bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neighborhood disadvantage is associated with altered cortical organization
Authors: Safai Apoorva , Johnson Sterling C. , Jonaitis Erin M. , Langhough Rebecca E. , Powell W. Ryan , Buckingham William R. , Bendlin Barbara B. , Kind Amy J.H. , Tiwari Pallavi 
Published: January 2025

AbstractBackgroundNeighborhood disadvantage is associated with worse health and cognitive outcomes. Morphological similarity networks (MSN) is a promising approach to elucidate cortical network patterns underlying complex cognitive functions. We hypothesized that MSNs can capture intricate changes in cortical patterns related to neighborhood disadvantage and cognitive function, potentially explaining risk for later life cognitive decline among individuals who live in disadvantaged contexts.MethodThis study included cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. and their neighborhood disadvantage was indexed by the area deprivation index (ADI), a metric representing income, education, employment, and housing quality at the census block group geographic level(n=526, age=62.96±8.377, gender(M:F)=181:345, ADI(L:H)=452,74). We compared MSNs by ADI state rank scores in the two highest (9,10) and lowest (1,2) ADI deciles based on previous studies reporting strongest health effects among individuals living at the highest levels of disadvantage. Cognitive performance was indexed by six tests evaluating memory, executive functioning, and the pre‐clinical Alzheimer’s cognitive composite(PACC). T1‐weighted MRI scans of all participants underwent standard preprocessing steps in CAT12 toolbox MSN was constructed for each participant (Figure 1). We used linear regression to examine ADI associations with cognitive scores and four local and four global MSN features. Mediating effect of MSN features on the relationship between ADI and cognitive performance was statistically assessed using a non‐parametric bootstrapping (10,000) approach. Model covariates included age, gender, education (years), and total intracranial volume.ResultADI rank showed negative association with category fluency(CF)(β=‐0.176, p=0.039), WAIS‐DigitSymbol(β=‐0.442, p=0.011), Wechler’s Memory scale(WMS‐LM)(β=‐0.218, p=0.001) and PACC scores (β=‐0.056, p=0.001), indicating worse cognitive function among those living in more disadvantaged neighborhoods. Local network features of frontal and temporal brain regions (Figure 2a,b) differed by ADI group. Centrality of left fusiform and bankssts showed a mediating effect between association of neighborhood disadvantage and performance on the WMS and PACC scores respectively (Figure 2c).ConclusionOur findings suggest differences in local cortical organization by neighborhood disadvantage, which also mediated the relationship between ADI and cognitive performance, providing a possible network‐based mechanism, explaining risk for cognitive decline and dementia associated with disadvantaged neighborhoods. Future work will examine the dosage and timing of neighborhood disadvantage on structural organization of the brain.
Amyloid burden in non‐Hispanic Black vs White adults: A F18‐florbetaben PET study
Authors: Rusinek Henry , Bokacheva Louisa , Vedvyas Alok , Masurkar Arjun V. , Osorio Ricardo S. , Betensky Rebecca A , Shao Yongzhao , Chodosh Joshua , Marsh Karyn , Wisniewski Thomas 
Published: January 2025

AbstractBackgroundAssessment of anti‐amyloid therapies for Alzheimer’s disease (AD) requires understanding racial differences in brain amyloid. We compared amyloid burden in non‐Hispanic Black/African American and White (NHB, NHW) adults in a cohort with over 40% NHB participants and explored factors associated with the inter‐group differences.MethodWe included consecutive non‐Hispanic participants who underwent brain amyloid PET‐MRI exams in 2021‐2023 at NYU Alzheimer's Disease Research Center. PET images were acquired on Siemens 3T PET‐MR system after an injection of 300 MBq of 18F‐florbetaben, reconstructed and normalized by the mean activity of the whole cerebellum. Composite SUVR was calculated by averaging frontal, parietal, temporal and cingulate cortical regions (Bullich 2021 PMID:33773598) segmented using FreeSurfer 7.1. White matter lesion (WML) volume was measured on FLAIR images. We used linear regression to test amyloid SUVR for association with demographic, cognitive, and MRI features.ResultA total of 178 participants were enrolled (age, 72.5 ± 6.6 years old; 66% female), including 77 (43%) NHB and 101 (57%) NHW (Table 1). NHB were significantly younger than NHW, showed significantly lower memory and cognitive performance, yet also had significantly lower mean value and third quartile of amyloid SUVR distribution (Figure 1). Most measures of brain atrophy and white matter lesion load were not significantly different between groups.Regression analysis showed that race was the strongest predictor of SUVR. This finding remained true in the regression model adjusted for age, sex, education and clinical diagnosis (Table 2).ConclusionConsistent with two prior studies (Xiong 2022 PMID:35218143, Deters 2021 PMID: 33568538), we found differences in amyloid SUVR distribution and an unexpected relationship to memory performance in NHB compared to NHW. The finding may stem from several factors, including social/environmental differences, cohort selection biases, cognitive reserve and educational attainment, genetics, and different resilience to amyloid burden. In our cohort, NHB and NHW had comparable volume of WML, therefore cerebrovascular disease was unlikely the primary driver. Since lower amyloid burden in NHB may create bias in inclusion in anti‐amyloid treatment trials, it merits further investigations to be better understood.
Effects of 17‐beta estradiol on inflammation and mitochondrial function in Alzheimer’s disease
Authors: Mishra Pranav , Esfahani Ehsan , Fernyhough Paul , Albensi Benedict C. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder primarily associated with aging, but manifests as a complex interplay of multiple factors. Decline in sex‐hormones, particularly 17‐beta estradiol, is linked to the aging process. The risk for onset of AD significantly increases with aging and loss of estradiol. This is concurrent with inflammation and metabolic defects, leading to cell death. Amyloid beta (Aβ), a hallmark of AD exacerbates these processes by activating pro‐inflammatory NF‐κB, leading to sustained chronic inflammation and mitochondrial dysfunction, contributing to neurotoxicity. Estradiol imparts neuroprotection by mechanisms including the regulation of mitochondrial proteins, reduction in oxidative stress, and by decreasing inflammation. So far, our preliminary studies have demonstrated the potential of estradiol in ameliorating AD, where primary cortical neuros treated with estradiol exhibited improved mitochondrial function. For our future work, we will induce AD‐like pathology in our cell cultures by exposing them to Aβ. The objective of this study is to investigate the neuroprotective effects of estradiol against Aβ‐mediated neuroinflammation and mitochondrial dysfunction.MethodPrimary cortical neurons from C57BL/6 mouse embryos were isolated and cultured under defined conditions. Glial inhibitor AraC (2uM) was used obtain pure neuronal cultures followed by estradiol treatment (10nM). Expression levels of phosphorylated AMPK (pAMPK), PGC‐1α and NF‐κB inhibitor IKbα was measured via western blotting. Culture purity was determined using immunostaining. Oxygen Consumption Rate (OCR), an established measure of mitochondrial function was evaluated in live cells using SeahorseXF24 bioanalyzer.ResultImmunocytochemical analysis confirmed that our primary neuronal cultures were >90% pure. Estradiol treatment increased both; the levels of cellular energy sensor pAMPK and master regulator of mitochondrial biogenesis PGC‐1α. Additionally, estradiol elevated ATP production and spare respiratory capacity in these cells. We also observed a decrease in pro‐inflammatory NF‐κB activation as estradiol decreased the phosphorylation and degradation of NF‐κB inhibitory protein IKbα.ConclusionEstradiol, by elevating the levels of pAMPK, PGC‐1α, ATP production and spare respiratory capacity, and by decreasing pro‐inflammatory NF‐κB activation, significantly underlines its importance in modulating mitochondrial function and inflammation in neurons. The anticipated outcomes hold promise for advancing our understanding of therapeutic strategies in alleviating neurodegenerative diseases including AD.
A supervised machine learning approach to predicting subjective cognitive decline (SCD) among diverse Hispanics/Latinos: The SOL‐INCA Study
Authors: Kuwayama Sayaka , Tarraf Wassim , Gonzalez Kevin A , Márquez Freddie , Penedo Frank J , Wassertheil‐Smoller Sylvia , Daviglus Martha L , Lamar Melissa , Gallo Linda C , González Hector M 
Published: January 2025

AbstractBackgroundIncreasingly, research evidence is identifying subjective cognitive decline (SCD) as a precursor for cognitive impairment and dementia. Identifying predictors of SCD is essential for understanding its utility as a preclinical indicator for impairment and especially pertinent for Hispanics/Latinos who have limited access to healthcare resources and clinical diagnostics and are disproportionally affected by Alzheimer’s disease and related dementias. We extend work on predictors of Mild Cognitive Impairment (MCI) in diverse Hispanics/Latinos in the US by modeling multidomain predictors of SCD.MethodWe use data (n = 4347, average baseline age = 56.4‐years) from the Hispanic Community Health Study/ Study of Latinos (HCHS/SOL; 2008‐2011; Visit 1), a multisite prospective cohort study of diverse Hispanics/Latinos, and its ancillary study, the SOL‐Investigation of Neurocognitive Aging (SOL‐INCA; average 7‐years after Visit 1). Our outcome is a composite SCD measured at SOL‐INCA by averaging the component items of the Everyday Cognition (ECog‐12) scale and is modeled using 37 cross‐domain Visit 1 indicators, previously linked to MCI, reflecting (1) sociodemographic characteristics, (2) childhood factors, (3) acculturation factors, (4) biological and (5) behavioral markers, and (6) mental and (7) functional health factors. We use supervised machine learning (ML: Random Forest = RF; regression = ML‐Reg) and standard statistical techniques (regression = Reg) for identifying leading predictors of SCD. In secondary analysis, we assess enhancement in predictive performance by accounting for Visit 1 global cognitive (GC) function.ResultOur best performing (i.e., R‐squared) ML model (ML‐Reg) explained only 17% of the variance in SCD. Leading identified predictors of SCD included physical health scores, airflow obstruction, anxiety, mental health scores, Hispanic/Latino heritage, education, depression, income, and language and social acculturation. GC was predictive of SCD and explained an additional 5% of the variance.ConclusionOur findings indicate that multidomain factors contribute to SCD prediction, but the explained variance was relatively low. Biological markers, previously linked to MCI in our cohort, played a less significant role. Notably, the fit of the ML models for SCD was low relative to MCI specific models in the same population. Follow‐up work investigates how incorporating contemporaneous measures of the factors (vs. baseline alone) may improve the predictive capacity of the ML models.
Varicella zoster and the risk of dementia: understanding the interplay between age, the genome and proteome
Authors: Amin Najaf , Argentieri M Austin , Xiao Sihao , Van Duijn Cornelia M 
Published: January 2025

AbstractBackgroundThe mechanism through which common viruses such as varicella zoster virus (VZV) may trigger the onset of AD in the elderly is far from understood. The poliovirus receptor (PVR) is a protein of interest as it was associated to AD in a brain proteomics study and interacts with multiple viruses (Wingo, et al. Nat Neurosci). In this study (UKB), we examine whether plasma PVR levels are associated to AD, two of its early blood‐based biomarkers (NeFL and GFAP), ageing and VZV seropositivity.MethodsPlasma proteins including PVR have been measured in 53,000 UKB participants using the OLINK platform. In this cohort, 592 individuals developed AD during the 13 years follow‐up. For 967 participants, seropositivity for VZV is measured. We used Cox regression to associate PVR and other proteins to AD, adjusting for age, sex, physical activity, smoking, body mass index, alcohol use, 25 medications for chronic diseases, and technical covariates. We used Mendelian Randomization (MR) to test whether PVR is likely in the causal pathway based on genetic variants in the encoding genes. Further, we associated PVR to NeFL, GFAP, a protein‐based biomarker for accelerated aging (Argentieri et al, medRxiv) and seropositivity for VZV.ResultsPVR was found to be one of the 37 plasma proteins that were significantly associated incident AD (false discovery rate < 0.05) (see Table). The MR experiment conducted suggests a causal association between PVR and AD. We further find that PVR is significantly associated with the two biomarkers of AD pathology studied, NeFL (p<2.00*10−16) as well as with GFAP (p<2.00*10−16). Since the gene encoding for PVR maps to the 19q31 region close to APOE, we adjusted for APOE genotypes. The association of PVR with AD, NeFL and GFAP remained significant. We further find that PVR is strongly associated to accelerated proteomic aging (p = 2.54*10−15) as well to VZV serum positivity (p = 0.05).ConclusionOur findings suggests that PVR may play a role in the interplay between VZV seropositivity, age and AD. PVR may be relevant for the association between other viruses and AD.
Impact of a High‐Performing Blood Test on Wait Times for Determination of Eligibility for a Disease‐Modifying Alzheimer’s Treatment in the U.S.
Authors: Mattke Soeren , Chen Jiahe , Hanson Mark 
Published: January 2025

AbstractBackgroundAs disease‐modifying treatments for Alzheimer’s disease (AD) are becoming available, concerns have been raised about wait times in the patient diagnostic journey due to a limited number of AD specialists and PET scanners. A high‐performance blood test used in the in primary care settings has the potential to address this concern. We estimate the impact of such a test on wait times in the U.S.MethodWe use a Markov model to predict wait times for individuals identified as eligible for AD treatment, taking into account constrained capacity for AD specialist visits and confirmatory biomarker testing. We assume that individuals would undergo a brief cognitive assessment in primary care and, if indicative of early‐stage cognitive impairment, be referred to a AD specialist under three scenarios: (1) no blood test, (2) blood test to rule out AD pathology, and (3) blood test to confirm AD pathology.We model the U.S. population aged 55+ from 2023 to 2032, assuming that 25% of all individuals, who have never been evaluated for cognitive decline, and 5%, who were previously found to be cognitively normal, would undergo a brief cognitive test. If found to have early‐stage cognitive impairment and a blood test indicative of AD (if available), 80% would be referred to an AD specialist. The AD specialist would assess the patient and order biomarker testing for 90% of patients with confirmed early‐stage cognitive impairment. Such biomarker testing would include CSF testing (10% and not capacity constrained) and PET imaging (90%). Patients would then return to the specialist to discuss test results and a treatment indication. If the blood test were used to confirm the AD pathology, patients would skip the first specialist visit.ResultThe figure shows the expected wait times for the three scenarios.ConclusionThe introduction of a blood test into the AD diagnostic pathway could reduce wait times substantially and prevent eligible patients from falling outside the treatment window. Ongoing work will assess additional scenarios and patient pathways as well as their cost implications.
Pharmacokinetics and Pharmacodynamics of an Antibody Targeting Pathological Tau for the Treatment of Alzheimer’s Disease: Nonclinical Studies in P301S Mice and Cynomolgus Macaques
Authors: Sadhu Chanchal , Liu Wencheng , Kundu Joydip , Thompson Jeffery , Emery Maurice , Epling Daniel , Smith Brandon , Shah Ishan , Paranjpe Maneesha , Lee Shiron , Fang Ching‐Lien , Walsh Alison , Placidi Matteo , Mathur Krishanu , Mondick John , Chapel Sunny , Ghetti Bernardino , Carter Todd , Paul Steven M. , Yao Johnny , Sah Dinah. W.Y 
Published: January 2025

AbstractBackgroundVY‐TAU01 is a recombinant humanized IgG4 monoclonal antibody (mAb) directed against pathological tau for the treatment of patients with mild dementia or mild cognitive impairment due to Alzheimer’s disease (AD). Both VY‐TAU01 and its parental mouse IgG1 mAb Ab‐01 target an epitope in the C‐terminus of tau, bind pathological tau with high affinity and selectivity over wild‐type tau, block paired helical filament seed‐induced tau aggregates in vitro, and selectively stain tau tangles in AD and P301S mouse (C57/B6J‐Tg[Thy1‐MAPT*P301S]2541Godt) brain. Ab‐01 robustly inhibits seeding and propagation of pathological tau in a P301S mouse seeding model.To support toxicology studies and the initiation of the first‐in‐human study, nonclinical studies have been conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of Ab‐01 in P301S mice and the PK of VY‐TAU01 in cynomolgus macaques.MethodThe PK of Ab‐01 in the P301S mouse after 5 weekly intravenous or intraperitoneal doses at 10 to 120 mg/kg and VY‐TAU01 in cynomolgus macaques after a single intravenous high or mid dose was evaluated with validated ELISAs using their target epitope peptide. The PD of Ab‐01 in the P301S mouse was also evaluated using an ELISA to quantify unbound p‐tau levels.ResultAb‐01 and VY‐TAU01 PK profiles in serum and cerebrospinal fluid (CSF) were characterized by a distribution phase followed by a typical elimination phase without evidence of substantial target‐mediated disposition in the respective compartments. Serum and CSF concentrations increased with increasing dose levels in an approximately dose proportional manner, and their half‐lives were approximately 9 to 13 days. CSF concentrations were 0.1 ‐ 0.2% of serum concentrations.PD effects of Ab‐01 in the P301S mouse were robust, with up to ∼90% lowering of unbound p‐tau. Additional PD as well as PK/PD modeling results will also be presented.ConclusionThe PK of Ab‐01 in the P301S mouse and VY‐TAU01 in the cynomolgus macaque, and CSF to serum ratios were typical of murine IgG1 and human IgG4 administered to these respective species. The PD of Ab‐01 in the P301S mouse demonstrated robust lowering of unbound p‐tau. These results support VY‐TAU01’s continued development and advancement into the clinic.
Disparity in Resilience: The role of educational attainment and APOE ε4 in Alzheimer Disease in a Puerto Rican cohort
Authors: Hamilton‐Nelson Kara L. , Rajabli Farid , Cai Dingtian , Adams Larry D. , Mena Pedro R. , Celis Katrina , Sanchez Jose Javier , Valladares Glenies S , Whitehead Patrice L. , Acosta Heriberto , McInerney Katalina F , Moise Rhoda , Griswold Anthony J. , Beecham Gary W , Feliciano‐Astacio Briseida E. , Vance Jeffery M. , Seixas Azizi A , Cuccaro Michael L. , Pericak‐Vance Margaret A 
Published: January 2025

AbstractBackgroundCognitive resilience research in African Americans (AA) shows that higher educational attainment (EA) can mitigate the impact of Alzheimer disease pathology (ADP). However, this mitigating effect is less pronounced in APOEε4 carriers. This finding suggests a disparity in resilience influenced by an interplay of educational and genetic factors. Expanding on this, our study examines Puerto Ricans (PR), a population with distinct social and ancestral background, to assess whether similar patterns of disparity are present. Our aim is to explore the role of education as a modifiable risk factor in Alzheimer disease (AD) and to determine whether the APOEε4 allele leads to differences in resilience among carriers and non‐carriers.MethodsWe studied 455 PR individuals, focusing on their completed education years, plasma pTau181 levels, and APOE genotypes. Using the non‐memory components of the Cognitive Dementia Rating scale, we formulated a composite score CDR‐FUNC to capture functional difficulties. EA was classified into low EA(≤9years) and high EA(>9years). We used plasma pTau181 as proxy for ADP. Those with log10(pTau181) >mean+1SD were considered as advanced pTau181 levels. Participants were also categorized based on their APOEε4 carrier status. The Mann‐WhitneyU test was used to evaluate the association between EA and CDR‐FUNC in individuals with advanced pTau181 levels and ε4 allele.ResultsThe study found a correlation between EA and CDR‐FUNC in PRs with high pTau181 levels. Individuals with high EA showed better functional ability than those with low EA(p = 0.014). Additionally, we found that the effect of high EA on functional resilience was stronger in ε4 non‐carriers (p = 0.038) compared to ε4 carriers (p = 0.277).ConclusionsOur study demonstrates that education is a modifiable risk factor for AD in PRs, contributing to resilience against ADP. Notably, we identified a disparity in the protective effect of EA between carriers and non‐carriers of the APOEε4 allele. Revealing patterns like those observed in AA, our research confirms the combined influence of education, genetics, and functional resilience in AD. The results highlight the importance of education and genetic factors across diverse ethnic and ancestral backgrounds. Our findings are essential for creating targeted interventions to improve health outcomes in PRs and diverse populations affected by AD.