bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do associations between mindfulness and cognitive reserve vary by APOE e4 carrier status?
Authors: O'Shea Deirdre , Besser Lilah M , Rader Katana , Zhang Andrea S. , Shakour Rebecca , Galvin James E 
Published: January 2025

AbstractBackgroundEvidence suggests that mindfulness practice may reduce the risk of dementia by enhancing cognitive reserve. However, it’s unclear whether APOE ε4 carrier status influences the link between mindfulness and cognitive reserve. This study examined whether associations between mindfulness and memory, language, executive and speed reserve differed by APOE ε4 carrier status.MethodData from 117 older adults without dementia (age = 67.8+9.8y, 67% female, 30% APOE ε4 carriers) from the Healthy Brain Initiative study were included. Cognitive reserve indices for memory, language, executive function, and speed were the residuals from regressing domain scores onto total hippocampal volume, total gray matter volume, and total white matter hyperintensities volume, with higher residuals indicating more reserve. Mindfulness was assessed using the 15‐item Applied Mindfulness Process Scale (AMPS). APOE ε4 status was coded dichotomously: presence of at least one ε4 allele (1) indicated carrier status, while absence (0) indicated non‐carrier status. Multiple linear regression models were used to test interactions APOE x AMPS on each cognitive reserve domain. All models were adjusted for age, sex, education, and depression levels.ResultHigher scores on the AMPS were associated with greater memory reserve in APOE ε4 carriers, (β = 0.17, 95% CI [0.01, 0.68]), but not in non‐carriers (β = 0.11, 95% CI [‐0.24, 0.20]). A similar association was found for executive function reserve (ε4 carriers: β = 0.17, 95% [CI ‐0.08 0.76]; ε4 non‐carriers: β = 0.11, 95% CI [‐0.24, 0.20]), and language reserve (ε4 carriers: β = 0.17, 95% CI [0.09, 0.76]; ε4 non‐carriers: β = 0.11, 95% CI [‐0.25, 0.18]). No significant interaction between APOE ε4 status and AMPS was observed for speed reserve.ConclusionMindfulness practice was associated with enhanced cognitive reserve in memory, executive function, and language among APOE ε4 carriers, but not in non‐carriers. This differential impact underscores the potential of mindfulness‐based interventions in improving cognitive outcomes, particularly for those at higher risk for dementia due to APOE ε4 carrier status. The cross‐sectional nature of the study limits the ability to infer causality; however, the patterns observed suggest that future longitudinal studies are warranted to explore these relationships.
Genetic variation of the Alzheimer’s disease risk gene CD33 modifies microglial immunometabolism
Authors: Tamucci Kirstin 
Published: January 2025

AbstractBackgroundGenome‐wide association studies (GWAS) have identified genetic loci that robustly associate with Alzheimer’s Disease (AD), many of which are preferentially or exclusively expressed in innate immune cells. Among the identified AD risk genes is CD33: a transmembrane, sialic acid‐binding protein expressed on the surface of myeloid cells including microglia, the innate immune cells of the CNS. The function of microglia is highly responsive to and regulated by metabolic changes, which allows them to rapidly change phenotype and maintain brain health. However, the examination of human microglial metabolism as a driving factor in AD pathogenesis is an underappreciated concept.MethodTo understand the molecular function of the CD33 protein in AD, our laboratory used a cutting‐edge mass spectrometry approach to identify binding partners of the CD33 sialic acid binding domain. We have also optimized a method using PBMCs from individuals of diverse age, sex, and ethnicity from which we can isolate monocytes to be differentiated to microglia‐like cells (MDMi).ResultOur mass spectrometry‐based approach revealed a novel interaction between CD33 and the glucose transporter GLUT1 that was further validated by proximity ligation assay (PLA) and co‐immunoprecipitation (co‐IP) in a human monocytic cell line. These findings prompted us to investigate CD33 genotype‐specific effects on microglial metabolism using human monocytes differentiated into microglia‐like cells (MDMi). We generated MDMi with different CD33 genetic backgrounds and measured their respiratory bioenergetics using a Seahorse extracellular flux analyzer. Interestingly, we found that the balance of ATP production via oxidative phosphorylation and glycolysis significantly varies with CD33 genotype at baseline. In a similar way, we found differences in glucose uptake and lactate secretion based on CD33 genotype, with AD‐risk (CD33CC) MDMi taking up more glucose yet secreting less lactate compared to AD‐protective (CD33AA) MDMi.ConclusionTogether, these results provide insight on microglia‐specific metabolic changes due to variations in the AD‐associated risk gene CD33. This novel link between genetic, immune, and metabolic risk factors in AD has the potential to reveal new therapeutic and immunomodulatory strategies with which to reduce susceptibility to this neurodegenerative disease.
Subjective Cognitive Complaints: Heritability and Correlations with Dementia Diagnosis, Depression and Memory, Across Multiple Twin Studies
Authors: Vella Ashleigh S. , Selwood Amanda , Catts Vibeke S. , Numbers Katya T. , Lee Teresa , Thalamuthu Anbupalam , Karlsson Ida K , Reynolds Chandra A. , Franz Carol E. , Kremen William S. , Gatz Margaret , Sachdev Perminder S. 
Published: January 2025

AbstractBackgroundSubjective Cognitive Complaints (SCCs) can often precede mild cognitive impairment and dementia longitudinally. While increasingly considered an early prodromal stage of dementia, SCCs can also be a symptom of depression. Previous research found that SCCs in the absence of cognitive impairment, controlling for symptoms of depression, were moderately heritable and genetically associated with memory. We aimed to replicate these previous findings by pooling data from a large consortium of twin studies across various countries.MethodData containing 2,041 participants (902 twin pairs; 497 MZ pairs) were pooled from twin studies contributing to the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium (Older Australian Twin Study (OATS); Study of Origins of Variance in the Oldest‐Old (OCTO‐Twin); and Vietnam Era Twin Study of Aging (VETSA)). Univariate AE model investigated the heritability estimates using four variables (depression, SCCs, word‐list recall and prose recall) from OATS, OCTO‐Twin, and VETSA. Multivariate models, using VETSA and OATs, calculated the genetic correlations between harmonised SCC scores, memory, and depression. Fisher’s z‐transformed correlations were meta‐analysed to obtain the combined estimates of heritability and genetic correlations.ResultsConsistent with previous research, SCC had a low combined heritability of 0.22(95% CI: [0.13,0.31]). The genetic influence on SCCs and memory were significantly related, such that as memory complaints increased memory performance decreased (word list recall, ‐0.17, 95% CI: [‐0.25, ‐0.10], prose recall, ‐0.21, 95% CI: [‐0.29, ‐0.14]), p < 0.05. An increase in depressive symptoms genetically correlated with a decline in memory (word list recall, ‐0.08, 95% CI: [‐0.16, ‐0.01], prose recall, ‐0.40, 95% CI: [‐0.49, ‐0.34]). No significant environmental correlations were observed between memory and either SCCs, or separately depression, p > 0.05.ConclusionsConsistent with our previous research, the heritability of SCC was low. The findings underscore the genetic connection between SCCs, objective memory performance, and depressive symptoms. The low heritability, however, suggests a substantial influence of environmental factors in explaining individual differences in SCC, highlighting the need for further research to better understand the dynamic influence of genetic and environmental influences on cognitive health.
Crosstalk between innate metabolism and gut microbiome
Authors: Kaddurah‐Daouk Rima 
Published: January 2025

AbstractBackgroundThe GI tract is home to approximately 70% of the body’s immune cells, >100 million enteric neurons, and ∼40 trillion bacteria. This co‐localization of myriad immune, neural and bacterial cells creates complex interactions that regulate almost every tissue in the body, including the brain. Importantly, peripheral and GI inflammation occur in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer (AD) contributing to gut brain axis. The activation state and function of microglia, brain‐resident innate immune cells, has been implicated in AD mouse models and is regulated by the gut microbiome. Gut microbial changes are linked to development of neuropsychiatric diseases. These disorders, classically studied from a brain‐centric view and associated with neuroinflammation, often exhibit GI symptoms and peripheral inflammation.MethodIn this session we will address metabolomics technologies applied by the Alzheimer Disease Metabolomics Consortium (ADMC) for the study of Alzheimer disease. State‐of‐the‐art metabolomics and lipidomics technologies combined with genomic and imaging data are used to map metabolic failures across the trajectory of the disease. Immune metabolomics platforms are being developed and used to link immune function changes and metabolic alterations in blood and in immune cells with link to cognition.ResultOur studies confirmed that peripheral metabolic changes influenced by the exposome and gut microbiome inform about cognitive changes, brain imaging changes, and ATN markers for disease confirming that peripheral and central changes are connected, in part through the metabolome. We defined metabolic differences between men and women with AD, developed initial brain metabolome for AD and defined lipidomics signatures that inform about mechanism of APOE ε2 resilience for AD. A major role for inflammation and immune dysregulation is noted and linked to signatures that inform about cognition and brain imaging changes. We will illustrate how we are applying immune metabolomics platforms to map cross talk between metabolism immune function inflammation and brain metabolic health.ConclusionMetabolomics presents powerful tools to the study of inflammation, immune dysregulation, in AD pathogenesis.
The anti‐platelet agent prasugrel reverses the cerebral blood flow deficit and memory impairment induced by hypertension in ApoE4‐positive mice
Authors: Trigiani Lianne J , Chernavsky Nicole E , Kim Rachel , Hawkins Robert F , Hong Nuri , Yamaguchi Keri , Bernard Jonah , Huang Amanda , Bae Gina H , Rivera Daniel A , Allan‐Rahill Nathaniel , Lamont Michael , Iadecola Costantino , Nishimura Nozomi , Schaffer Chris B 
Published: January 2025

AbstractBackgroundSeveral genetic and cardiovascular risk factors increase incidence of Alzheimer’s disease and related dementias (ADRD). Hypertension and the ε4 allele of apolipoprotein E (ApoE) are powerful drivers of cognitive impairment in ADRD. These risk factors are also associated with decreased cerebral blood flow (CBF). Experimental data suggest that the CBF reduction may be due to temporary capillary occlusions (capillary stalls) caused by circulating vascular and immune cells. To gain insight into how these risk factors may contribute to cognitive decline, we induced hypertension in mice expressing human ApoE3 or E4 (ApoE3‐ or E4‐TR mice), and focused on the resulting CBF and cognitive alterations, and their potential reversal by preventing capillary stalling.MethodsMale ApoE3 and 4‐TR mice (n = 9‐15/group) were assessed at three timepoints: Baseline, following two weeks of angiotensin II‐induced hypertension (AngII, 500ng/kg/min), and after an additional week of anti‐platelet treatment (prasugrel, 10mg/kg, daily). We tested spatial memory function in a Y‐maze, and imaged cortical microvascular flow using two‐photon microscopy.ResultsAt baseline, ApoE3 and 4‐TR mice showed similar memory performance, but with hypertension (∼25 mmHg increase in blood pressure) ApoE4‐TR mice exhibited a spatial working memory deficit, which coincided with a 26% decrease in capillary flow speed (4.11±0.3 vs. 3.05±0.29 mm/s, p<0.01), and a 1.8X increase in the incidence of non‐flowing capillaries. Most stalled capillaries contained only red blood cells in the stalled segment (57%), with some also containing leukocytes (30%), or platelets (12%) (Fig. 1). Treatment with prasugrel led to a 55% reduction in stalling (65±9 vs. 144±24 stalls/mm3), and a concomitant 23% increase in capillary blood flow (3.75±0.36 vs. 3.05±0.29 mm/s, p = 0.11), and significantly improved blood flow in penetrating arterioles that correlated with restored performance on the Y‐maze task (Fig. 2). Immunohistochemistry further revealed improved BBB integrity and reduced gliosis following prasugrel treatment.ConclusionParalleling human findings, we show that mice with the e4 allele of ApoE experience more deleterious consequences from hypertension, as compared to their e3 counterparts. Prasugrel treatment led to an almost complete recovery of these deficits, suggesting that anti‐platelet agents may be of therapeutic value by improving CBF and cognitive function in the presence of these risk factors.
Deciphering Iron Redox Changes in Alzheimer’s Disease using DNAzyme Sensors that can Simultaneously Monitor Fe2+ and Fe3+
Authors: Wu Yuting , Torabi Seyed‐Fakhreddin , Lake Ryan , Yang Zhenglin , Hong Shanni , Yu Zhengxin , Mirica Liviu M , Fonken Laura , Lu Yi 
Published: January 2025

AbstractBackgroundImbalanced Fe levels can lead to oxidative stress and initiate ferroptosis, an Fe‐dependent cell death that involves lipid peroxidation and can lead to neuron cell loss in neurodegenerative diseases including Alzheimer’s disease (AD). While the Fe3+/Fe2+ ratio has been identified as the primary determining factor for lipid peroxidation, the role of Fe redox equilibrium and dynamic in AD is not well understood, due to limited tools for visualizing Fe2+ and Fe3+ simultaneously. To overcome this limitation, we recently reported DNAzyme‐based sensors for simultaneous imaging of Fe2+ and Fe3+. In this research update, we have integrated the sensors with brain‐wide immunohistochemistry staining to identify cellular correlations between Fe redox changes and AD progression.MethodWe obtained DNAzymes that are highly selective for either Fe2+ or Fe3+ from a DNA library of up to 1015 sequences and used counter‐selection to remove sequences binding competing metal ions. We converted the DNAzymes into fluorescent turn‐on sensors using a method called “catalytic beacon” approach. With these sensors, we imaged Fe2+ and Fe3+ simultaneously in AD mouse brains. We also performed immunohistochemistry to evaluate neurodegeneration (NeuN), gliosis (Iba1&GFAP), amyloid beta pathology (HJ 3.4), and their correlation with Fe redox changes.ResultWe observed correlated signal changes with the regulation of iron levels. We further applied these sensors in ferroptosis and observed a decrease in Fe3+/Fe2+ redox ratio over time, indicating Fe redox changes as a potential source of oxidative stress in ferroptosis. These sensors also detected an elevated Fe3+/Fe2+ ratio in the AD mouse brain, particularly in amyloid plaque regions, suggesting a correlation between amyloid plaques and the accumulation of Fe3+ and/or conversion of Fe2+ to Fe3+. Furthermore, by co‐staining the Fe sensors with immunohistochemistry biomarkers, we found correlations between Fe, Fe redox changes, and neurodegeneration among mice groups differing in genotype, sex, and age.ConclusionWe have developed highly selective sensors for simultaneously imaging Fe2+ and Fe3+. By integrating these sensors with immunohistochemistry, we have identified correlations between Fe redox, amyloid plaques, and neurodegeneration in AD mice. Our sensors can offer deep insights into the detailed mechanism of ferroptosis and its role in AD.
Associations of Subjective Memory Concerns with Chronic Stress and Social Support in Mexican Americans: A Longitudinal Study
Authors: Gonzalez Alexa S. , Atherton Olivia E. , Krause Christopher A. , Garcia Joshua M. , Martinez Michelle N. , Medina Luis D. 
Published: January 2025

AbstractBackgroundThe progression of Alzheimer’s disease and related dementias (ADRDs) from prodromal state to dementia syndrome prompts researchers to identify early markers of cognitive decline. One potential risk marker is subjective memory concerns (SMCs). Individuals with greater perceived stress often report more cognitive concerns. Moreover, increased social support is linked to lower perceived stressors. Our previous cross‐sectional work with an ethnoracially diverse sample of older adults reveals a positive relationship between chronic stress and SMCs, adjusting for demographic factors. It remains unknown if chronic stress and social support are longitudinally associated with SMCs (at the between‐ and within‐person levels), particularly among older Hispanic/Latin Americans, who are notably underrepresented in ADRD research. The present research aims to address these gaps.MethodData for 84 Mexican Americans (Age = 62±6.97; Education = 10±3.57) were collected across three waves (24‐to‐30‐month intervals) via the Health and Aging Brain Study: Health Disparities (HABS‐HD). Exclusion criteria included depression, stroke, Alzheimer’s disease, and/or other dementia diagnoses. Participants self‐reported subjective memory concerns, chronic stress, and social support levels. Multilevel models were conducted to explore longitudinal associations between chronic stress and social support on SMCs, controlling for age, gender, and education.ResultsFindings showed significant between‐subject effects of chronic stress (β = .15, p = .018, 95% CI [.03, .27]) and of social support (β = ‐.26, p < .001, 95% CI [‐.40, ‐.12]) on SMCs. There were no significant within‐person effects of chronic stress (β = .046, p = .122, 95% CI [‐.012, .10]) or social support (β = ‐.045, p = .098, 95% CI [‐.11, .0093]) on SMCs.ConclusionsIndividuals with higher chronic stress and lower social support tended to report more memory concerns compared to individuals with lower chronic stress and higher social support. These findings suggest that Mexican Americans facing stressors or having fewer social supports may be a group particularly at risk for ADRDs. Future research may examine if social support mediates the between‐person effects of long‐term stressors on SMCs through a longitudinal mediation model.
Whole Genome Sequencing Analysis of Cognitively Wellderly Individuals Identifies Potential Protective Genetic Variants for Alzheimer’s Disease
Authors: Wang Dongyu , Choi Seung Hoan , Abbruzzese Sabrina , Rosser Morgan A , Bis Joshua C , Fornage Myriam , Boerwinkle Eric , Satizabal Claudia L , Psaty Bruce M. , Lopez Oscar L. , Mosley Thomas H. , Wang Yanbing , Dupuis Josée , DeStefano Anita L. , Seshadri Sudha , Peloso Gina M. 
Published: January 2025

AbstractBackgroundGenetic variants that confer protection from Alzheimer’s disease (AD) may be particularly critical in developing therapeutics. To target protective variant identification, we performed genetic association testing among selected individuals with whole genome sequencing (WGS) that remained alive and dementia‐free beyond age 85 (“Wellderly”).MethodsWe selected 1,873 White and Black Wellderly individuals with documented normal cognition beyond age 85 as determined by direct, in‐person assessment with WGS from the NHLBI TOPMed project. We used two sets of comparison groups: (i) general controls, non‐Wellderly individuals including persons without and with dementia [n = 8,502] and (ii) individuals who developed dementia before age 85 [n = 810]. We performed generalized mixed model regression for each variant with a minor allele frequency (MAF) > 1%, as well as analysis of aggregation of rare (MAF ≤ 1%) coding and non‐coding variants via a modified STAAR approach, with and without adjusting for APOE status.ResultsWe observed a reduced likelihood of Wellderly status compared to general controls at the APOE locus (rs429358, MAF = 14%, odds ratio [OR] = 0.69, p = 1.6 × 10‐10), consistent with the known association of the APOE locus with dementia. We also observed 7 coding gene‐based tests associated with Wellderly status at an alpha of 5 × 10‐8 (Figure). For the aggregation of non‐coding variants, we observed Wellderly status associated with PRB4 (p = 4.7 × 10‐10) and suggestively (p<1 × 10‐6) associated with 3 additional genes. None of the variant aggregates showed significant association with Wellderly status when compared to the diseased controls. IKBKB encodes an inhibitor of nuclear factor kappa B kinase subunit beta, and deficiency of IKBKB protein in myeloid cells was reported to have improved cognitive functions in the AD mice. KCNK4, the potassium channel subfamily K member 4, plays an important role in controlling the cell potassium flux and dysregulated KCNK4 function can cause neurodevelopmental abnormalities.ConclusionAlthough only variants in the APOE locus have a reduced likelihood of Wellderly status in the single variant analysis, our aggregated tests suggest genes aside from APOE that are associated with Wellderly status with biological plausibility. We are pursuing replication using the Alzheimer’s disease Sequencing Project (ADSP) WGS data.
Deciphering spatial microglial diversity in the brain of Alzheimer’s disease patients
Authors: Sanchez‐Molina Paula , Brownell Dillon , Pratapa Aditya , Nikulina Nadezhda , Cheikh Bassem Ben , Singh Jasmine , Bogachuk Alina , Chiot Aude , Chin Gregory , Emberley Katie , Crotti Andrea , Woltjer Randall , Svara Fabian , Braubach Oliver , Ajami Bahareh 
Published: January 2025

AbstractBackgroundSingle‐cell technologies have revealed significant microglial cell heterogeneity across the human brain in both health and disease. However, the integration of high‐plex protein and spatial information in single‐cell approaches constitutes a challenge essential for advancing our cell biology comprehension in the neuroscience field.MethodIn the present study, we employed co‐detection by indexing (CODEX), a protein multiplexed imaging technology, for the first time to unravel the association between different microglial populations and pathological features of Alzheimer’s disease (AD) in the human brain. We used a 32‐plex panel of DNA‐barcoded antibodies able to detect neurons, oligodendrocytes, astrocytes, myeloid cells, vascular components, and pathological markers, in the same brain tissue section. In addition, we implemented algorithms to segment morphologically complex cells and advanced data analysis pipelines.ResultOur results provide a comprehensive mapping of the human brain cytoarchitecture, showing different cell phenotypes based on their protein expression and morphology, cell interaction dynamics, and cell spatial organizations in healthy and AD individuals. Through the identification of different microglial phenotypes, we found a specific subpopulation associated to amyloid‐ß plaques in AD brains. Interestingly, this subpopulation exhibited shared properties with border‐associated macrophages.ConclusionThis study presents a novel approach to explore spatial brain cell heterogeneity in the context of neurological diseases and brings new insights into the microglial diversity in AD.