bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuro‐Dynamic Quantitative Systems Pharmacology (Qsp) Model Supports Continued Lecanemab Treatment With Maintenance Dosing For Alzheimer’s Disease
Authors: Cao Youfang , Willis Brian A. , Sachdev Pallavi , Penner Natasha , Wildsmith Kristin R , Charil Arnaud , Horie Kanta , Koyama Akihiko , Reyderman Larisa 
Published: January 2025

AbstractA 10 mg/kg every 2 week (Q2W) dose of the humanized IgG1 monoclonal antibody lecanemab was approved after demonstrating significant clinical benefit in slowing cognitive decline in early Alzheimer’s disease (AD) in two clinical studies (the phase 2 Study 201 and phase 3 Clarity AD). A less frequent every 4 weeks lecanemab 10 mg/kg maintenance dosing (Q4W) has been proposed after a sufficient initial Q2W treatment. To further understand long‐term benefit of continued Q4W lecanemab treatment, a quantitative systems pharmacology (QSP) model was developed which mechanistically describes AD pathophysiology using multivariate data from clinical studies. The population QSP model incorporated 3 interlinked modules describing Aβ pathway, tau pathology and cognitive decline, where Aβ triggers tau pathology and tau pathology leads to cognitive decline due to neuronal damage and degeneration. The model was developed using nonlinear mixed‐effect modeling and was successfully validated using a multivariate dataset (N = 4057) consisting of amyloid PET, CDR‐SB, ADAS‐Cog14, plasma Aβ42/40 ratio and ptau181, and tau PET data from the lecanemab trials, as well as amyloid PET, ADAS‐Cog and CDR‐SB data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Simulations were conducted to investigate long‐term lecanemab benefits with Q4W dosing following the initial lecanemab Q2W treatment. QSP simulations showed additional benefits gained across clinical outcomes, amyloid plaque and protofibrils, Tau PET, and plasma biomarkers with continued lecanemab treatment beyond 18 months. Specifically, maintenance lecanemab continued to reduce brain amyloid plaques and protofibrils in subjects who did not reach amyloid negativity following the initial 18‐month Q2W lecanemab. Simulations showed plasma ptau‐181 continued to decline and plasma Ab42/40 ratio continued to increase with Q4W maintenance dosing. Furthermore, simulations showed continued suppression of tau PET, and additional reductions in cognitive decline (CDR‐SB, ADAS‐Cog14) with Q4W maintenance dosing. Sustained protofibril clearance was indicated as a key driver for long‐term (>18 months) lecanemab effect on halting tau pathology and slowing cognitive decline, particularly after plaques are cleared following initial lecanemab Q2W treatment. QSP simulations demonstrated the importance of continuing lecanemab treatment after plaque removal and support Q4W maintenance dosing following initial treatment.
Associations between Social Determinants of Health and Alzheimer’s Disease and Related Dementia among American Indian and Alaska Native and White Medicare Beneficiaries
Authors: Yang Manxi , Abdulsalam Ruqoyat , Adjei‐Boateng Richard , Li Lingling , Manson Spero , O'Connell Joan , Jiang Luohua 
Published: January 2025

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) present a growing challenge in the US and has emerged as a significant health concern in American Indian and Alaska Native (AI/AN) communities. ADRD prevalence and risk factors among AI/AN adults remain poorly understood and plagued by inconsistent findings. This study addressed this knowledge gap by examining the associations of social determinants of health (SDOH) with ADRD between AI/AN and non‐Hispanic White (White) populations.MethodAI/AN and a 5% random sample of White adults aged 68 and above enrolled in fee‐for‐service (FFS) Medicare in 2019 were included in this study. We used the 2019 Medicare Beneficiary Summary File to obtain data on beneficiaries’ demographics, chronic conditions, and health coverage. We obtained county‐level data from the 2019 Area Health Resource File and the National Center for Health Statistics. Medicaid eligibility and Part D enrollment were used as proxies for individual‐level SDOH. County‐level measures were defined by the percentage of households with incomes below the federal poverty level, the percentage of adults without a high school degree, and county rurality. Separately for AI/AN and White populations, we calculated crude and age‐adjusted prevalence of ADRD and used logistic regressions to examine associations between ADRD and SDOH, controlling for demographics and chronic conditions.ResultAmong 111,635 AI/AN and 1,015,809 White Medicare beneficiaries included, the ADRD prevalence was 15.6% (age‐adjusted) and 13.4% respectively (OR = 1.24, 95% CI:1.22, 1.27) (Table 2). After multivariate adjustment, the odds ratio of AI/AN for ADRD was not statistically significant (OR = 1.006, 95% CI: 0.980, 1.033). As shown in the Figure, Medicaid eligibility was associated with a substantially higher odds of ADRD among both AI/AN (OR = 2.38, 95% CI: 2.26, 2.50) and White individuals (OR = 3.23, 95% CI: 3.17, 3.29). Part D enrollment was associated with higher odds of ADRD among AI/AN individuals only while county‐level income and education were associated with higher odds of ADRD among White individuals only. Additionally, rurality was associated with lower odds of ADRD in both populations.ConclusionSDOH are potentially modifiable factors, therefore, a deeper understanding of their effects on ADRD can inform future interventions aimed at reducing ADRD prevalence and disparities.
Impacts of cardiovascular risk factors and APOE on cognitive decline in late‐life
Authors: Wang Xinhui , Asante Isaac , Yu Lei , Wilson Robert S. , Bennett David A. , Arvanitakis Zoe , Yassine Hussein N 
Published: January 2025

AbstractBackgroundApolipoprotein E (APOE) is a known genetic risk factor for dementia. Midlife cardiovascular risk factors are associated with lower cognitive performance and increased dementia risk. However, little is known whether cardiovascular risk factors mediate or modify the associations between APOE and cognitive decline in late‐life.MethodWe conducted longitudinal data analyses on 1180 participants (aged 79.3±6.9 years at baseline) from Religious Orders Study and Rush Memory and Aging Project. Participants had ≥4 cognitive assessments with the last one within 2 years before death and APOE genotyped as ε4 carrier (ε3/ε4 or ε4/ε4) or non‐carrier (ε3/ε3). Annual global cognitive function was assessed via a battery of 19 tests and averaged into a summary measure. Cardiovascular risk factors included depression, hypercholesterolemia, and hypertension defined by corresponding medication usage in last 2 weeks at baseline, and diabetes based on self‐report or medication use. We constructed random change point models to analyze cognitive trajectories before death and estimate the subject‐specific change point, slopes before (pre‐terminal decline) and after (terminal decline) the change point, and level of cognition at death. We used linear regression to analyze the associations between APOE, cardiovascular risk factors, and these trajectory parameters adjusting for age at death, sex, and education. Interactions between APOE and risk factors were also examined.ResultOn average, the onset of terminal decline happened at 2.9 years before death and the decline speed increased 5.6 times afterwards. Compared to non‐carriers, ε4 carriers had significantly lower cognition at death, earlier onset of terminal decline, faster pre‐terminal (β = ‐0.017, 95%CI = [‐0.023,‐0.012]) and terminal declines (β = ‐0.026, 95%CI = [‐0.044,‐0.008]) – equivalent to 2 years and 0.9 years of age effect respectively. Treated hypercholesterolemia and hypertension showed protective effects on cognitive trajectories, while depression showed adverse effect and no effect observed for diabetes. None of them changed the APOE adverse effects. No interactions were found between risk factors and APOE either (all p>0.05).ConclusionAPOE ε4 carriers were associated with worse global cognitive trajectories before death and these were not impacted by depression, hypercholesterolemia, hypertension, or diabetes. The protective effects of treated hypercholesterolemia and hypertension on cognitive trajectory did not differ by APOE genotype.
Epidemiology of cognitive impairment in rural and urban settings in southern Peru
Authors: Rivera‐Fernandez Claudia , Herrera‐Perez Eder , Soto‐Añari Marcio F. 
Published: January 2025

AbstractBackgroundIn Peru, the prevalence of dementia is associated with a significant number of social, ethnic, and demographic factors. Data on prevalence is still limited, especially in regions distant from major urban centers. Our objective was analyze the prevalence of dementia in the southern population of Peru.MethodWe conducted an epidemiological study on cognitive impairment and dementia in southern Peruvian populations. A total of 314 older adults (mean age = 68.45, SD = 9.57), comprising 74.03% women and 25.96% men, were recruited from the city of Arequipa in the southern region of Peru. We applied a clinical protocol that included brief cognitive tests (Addenbrooke Cognitive Examination and Rowland Universal Dementia Assessment Scale (RUDAS)). Functional status measures were evaluated using the Pfeffer questionnaire (PFAQ). Additionally, a brief questionnaire on social determinants of health and clinical health information was administered. The cut‐off point of the brief cognitive test and functional measurement was applied to approximate the diagnosis. Binary logistic regression was performed with positive and negative cases as the dependent variable and gender, education, and ethnicity as predictors.ResultWe observed a global prevalence of 7.35%, which can vary according to the number of years of education. Individuals with more than 6 years of education showed a prevalence of 10.71%, while low‐educated populations exhibited a higher prevalence (23.53%). Additionally, we observed some minor variations based on ethnicity, health issues, and emotional states.ConclusionWe identified a lower prevalence of cognitive impairment compared to previous reports. Social determinants of health appear to exert a significant impact on prevalence. This initial study in the southern Peruvian population highlights a noteworthy interaction between nature and nurture in the risk of dementia.
Age adjustment approaches to estimating the association of neuroimaging biomarkers and cognition in the oldest‐old, LifeAfter90 Study
Authors: Lor Yi , Posis Alexander Ivan B. , George Kristen M. , Peterson Rachel , Gilsanz Paola , Corrada María M. M. , Whitmer Rachel A. 
Published: January 2025

AbstractBackgroundAppropriate methods for age adjustment in associations of neuroimaging and late‐life cognition is not well defined, especially among those 90+ years old. We examined how different age adjustment approaches affect the associations of MRI/PET‐based regional brain markers and cognitive change in the oldest‐old.MethodLifeAfter90 is a diverse cohort study of adults ages 90+ in Northern California. We evaluated the associations of volumetric MRI/PET brain regions of interest (ROI) with change in executive function and verbal episodic memory over 8 visits (∼6 months apart) using linear mixed models. The cognitive domains were assessed with the Spanish and English Neuropsychological Assessment Scales. All ROI were adjusted for total cranial volumes while free water, fractional anisotropy, and amyloid standardized uptake ratio (SUVR) were not. Age‐adjustment was assessed using five approaches: 1) no adjustment, 2) residual age at MRI scan estimated from regression models on total cranial volume, 3) within model adjustment for age at baseline cognitive interview, 4) age at MRI scan, and 5) age at both baseline interview and MRI scan. All models adjusted for practice effects and interview mode (telephone/in‐person).ResultAmong 209 participants (mean age at baseline cognition = 91.7±2.0, mean age at imaging = 93.2±2.2), 58% were female, and 74% had some college or more. Older age at baseline cognitive assessment was associated with larger volumes in certain ROI (hippocampus, parietal, third ventricle), but lower in other ROIs (cerebrum gray, frontal) (Figure 1). Older age was also associated with higher white matter hyperintensities (WMH), free water, and amyloid SUVR. Adjustment for age using approaches 2‐5 resulted in no significant changes in the estimated association for each measure of ROI (e.g. hippocampus, third ventricle, WMH, amyloid SUVR) with baseline cognition and longitudinal cognitive change compared to approaches 1 (Figure 2). Model fit statistics (AIC, BIC, and log‐likelihood) indicate that approach 1 yielded the best fit.ConclusionAge adjustment does not meaningfully change the magnitude of the estimated association of neuroimaging biomarkers with baseline cognition and cognitive change. In those 90+, adjustment for age in models may not be necessary potentially due in part to the narrow age range and smaller age variation in this group.
Associations of several common infections with amyloid‐β pathology in vivo: a population‐based study
Authors: Felici Caterina , Green Rebecca E , Warren‐Gash Charlotte , Butt Julia , Waterboer Tim ,   Insight 46 study Team, Hughes Alun D , Schott Jonathan M , Keshavan Ashvini , Chaturvedi Nishi , Richards Marcus , Williams Dylan M 
Published: January 2025

AbstractBackgroundAssociations of common infections with Alzheimer’s disease have been reported, but potential mechanisms underlying these relationships are unclear. A hypothesised mechanism is amyloid‐beta (Aβ) aggregation as a defense mechanism in response to infection, with subsequent tau accumulation. However, no studies have assessed associations of infections with cerebral Aβ and tau pathology in vivo. We investigated relationships between serum antibodies to common infections and Aβ pathology quantified using PET in the Insight 46 neuroimaging cohort.MethodCirculating antibody levels against 14 pathogens, measured at age 60‐64, were modelled as pathogen serostatus, cumulative pathogen burden, and seroreactivity tertiles. Their associations with Aβ‐PET positivity, assessed 7.3(±1.3) years after serology measurement, were modelled using multivariable logistic regression. Model 1 adjusted for sex and ages at serology and PET scan, models 2‐4 additionally adjusted for APOE ε4 carriage, education, and inflammatory markers respectively. We tested for interactions in associations by APOE ε4 carriage and education, and interactions between herpes simplex virus 1 and both cytomegalovirus and varicella‐zoster virus. Analyses were repeated using Aβ‐PET deposition as a continuous variable.Result424 individuals had serology and Aβ‐PET data (Tables 1 and 2). Individuals seropositive to Epstein‐Barr virus (EBV) had higher odds of Aβ‐PET positivity in all models, with a large point estimate but wide confidence intervals including null (Model 2: OR 3.11; 95% CI: 0.96,10.09; Figure 1). Similar patterns were observed when analysing Aβ‐PET continuously (Model 2: 22% higher burden; 95% CI: ‐4, 47%). Individuals seropositive to Toxoplasma gondii (T.gondii) had a higher likelihood of Aβ‐PET positivity with large confidence intervals including null (Model 2: OR 1.60; 95% CI: 0.87, 2.94; Figure 1). There was modest evidence for an interaction between human herpesvirus 7 (HHV7) and education in relation to Aβ‐PET positivity (lower Aβ risk among HHV7 seropositives with higher education). No other pronounced findings were observed.ConclusionResults suggest potentially strong associations of EBV and T.gondii seropositivity with Aβ burden, however, the large CIs including null suggest the study lacked power to generate precise estimates. Findings warrant replication in other larger cohorts and with other neurobiomarkers. We plan to expand our analyses to plasma p‐tau217 as another outcome (N≤1454).
Salivary biomarkers for the molecular diagnosis of Dementia with Lewy Bodies
Authors: D'Antonio Fabrizia , Vivacqua Giorgio , Serrentino Marco , Podgajna Martyna , Kaczynska Aleksandra , Peconi Martina , Bartolo Maria Ilenia De , Panigutti Massimiliano , Sepe‐Monti Micaela , Talarico Giuseppina , Fabbrini Giovanni , Bruno Giuseppe 
Published: January 2025

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia. Although its prevalence, DLB is under‐investigated and frequently misdiagnosed and there are no available biomarkers. The aim of this study was to investigate salivary a‐synuclein (a‐syn) and tau species in DLB patients as potential disease biomarkers and to assess their potential in differential diagnosis with Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).MethodWe measured total‐ and oligomeric a‐syn, total‐tau and S199‐phosphorylated‐tau (pS199‐tau) in the saliva from 21 DLB, 20 AD, 20 PD patients and 20 Healthy subjects (HC), using quantitative enzyme‐linked immunosorbent Assay (ELISA) analyses.ResultSalivary total a‐syn was higher in DLB compared to PD, whereas all pathological groups had higher concentration of oligomeric a‐syn compared to HC. Salivary total‐tau concentration was higher in all the pathological groups compared to HC, whereas the concentrations did not differ among patients’ groups. Conversely, salivary levels of pS199‐tau were higher in DLB and AD patients in comparison to both HC and PD patients. Both correlation matrix and Principal Component Analysis showed that core clinical DLB features were related to a‐synuclein pathology, while the cognitive decline was associated with salivary levels of pS199‐tau. Receiver operating characteristic analysis reported high diagnostic accuracy for both a‐syn oligomers and pS199‐tau, between DLB and HC and an adequate accuracy between DLB and PD.ConclusionSalivary total and oligomeric a‐syn were accurate in differentiating DLB from HC, whereas pS199‐tau might represent a marker of cognitive decline. These findings provide a preliminary evidence that salivary a‐syn and tau species might be promising in identifying DLB patients with potential implications for early diagnosis and disease modifying therapies.
Association of Blood‐Based Biomarkers: GFAP, Amyloid 42/40 and Perivascular Spaces in Relation to Cognitive Domains in Vascular Cognitive Impairment Participants
Authors: Wang Jia Dong James , Leow Yi Jin , Vipin Ashwati , Sandhu Gurveen Kaur , Tanoto Pricilia , Azam Mohammed Adnan , Zailan Fatin Zahra , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran 
Published: January 2025

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces in the brain, hypothesized in promoting clearance of metabolites implicated in dementia through glymphatic system drainage. PVS are classified according to Grades (0‐4). Blood‐based biomarkers including Glial fibrillary acidic protein (GFAP), Amyloid β 42/40 (Aβ42/40) ratio have shown promise in diagnosing and prognosing dementia.However, the association between blood‐based biomarkers and PVS remains relatively unexplored in Vascular Cognitive Impairment (VCI) participants. Thus, this study aims to characterize association between blood‐based biomarkers and PVS in relation to cognitive domains in VCI participants.MethodParticipants from the Biomarkers and Cognition Study, Singapore were included and VCI was defined in participants with confluent white matter hyperintensities (WMH), >1 lacunae and Montreal Cognitive Assessment (MoCA) score <26.108 participants (mean age 67.3, education years 13.3, 51.9% females) were included.Normality tests, multivariate ordinal correlation analysis was performed to understand association between blood‐based biomarkers and PVS grade, with correction for age, diastolic blood pressure and WMH.Aβ42/40 and GFAP ratio values of 0.05 and 54.1pg/ml were utilized to segregate VCI participants to different subgroups (high vs low levels) and their association with cognitive domain performance was assessed.ResultHigher GFAP (p=0.026) and lower Aβ42/40 ratio (p=0.049) was associated with higher PVS grade.In the low Aβ42/40 ratio subgroup, higher PVS grade was most significantly associated with executive function impairment (p = 0.045, β = 0.612). For the subgroups of high Aβ42/40 ratio (p=0.017, β = 0.325), low GFAP (p = 0.027, β = 0.610), high GFAP (p = 0.006, β = 0.375), higher PVS grade was most significantly associated with learning and memory impairment.ConclusionThese results demonstrate that low Aβ42/40 ratio, high GFAP levels were associated with higher PVS grade in VCI participants, suggesting their utility as markers for VCI.Furthermore, higher PVS Grade in VCI participants with low Aβ42/40 ratio were associated with executive function impairment compared to other subgroups which were associated with learning and memory impairment. This could be an important clinical marker when examining patients with high PVS Grade as it could be associated with a more sinister disease progression.
Dynamic functional connectivity evolution across the Alzheimer's Disease spectra
Authors: Carrasco‐Gómez Martín , Cabrera Jesús , García‐Colomo Alejandra , Fernández Ricardo Bruña , Maestú Fernando , Santos Andrés ,   Center for Cognitive and Computational Neuroscience
Published: January 2025

AbstractBackgroundRecent studies in brain functional connectivity (FC) have shifted focus to dynamic functional connectivity (dFC), exploring transient aspects of FC over time. This shift is particularly relevant for Alzheimer's Disease (AD), as it involves altered cognition‐supporting networks. Our study aims to characterize the evolution of dFC across the entire pre‐dementia AD spectrum using Amplitude Envelope Correlation (AEC) recurrence matrices and to link this to cognitive decline.MethodWe analyzed 143 healthy controls (HC), 72 subjective cognitive decline (SDC) participants, and 106 Mild Cognitive Impairment (MCI) patients. Leakage‐corrected AEC was computed in alpha (8‐12 Hz) and beta (12‐30 Hz) bands from resting eyes‐closed magnetoencephalography (MEG) signals. Recurrence matrices representing dFC stability over time were obtained by correlating AEC matrices over signal segments. Between‐group differences were tested via linear regression, controlling for sex and age. Group differences were further explored with cluster‐based permutation tests (CBPT), and MCI whole‐brain stability was correlated with mini mental state evaluation (MMSE) scores. All results are FDR corrected (q = 0.05).ResultsSignificant decreases in dFC stability between the HC and MCI groups were observed in both alpha and beta bands (Figure 1, alpha: p‐value < 0.001, β‐value = 0.0265; beta: p‐value < 0.001, β‐value = 0.0135). CBPT analyses identified significant differences in orbitofrontal and left temporal cortices in alpha (Figure 2A; p = 0.028), and in the left orbital and temporal regions and in several areas related to the Default Mode Network (DMN), including the hippocampus and precuneus in beta (Figure 2B; p = 0.009). Additionally, a significant inverse correlation between MCI whole‐brain stability and MMSE scores was found in both frequency bands (alpha: R = ‐0.27, p‐value = 0.0084; beta: R = ‐0.26, p‐value = 0.0117).ConclusionOur findings suggest a decrease in dFC dynamics along the AD continuum, particularly affecting orbitofrontal and temporal regions, as well as DMN‐related areas like the hippocampus and inferior parietal gyrus. These changes are inversely correlated with cognitive performance in MCI patients. This indicates that dFC parameters derived from AEC recurrence matrices could be valuable in identifying early AD progression.