bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ffar4 regulates inflammatory oxylipin balance in the brain
Authors: Murphy Katherine A , Harsch Brian A , Shearer Gregory C , O'Connell Timothy D 
Published: January 2025

AbstractBackgroundOxylipins are oxygenated fatty acid (FA) metabolites that are important mediators of inflammation. Neuroinflammation is a hallmark of Alzheimer’s disease (AD), and brains of AD patients contain more pro‐inflammatory and less anti‐inflammatory oxylipins compared to healthy controls. Free fatty acid receptor 4 (Ffar4) is a G‐protein coupled receptor for medium and long‐chain FAs, including, but not limited to, omega‐3‐polyunsaturated FAs. Ffar4 is expressed in a variety of tissues, including neurons, astrocytes, and microglia. Ffar4 signaling produces anti‐inflammatory and pro‐resolving oxylipins that can attenuate inflammation, reduce oxidative stress, and prevent apoptosis. This suggests that targeting Ffar4 signaling will preserve a more anti‐inflammatory/pro‐resolving oxylipin profile and potentially improve outcomes.MethodWe accessed a biorepository that contains de‐identified electronic health records linked to patient genetic data for associations with Ffar4 polymorphisms and health reports. APPSAA knock‐in (KI) mice (Jackson, strain #034711) were used to model AD. Brain regions from wild‐type (WT), APPSAA KI, Ffar4 knockout (KO), and APPSAA KI/Ffar4KO mice underwent LC/MS/MS analysis to detect oxylipins. RAW264.7 cells were treated with the Ffar4 agonist, TUG‐891, and subjected to LC/MS/MS to detect oxylipins.ResultIn humans, we discovered that the Ffar4 inactivating polymorphism, R270H, was associated with an increased risk of AD and memory loss. We observed pronounced alterations in the oxylipin content of brain tissues, with a reduction in anti‐inflammatory oxylipins in Ffar4KO brains compared to WT. APPSAA KI mice had an increase in pro‐inflammatory oxylipins that was exacerbated by loss of Ffar4. Ffar4 activation with a synthetic agonist in a macrophage cell line resulted in increased production of anti‐inflammatory oxylipins, while decreasing pro‐inflammatory oxylipins. These data indicate that Ffar4 mediates oxylipin production and Ffar4 activation promotes the production of anti‐inflammatory and pro‐resolving oxylipins.ConclusionThe anti‐inflammatory properties of Ffar4 make it an intriguing target for diseases that result from chronic inflammation, such as AD. Our data show that Ffar4 can modulate the inflammatory tissue environment by controlling oxylipin synthesis. Given that Ffar4 attenuates inflammation, activating Ffar4 could mitigate AD‐related neuroinflammation. By targeting Ffar4 it might be possible to redirect the immune response, alter oxylipin profiles, and improved prognosis.
Sabirnetug (ACU193) Lowers CSF Levels of Synaptic Biomarkers in INTERCEPT‐AD Phase 1 Study in Early AD
Authors: Cline Erika N , Johnson Elizabeth , Sundell Karen , Antwi‐Berko Daniel , Koel‐Simmerlink Marleen JA , Teunissen Charlotte , Siemers Eric , Zhang Hao , Hyland Maddelyn , Sethuraman Gopalan , Vanderstichele Hugo , Kaplow June , Dean Robert A , Jerecic Jasna 
Published: January 2025

AbstractBackgroundSabirnetug (ACU193) is a humanized IgG2 antibody targeting soluble, synaptotoxic amyloid β oligomers (AβOs). AβOs accumulate in Alzheimer’s disease (AD) and induce pre‐ and post‐synaptic changes, resulting in dendritic spine loss, neuronal degeneration, and release of synaptic proteins into the CSF. Recently, we reported that three administrations of sabirnetug in an early AD population (INTERCEPT‐AD Phase 1 study, NCT04931459) significantly lowered CSF levels of the post‐synaptic protein neurogranin as well as pTau181. Here, we present data on additional CSF synaptic biomarkers and AD plasma biomarkers measured in INTERCEPT‐AD.MethodINTERCEPT‐AD was a randomized, placebo‐controlled study with two parts: single ascending dose (SAD) randomized in a 6:2 ratio to sabirnetug (2, 10, 25, 60 mg/kg) or placebo and multiple ascending dose (MAD) randomized 8:2 to sabirnetug (three administrations at 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) or placebo. Biomarkers were measured blinded in CSF and EDTA‐plasma, before and after drug administration, by Amsterdam UMC.ResultCSF levels of vesicle‐associated membrane protein 2 (VAMP2), a protein involved in pre‐ and post‐synaptic vesicle trafficking, were significantly normalized (lowered) in sabirnetug treated participants relative to placebo in all three MAD cohorts. Levels of the pre‐synaptic protein neuronal pentraxin 2 (NPTX2), which acts on post‐synaptic excitatory synapses, regulates complement activity, and lowers with cognitive decline, trended lower with sabirnetug than placebo. Plasma levels of GFAP, pTau181, and pTau217 trended towards normalization (lowering) of AD‐dependent changes in the 60 mg/kg Q4W cohort.ConclusionIn INTERCEPT‐AD, three administrations of sabirnetug lowered CSF levels of both pre‐ and post‐synaptic proteins, consistent with sabirnetug’s proposed mechanism of action to inhibit AβO synaptic binding. VAMP2 appeared most sensitive to sabirnetug in this study, lowering significantly in all three MAD cohorts; other markers previously reported to have a statistically significant response to sabirnetug ‐ neurogranin and pTau181 ‐ did so at the highest dose. No statistically significant changes in plasma biomarkers were observed in this short study. Long‐term changes in biomarker levels and their relationship to clinical efficacy will be evaluated in the 18‐month ALTITUDE‐AD phase 2 study of sabirnetug beginning in the first half of 2024.
Tau‐related cortical thinning is concentrated in sulcal depths
Authors: Maboudian Samira A. , Parker Benjamin J. , Weiner Kevin S. , Jagust William J. 
Published: January 2025

AbstractBackgroundPrior studies suggest sulci are more vulnerable to age‐ and Alzheimer’s disease (AD)‐related atrophy than gyri, but the pattern of regional vulnerability to tau pathology is incompletely understood. We performed this study to determine whether tau‐related atrophy preferentially affects sulci and specifically the early‐developing, deepest portions of sulci, which have been shown to be connectivity hubs.MethodsWe used MRI, amyloid and tau PET scans from 809 Alzheimer’s Disease Neuroimaging Initiative participants: 92 with AD, 249 with MCI, 468 cognitively normal. Correlation between vertex‐wise cortical thickness and whole‐brain tau was performed using FreeSurfer’s GLM pipeline. Following cluster‐wise multiple comparisons correction, an ROI of significant clusters was generated (“clusters;” Fig. 1). Overlap between the clusters and whole‐brain sulcal or gyral ROIs was calculated using the dice coefficient. We then generated labels of the deepest 5% of points in the sulcal ROI or the remaining 95%, as well as the deepest 5% of points of the superior temporal sulcus (STS) and collateral sulcus (COS, chosen as a control), and calculated their overlap with the clusters. For all comparisons we used mixed‐effects ANOVAs to examine the effects of ROI (sulcal/gyral, deeper/shallower points, STS/COS) and hemisphere (left/right) on the amount of overlap with the clusters.ResultsClusters of significant negative tau‐thickness correlation overlap significantly (p<.0001) more with sulci than gyri (Fig. 2B). This overlap is also significantly (p<.0001) greater in the deepest sulcal points compared to the rest of the sulci (Fig. 2C). This effect was greater in the STS than COS (Fig. 3). There is a right hemisphere (RH) bias in this overlap, which is stronger for the STS.ConclusionsWe find that tau‐related thinning occurs mostly in sulci, and particularly in sulcal depths. This overlap is particularly striking within the STS, a brain region particularly vulnerable to AD pathology and deeper in the RH. These results show greater specificity for sulcal vulnerability in aging and AD, particularly in the deepest parts of sulci. This anatomical specificity may underlie the profound effects of tau deposition on cognition.
Behavioral deficits in an Alzheimer’s Disease mouse model containing both APOE4 and Tau
Authors: Booth Aaron , Neff Samuel , de Lillo Vincenzo , Campitell John , Marediya Amrah , Gray Samantha , Flinn Jane 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is a neurological disease characterized by two major biological components; amyloid beta (abeta) and hyperphosphorylated tau. Research suggests that the hyperphosphorylated tau aggregation seen in late‐onset AD is characterized by two independent pathways, one caused by abeta buildup, and the other potentially caused by Apolipoprotein 4 (APOE4). However, research examining the relationship between hyperphosphorylated tau and APOE4 in the absence of abeta has been both inconsistent and lacks behavioral results. Likewise, research suggests that zinc exacerbates the effects of both tau and abeta in AD mouse models, however, there is limited research in how zinc interacts with APOE4.MethodWe analyzed 8 groups of mice; 4 genotypes (WT, APOE4, Tau, APOE4xTau), 2 treatment groups (lixit water, zinc water), none of which contained abeta. Behavioral tests were run at 3 and 6 months of age to examine activities of daily living (Nesting & Burrowing), anxiety & motor ability (Open Field), and spatial memory (Morris Water Maze).ResultInitial results at 3 months indicate that Tau and APOE4xTau mice demonstrated impaired activities of daily living (Nesting; (p<.001), Burrowing (p<.001)), higher risk taking (p<.001), and impaired spatial memory (p<.001) compared to WT or APOE4 mice. APOE4 mice demonstrated improved spatial memory compared to WT; p<.001, and APOE4xTau mice demonstrated improved spatial memory compared to Tau; p<.001. However, APOE4 and APOE4xTau mice did not show differences in activities of daily living, nor anxiety compared to WT and Tau mice respectively. Additionally, Zinc did not significantly influence behavior at 3 months. Results will be re‐analyzed at 6 months of age, and brains will be analyzed for proteins of interest.ConclusionOur initial findings provide evidence that APOE4 enhances certain behaviors at 3 months of age. This is consistent with previous research that APOE4 may show beneficial effects at a young age in both humans and mouse models. Subsequent analysis at 6 months will determine whether these beneficial effects continue at an older age.
Project FRONTIER: a Cohort to Study Aging in Rural West Texas
Authors: Decourt Boris , Singer Jonathan , Molinar‐Lopez Veronica , Yin XiangLing , Neugebauer Volker 
Published: January 2025

AbstractBackgroundIn the past decades, the NIH has identified a large knowledge gap in the study of health and disease in diverse and underserved inhabitants. The most recent estimates (2020) indicate that rural dwellers represent 15‐20% of the total US population, but these individuals experience worse health status than urban counterparts. A major challenge to the study of health disparities in rural areas is the dearth of structured rural cohorts that can be used for scientific research purposes.MethodProject FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) was initiated in 2006 as an epidemiological study to explore the natural course of chronic disease development and its impact on longitudinal cognitive, physical, social and interpersonal functioning in a multi‐ethnic adult sample from rural communities of West Texas.ResultCurrently, project FRONTIER is collecting data from Cochran, Bailey, Parmer, Hockley and Lubbock counties, with expansion to additional counties soon [update: Lamesa/Dawson county]. In recent years, the cohort has been utilized more for cognitive and Alzheimer’s disease research than other conditions, though we collected limited data and biospecimens. Thus, there is a huge opportunity to better characterize this cohort at the genetic and metabolic levels to gain large amounts of information on the aging processes in rural dwellers. The demographics of this cohort are: 1374 unique individuals, 66% female, 56% Hispanics, mean age of 58.9±12.2 years, 21% with a high school degree, and 23% with some college education. Although challenging, we are attempting longitudinal collections on this cohort. However, as our group is recruiting more experts on rural cohort research, we are currently implementing more rigorous protocols to collect accurate data and high quality biospecimens more frequently from this cohort.ConclusionOur Project FRONTIER cohort provides very informative data on dementia risk factors in rural dwellers. As we make progress, we intend to share these materials with the scientific community for the deep genotyping and phenotyping of our study participants.
Self‐reported sleep health characteristics may capture attention, memory, and global cognitive performance in older African‐Americans
Authors: Romain Stanley , White Payton G. , Fausto Bernadette A. , Gluck Mark A. 
Published: January 2025

AbstractBackgroundOlder African Americans bear a disproportionate burden of both sleep problems and cognitive dysfunction. Alarmingly, poorer sleep health may put an individual at higher risk of cognitive dysfunction. However, the relationship between sleep and cognition in older African Americans continues to be understudied. This study aimed to examine the relationship between subjective sleep health characteristics and cognitive function among older African Americans.Method62 older African American participants (mean age = 72.19; SD = 6.651; mean education = 14.28; SD = 6.651; 51 female; 11 male) from the Pathways to Healthy Aging in African Americans study completed a demographic questionnaire as well as cognitive assessments of attention, episodic memory, executive function, language, and global cognition. The following sleep health characteristics were derived from the Pittsburgh Sleep Quality Index: Subjective sleep quality; sleep latency; sleep duration; sleep disturbances; use of sleeping medications; daytime dysfunction; and global index score. Hierarchical linear regression analyses were employed to investigate the relationship between sleep health characteristics and cognitive function while controlling for age, sex, education, waist‐to‐hip ratio, and depressive symptomology.ResultThe relationship between subjective sleep quality and episodic memory (B = ‐1.715; p < 0.001); sleep disturbances and global cognition (B = ‐1.581; p = 0.020); sleep latency and global cognition (B = ‐1.033; p = .011); and sleep efficiency and attention (B = 0.249; p = 0.038) were significant before and after controlling for covariates. Overall, poorer sleep health across multiple characteristics was associated with worse cognitive function.ConclusionSelf‐reported sleep disturbances and longer sleep latency appear to be tapping into poorer global cognition, whereas poorer subjective sleep quality and sleep efficiency are tapping into worse episodic memory and attention, respectively. These findings highlight the importance of assessing self‐reported sleep health in populations at higher risk for both sleep disorders and cognitive dysfunction.
Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans
Authors: Liu Hesong , Bas Brouwers , He Yang , Liu Hailan , Yin Na , Yang yongjie , Yu Meng , Wang Chunmei , Xu Yong 
Published: January 2025

AbstractBackgroundA decline in memory is a hallmark of Alzheimer’s disease (AD). Experiments in rodents and post‐mortem studies in humans with AD suggest that serotonin (5‐HT) plays a role in memory, but the molecular and neural mechanisms mediating its effects are unknown.Method100,000 individuals in UK Biobank were studied for the role of serotonin 2C receptor (5‐HT2CR) in the regulation of memory. We examined both wild‐type (WT) and transgenic mice (F327L) expressing a human loss‐of‐function serotonin 2C receptor (HTR2C). Memory function was assessed using Radial Arm Water Maze test. Additionally, we conducted neural tracing by injecting retrograde viruses expressing GFP into the vCA1 of WT mice. We disrupted serotonin synthesis in vCA1‐projecting neurons using AAV‐Cre virus in Tph2‐CreER mice and deleted 5‐HT2CRs on vCA1 neurons in Htr2cflox/Y
mice. Furthermore, we evaluated the integrity of 5‐HT to vCA1 circuit using Tph2‐CreER/Rosa26‐LSL‐tdTOMATO/ AppNL‐G‐F
mice. Lastly, we explored the effects of lorcaserin, a selective 5‐HT2CR agonist, in AppNL‐G‐F
mice.ResultOur findings revealed that a rare loss‐of‐function mutation in HTR2C significantly impaired short‐term memory in both humans and F327L mice. Neural tracing experiments demonstrated that midbrain serotonin neurons project to the vCA1 hippocampal region. Disruption of serotonin synthesis in vCA1‐projecting neurons and deletion of 5‐HT2CRs on vCA1 neurons led to memory impairment. Notably, the 5‐HT to vCA1 circuit was disrupted in AppNL‐G‐F
mice. However, lorcaserin corrected memory loss in a mouse model of amyloid pathology.ConclusionThe 5‐HT to vCA1 circuit regulates working memory. By utilizing 5‐HT2CR agonists, we can potentially bypass the damages in this circuit and enhance memory function in AppNL‐G‐F
mice.
Digital marketing for increasing participant diversity in ADNI4 – early insights from initial rollout
Authors: Conti Catherine C. , Amaza Hannatu , Miller Melanie J. , Thao Mai Seng , Flenniken Derek , Kwang Winnie , Ashford Miriam T. , Fockler Juliet , Truran‐Sacrey Diana , Strong Joseph , Sorce Jennefer , Alaniz Roxanne , Weiner Michael W. , Okonkwo Ozioma C , Mindt Monica Rivera , Nosheny Rachel L. 
Published: January 2025

AbstractBackgroundThe Alzheimer’s Disease Neuroimaging Initiative (ADNI4), whose goal is to validate biomarkers for AD clinical trials, aims to increase participation of individuals from historically underrepresented populations (URPs) so results are more generalizable. ADNI uses digital marketing to recruit and enroll older adults into a digital cohort, for screening into in‐clinic ADNI. Challenges and insights from initial marketing efforts, including enrollment rates, local demographics, and effectiveness at enrolling URPs are presented.MethodsWe employed a culturally‐informed marketing approach developed in partnership with ADNI’s Community Scientific Partnership Board and marketing firm, including digital campaigns (Meta ads, websites, and emails) designed using themes aimed to resonate with Black and Latinx communities (solo, family, community; Fig. 1). Varying ads run simultaneously to compare effectiveness. Ads direct to study websites, registration pages, and consent to join a digital cohort. Ads run in geographies based on clinical site readiness to enroll participants.ResultMost initial sites to utilize digital marketing (Universities of Kansas, Kentucky, and Mayo Clinic) were in areas of lower ethnocultural diversity compared to other ADNI sites (Table 1). Three months into recruitment, we shifted to optimizing ads in an area with higher ethnocultural diversity (UKentucky) to maximize data on highest enrolling ads (Tables 1&2). Additional digital recruitment began for sites in areas with higher ethnocultural diversity (UCSF, Wake Forest; Table 1). We subsequently saw a 317% increase in enrollment of Black older adults, with no significant improvement for other URPs (Fig. 1c). Following campaign launches (Butler, Georgetown) further supported our campaigns’ ability to enroll Black adults (Table 2). Initial results suggest “solo” and “community” themed ads yield highest enrollments in Black population campaigns. (Fig. 1b). Despite running in areas with large Latinx populations (UCLA), ADNI4’s Latinx campaigns were generally not obtaining enrollment rates comparable to our Black population campaigns (Tables 1&2).ConclusionOur early successes in recruitment of older Black adults (43% of digital cohort enrollments) strongly demonstrates the feasibility of culturally‐informed, site‐specific digital marketing to specific URPs for AD clinical studies. More work is needed to increase inclusion of Latinx adults (7% of enrollments) and other URPs in ADNI4’s digital cohort.
Amyloid‐ß oligomer Aß*56 is associated with Alzheimer’s dementia independently of amyloid pathology
Authors: Liu Peng , Lapcinski Ian , Ashe Karen 
Published: January 2025

AbstractBackgroundA current hypothesis of the etiology of Alzheimer’s disease (AD) suggests that soluble amyloid‐ß (Aß) oligomers (Aßo) play a more significant role than amyloid plaques. Among the numerous Aßo discovered in the brain, Aß*56 has been shown to be associated with aging and cognitive dysfunction in mice, dogs, and humans, and impair memory in rodents. Evidence from our recent study indicates that Aß*56 produced from Tg2576 mice modeling AD is a ∼56‐kDa, SDS‐stable, A11 (anti‐amyloid oligomer antibody)‐reactive, water‐soluble oligomer that impairs memory in healthy wild‐type mice; and that there exist at least two Aß*56 variants—Aß(40)*56 and Aß(42)*56—that contain canonical Aß(1‐40) and Aß(1‐42), respectively, in AD mouse models. In addition, Aß*56 appears prior to the formation of amyloid plaques in Tg2576 mice, suggesting that the biogenesis of Aß*56 is independent on plaques. Here, we extend the characterization of this non‐plaque‐dependent oligomer to human AD cases and investigate the relationship between Aß*56 and cognitive dysfunction in AD dementia.MethodWe analyzed AD‐affected, inferior temporal gyrus (ITG) postmortem specimens from de‐identified elderly individuals enrolled in the Religious Orders Study/Memory and Aging Project. This cohort consisted of cognitively normal (CN) individuals, individuals with mild cognitive impairment (MCI), and individuals with AD dementia (N = 19‐23 per group) that were age‐matched, sex‐balanced, and contained comparable amyloid plaque loads in the ITG. Using immunoprecipitation/western blotting coupled with densitometry‐based semi‐quantitative analysis, we measured levels of Aß(40)*56 and Aß(42)*56. We then compared levels of Aß*56 variants between different clinical diagnoses and correlated them to cognitive assessments.ResultWe showed that both levels of Aß(40)*56 and Aß(42)*56 are elevated in individuals with AD dementia compared to CN individuals and individuals with MCI. In addition, we showed that levels of Aß*56 variants are correlated to mini‐mental state examination scores and severity of impairment in global cognitive function, episodic memory, and semantic memory, but not working memory.ConclusionOur data suggest an association between Aß*56 to AD dementia in elderly human brains that is independent of amyloid pathology. Such findings support the use of Aß*56 as a molecular marker for AD diagnosis.