range of human and nonhuman studies.
A shared behavioral framework for assessing preserved cognitive function in aging in rodent models
Authors: Branch Audrey E , McQuail Joseph , Kaczorowski Catherine C. , Foster Thomas C , Disterhoft John F. , Huentelman Matthew J. , Rapp Peter R. , Barnes Carol A 
Published: January 2025

AbstractBackgroundAnimal models provide a valuable basis for identification of conserved pathological substrates and processes underlying age‐related diseases as well as neurobiological features supporting cognitive resilience in the aging brain. Behavioral measures are a fundamental component in the assessment of cognitive processes but are rarely standardized across laboratories. Currently, there is a scarcity of centralized and standardized data infrastructure for behavioral experiment data collected across laboratories which presents a barrier for data sharing, hypothesis generation, and collaboration. A key goal of the Reserve and Resilience Collaboratory has been to create consensus approaches and definitions for the study of cognitive aging. We have designed a standard reporting framework and a centralized database across several labs.MethodIn rodent model studies of cognitive aging trajectories, the Morris water maze spatial learning paradigm is a widely used test for characterization of age‐ and disease‐related cognitive decline. The place learning version of this test depends on intact limbic and cortical systems which are key sites of dysfunction in both healthy aging and late life neurodegenerative diseases. Importantly, learning index and memory scores derived from Morris water maze testing in aged subjects replicate individual differences observed in human subjects and provide a basis for identifying covarying neurobiological changes supporting cognitive reserve and maintenance. Given the prevalence of this test for characterization of individual cognitive aging trajectories and preclinical intervention studies we have designed a standard reporting framework and centralized database housing Morris water maze behavioral data collected from rodent models across several labs.ResultFour laboratories have committed behavioral measures to the database allowing meaningful comparisons to be made across rodent strains. Initial comparisons will include variables relating to sex differences, strain, and age of testing.ConclusionAs we develop this resource, we intend to include access to biological measures, tissue banks, and additional behavioral measures taken from subjects in the database. Our goal is to provide a resource to enable collaborations and initiatives to advance the study of cognitive and brain reserve in aging, toward the prevention of Alzheimer’s disease.
Plasma β2‐microglobulin and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study
Authors: Huang Yi‐Ming , Tan Lan , Yu Jin‐Tai 
Published: January 2025

AbstractBackgroundPrevious studies have suggested a correlation between elevated levels of β2‐microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyse the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers, and cognition.MethodTo track the dynamics of plasma B2M in preclinical AD, 846 cognitively healthy individuals in the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups (suspected non‐AD pathology [SNAP], 2, 1, 0) according to NIA‐AA criteria. Multiple linear regression models were employed to examine plasma B2M’s relationship with cognitive and CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognition.ResultWe found that the levels of plasma B2M were increased in stages 1 (P=0.0007) and 2 (P< 0.0001), in contrast to stage 0. In total participants, higher levels of B2M were associated with worse cognitive performance (P = 0.006 for MMSE; P= 0.012 for MoCA). Moreover, a higher level of B2M was associated with decreases in Aβ1‐42 (P<0.001) and Aβ1‐42/Aβ1‐40 (P=0.015) as well as increases in T‐tau/Aβ1‐42 (P<0.001) and P‐tau/Aβ1‐42 (P<0.001). Subgroup analysis found B2M correlated with Aβ1‐42 in non‐APOE ε4 individuals (P<0.001) but not in APOE ε4 carriers. Additionally, the link between B2M and cognition was partially mediated by Aβ pathology (percentage: 8.6% to 19.3%), whereas tau pathology did not mediate this effect.ConclusionThis study consolidated demonstrated the association of plasma B2M with CSF AD biomarkers as well as a possible important role of Aβ pathology in the association between B2M and cognitive impairment, particularly in cognitively normal individuals, particularly in cognitively normal individuals. The results indicated that B2M could be a potential biomarker for preclinical AD and might have varied functions throughout various stages of preclinical AD progression.
Aberrant resting‐state functional connectivity of the default‐mode network relates to cognitive decline in the earliest Alzheimer's continuum
Authors: Lizarraga Aldana , Kassinopoulos Michalis , González‐de‐Echávarri José María , Huguet Jordi , Sánchez‐Benavides Gonzalo , Brugulat‐Serrat Anna , Suarez‐Calvet Marc , Milà‐Alomà Marta , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Gispert Juan Domingo , Cacciaglia Raffaele ,   ALFA study
Published: January 2025

AbstractBackgroundAmyloid‐β (Aβ) pathology affects resting state functional connectivity (RSFC), even in cognitively unimpaired (CU) individuals. However, the impact of such an aberrant RSFC on cognitive decline is yet to be determined. Moreover, most prior research focused on fibrillary Aβ deposition to predict RSFC, while early Aβ dysmetabolism as reflected by cerebrospinal fluid (CSF) concentrations has received less attention. We assessed RSFC as a function of both CSF Aβ and p‐tau in CU individuals, and further analyzed the impact of biomarker‐dependent RSFC on the longitudinal cognitive performance.MethodAnalyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). RSFC was computed amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p<0.005. The effects of CSF biomarkers on RSFC were adjusted by age, sex, years of education and APOE‐ε4 status.ResultOf the entire sample, 38.4% had positive CSF Aβ42/40 markers. Low CSF Aβ42/40 ratios were associated to a higher RSFC between visual areas and anterior as well as posterior subdivisions of the default‐mode network (DMN) (Figure 1). These results survived a family‐wise error rate p‐value<0.005. High levels of CSF p‐tau were related to a higher RSFC between inferior temporal areas and the anterior DMN, as well as a reduced RSFC between visual and the somatomotor network. The Aβ‐related higher RSFC significantly predicted longitudinal cognitive decline in PACC, episodic memory (EM) and executive control (EC), in models adjusted by CSF biomarkers (Figure 2), and further modulated the association between CSF Aβ42/40 and PACC longitudinal decline (Figure 3)ConclusionIn CU individuals, CSF Aβ and p‐tau affect RSFC in networks relevant for cognitive performance. Low CSF Aβ42/40 was related to hyperconnectivity between the DMN and the visual system. Lack of DMN segregation as a function of CSF Aβ42/40 may represent a driving mechanism of cognitive decline in the earliest Alzheimer’s continuum.
The association between liver fibrosis and dementia risk: a nationwide retrospective cohort study
Authors: Schonmann Yochai , Yeshua Hanny , Zelber‐Sagi Shira , Weinstein Galit 
Published: January 2025

AbstractBackgroundLiver fibrosis is a prevalent, most often clinically silent condition. Accumulating literature suggests that liver fibrosis may be related to brain health measures. However, its predictive role in assessing dementia risk is conflicting. Hence, we assessed the relationship of liver fibrosis with incident dementia in a large, nation‐based cohort.MethodThis retrospective cohort study utilized data from electronic health records of the Clalit Health Services (CHS), the largest health maintenance organization in Israel. We included dementia‐free CHS members aged 40‐69 years who were members for >1 year on January 1st, 2006 (baseline). All‐cause dementia was ascertained via ICD‐9 codes, hospital discharge letters and purchase of medications. Liver fibrosis was assessed from recent laboratory measures using the FIB‐4 index, a serum‐based algorithm. Cox regression models were used to assess the relationship between liver fibrosis and dementia incidence while adjusting for various sociodemographic, life‐style and comorbidities. Interaction of liver fibrosis with age, sex, socioeconomic status, ethnicity, obesity, smoking, prevalent diabetes, IHD and history of stroke were further assessed. Lastly, we conducted several sensitivity analyses, among them excluding dementia cases occurring at the first 5‐years of follow‐up.ResultOf the 826,578 individuals included in the study (mean age 55±8y at baseline), 636,967 (77%) had no fibrosis, 180,114 (21.8%) had inconclusive fibrosis status and 9,497 (1.2%) had high risk for advanced fibrosis according to FIB‐4. Over a mean follow‐up of 15 years, 41,089 dementia diagnoses were recorded. After adjustment for potential confounders, individuals with inconclusive liver fibrosis range and those with advanced fibrosis had a 9% (Hazard Ratio (HR) 1.09, 95%CI 1.07, 1.11) and 18% (HR 1.18 95%CI 1.10, 1.27), respectively, higher dementia risk compared to those with no fibrosis (Figure). The association between liver fibrosis and dementia risk were stronger in those aged 45‐54y compared to other age groups and in persons with no history of diabetes, Ischemic heart disease and stroke. The results remained robust after exclusion of dementia cases occurring in the first years of follow‐up.ConclusionLiver fibrosis assessed through a non‐invasive serum‐based algorithm may serve as a novel risk factor for dementia in the general population.
Human iPSC‐based models of Alzheimer’s disease
Authors: Shi Yanhong 
Published: January 2025

AbstractBackgroundBrain organoid models were generated from healthy control or Alzheimer’s disease patient iPSCs to facilitate our understanding of AD pathogenesis.MethodApoE3 and ApoE4 iPSCs were developed into brain organoids using our recently developed brain organoid platform that allows prolonged culture of brain organoids. Human iPSCs were also differentiated into microglia, which were then co‐cultured with brain organoids. These neuroimmune organoids were used to uncover mechanisms underlying neurodegeneration.ResultWe developed a long‐term brain organoid system that can undergo prolonged culture. Moreover, these organoids can support long‐term microglial co‐culture. Microglia can prevent neurons from degeneration in the long‐term brain organoids. ApoE4 microglia are less effective in reducing neuronal degeneration than ApoE3 microglia.ConclusionThe microglia‐containing long‐term brain organoid platform generated in this study provides a promising human cellular model for studying brain‐immune interactions in brain development and pathogenesis of neurological diseases such as AD.
The inverse association between cancer and Alzheimer’s disease: evidence from neuropathological studies
Authors: Abner Erin L. , Karanth Shama D , Aung Khine Z , Nelson Peter T 
Published: January 2025

AbstractBackgroundSome types of cancer have been associated with reduced risk of clinical dementia diagnosis. Whether cancer history may be associated with neuropathological features of neurodegeneration or cerebrovascular disease is not well understood. We investigated the relation between cancer diagnosis and brain pathology in a sample of community‐based research volunteers enrolled in an Alzheimer’s Disease Research Center (ADRC) cohort.MethodData from autopsied participants from the University of Kentucky ADRC were linked to the population‐based Kentucky Cancer Registery, which is a CDC Surveillance, Epidemiology, and End‐Results (SEER) program. We examined the relationship between cancer diagnosis, clinical dementia diagnosis, Mini‐Mental State Examination scores and neuropathological features using inverse probability weighting to address bias due to confounding and missing data. To address bias due to inclusion of participants with dementia at cohort baseline, we repeated all analyses restricted to the participants who were cognitively normal at baseline.ResultIncluded participants (n = 785) had a mean ± standard deviation age of death of 83.8 ± 8.6 years; 60.1% were female. Cancer diagnosis was determined in 190 (24.2%) participants. Participants with cancer diagnosis had lower odds of mild cognitive impairment or dementia, and higher cognitive test scores (e.g. Mini‐Mental State Examination scores evaluated 6 and ≤2 years antemortem, P < 0.001 for both comparisons). Cancer diagnosis also associated with lower odds of higher Braak neurofibrillary tangle stages (III/IV) or (V/VI), moderate/frequent neuritic plaques, moderate/frequent diffuse plaques and moderate/severe cerebral amyloid angiopathy (all P < 0.05). By contrast, TDP‐43, α‐synuclein and cerebrovascular pathologies were not associated with cancer diagnosis. Cancer diagnosis was associated with a lower burden of Alzheimer’s disease pathology and less cognitive impairment.ConclusionThis study provides evidence that the inverse association between cancer and Alzheimer’s disease may not be fully explained by selection and survival bias. Ongoing research by our team is investigating the association between genetic burden of cancer risk and neuropathological features.
Cognitive assessment tools for older adults in the Arabic language: a systematic review
Authors: Kabalan Mayssan , Bazzi Ola , Al‐Barathie Josleen , Zein Ola El , Chehabeddine Lara , Chaaya Monique , de Leon Carlos Mendes , Elbejjani Martine 
Published: January 2025

AbstractBackgroundAcross the Arab world, Alzheimer’s disease and related dementias (ADRD) are a growing public health concern with the increase in the proportion of older adults. Yet, our understanding of these conditions remains limited because of a lack of data. Robust assessments of cognitive function are crucial for screening, prevention, and risk factor identification. This systematic review aims to identify available cognitive assessments in Arabic and assess their validity and performance.MethodWe conducted a comprehensive search with a broad inclusion criterion using Medline OVID, EMBASE, and APA PsychInfo up to November 2023. Our search included both studies developing or validating cognitive assessment tools in Arabic for individuals aged 50 and above, and studies applying any such tool in the Arabic language. Study selection and data abstraction were carried out in duplicate and independently and using standardized and pilot‐tested forms. We analyzed and reported the availability, appropriateness, and use of the available cognitive assessment instruments.ResultOur review yielded 154 studies, of which 27 studies involved developing or validating a tool and 127 studies used a cognitive assessment tool. Among the validation studies, measures of validity, reliability, or normative data were available for 22 cognitive assessment tools. 21 studies focused on criterion validity with 18 testing tools compared to clinical assessments and 3 compared to other scales. Cut‐off scores, sensitivity, and specificity were tested in 21 studies for a total of 15 tools. 35% of the validation studies had no reliability measures. Three studies developed a new assessment tool. The Mini Mental State Examination was the most frequently validated and used instrument across diverse settings. Studies validating domain‐specific tools were limited, with memory being the most frequently validated. Among studies using a cognitive tool in Arabic, over half used unvalidated versions.ConclusionPsychometric evaluations of cognitive assessments for older Arabic‐speaking adults remain scarce with limited data regarding domain‐specific assessments, reproducibility, and suitability in different settings (different countries or different samples: clinical, community, nursing home). Findings emphasize this important challenge that can hinder robust data on ADRD burden and risk trajectories in Arab populations.
The combined effect of cognitive impairment and pain on functional and mobilitydisability among older adults in India
Authors: Muhammad Thalil , Pai Manacy 
Published: January 2025

AbstractBackgroundWe examined the associations between cognitive impairment, experiences of pain, and functional and mobility disability among older adults in India. Moreover, we assessed the combined effects of cognitive impairment and pain on functional and mobility disability among older Indians.MethodData come from baseline wave (2017‐19) of the Longitudinal Aging Study in India, with a sample of 31,464 older adults aged 60+ years. Cognitive impairment was assessed using measures of memory, orientation, arithmetic function, and visuo‐spatial construction skills. Functional and mobility disability was evaluated using the scales of activities of daily living (ADLs, score 0‐6), instrumental activities of daily living (IADLs, score 0‐7), and mobility (score 0‐9). Pain and pain frequency was self‐reported. Multivariable linear regression models were employed to examine the association between variables, and the interaction terms were used to test the moderation effects.ResultOlder adults who were cognitively impaired were more likely to report ADL (beta: 0.295, CI: 0.238, 0.352), IADL (beta: 0.642, CI: 0.547, 0.737), and mobility disability (beta: 0.605, CI: 0.490, 0.719). Similarly, those reporting any pain were more likely to report ADL (beta: 0.258, CI: 0.224, 0.292), IADL (beta: 0.421, CI: 0.367, 0.475), and mobility disability (beta: 1.320, CI: 1.244, 1.396). Further, the interactions between cognitive impairment and pain were statistically consequential (p<0.001) for ADL, IADL, and mobility disability, and the associations between cognitive impairment and functional and mobility disability were more pronounced among older women and those experiencing frequent pain (5+ days/week).ConclusionOur findings underscore the need for integrated healthcare approaches that address cognitive health and pain management simultaneously to help older adults maintain functional abilities and mobility. That female gender and frequent pain magnify the association between cognitive impairment and functional and mobility disability is useful information for providers and practitioners offering individualized care plans to older patients.