bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiregional neuropathological changes and cellular correlates of Alzheimer’s disease
Authors: Gabitto Mariano I 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease is marked by the gradual aggregation of pathological proteins, Tau and beta‐amyloid, throughout various areas of the brain. The progression of these pathologies follows a consistent pattern, impacting various cellular populations as it advances through each brain region. Previously, we used Bayesian algorithms to create a continuous progression score to mathematically capture the collective aggregation of multiple pathological variables within a specific brain region. This score allowed us to discern the cellular and molecular alterations associated with the disease, offering valuable insights into the etiology of these changes within a single brain region.MethodAs part of The Seattle Alzheimer’s Disease Cell Atlas (SEA‐AD, https://sea‐ad.org), we stained and quantified multiple neuropathological proteins (a‐Syn, pTDP43, pTau and beta‐amyloid) and cellular populations (neurons, astrocytes and microglia) in several brain regions (middle temporal gyrus, the middle frontal gyrus, hippocampus, and medial entorhinal cortex). Next, we profiled multiple brain regions using single nucleus RNA‐seq and a subset of donors and regions were profiled with ATAC‐seq or multiome in each SEA‐AD brain donor. We integrated these single nucleus datasets into a common latent representation, and mapped cellular types to our MTG taxonomy, adding additional cell types occurring in specific brain regions.ResultWe mapped the progression of pathology using our Bayesian algorithms in each individual region. Next, we identified the order of the successive regions affected sequentially by disease. Additionally, we segmented the hippocampal formation and characterized the progression of pathology within it and linked it to synaptic connectivity across regions. Next, we used our scale of disease progression to identify the vulnerable populations in each region. After comparing populations with the known burden of pTAU and beta‐amyloid, we repeated the test to associate affected populations with the burden of each individual pathology, controlling for covariates such as sex, age and race.ConclusionThe Bayesian algorithms we developed permitted to create a continuous axis of disease progression across multiple brain regions and stage these regions given the progressive accumulation of pathology. By combining single‐nucleus experiments with detailed disease pathologies we identified a common set of affected populations in disease.
Trans‐ancestry GWAS for Alzheimer’s Disease Reveals a Novel Locus interacting with APOE*4
Authors: Belloy Michael E. , Reid Danielle M. , Guen Yann Le , Napolioni Valerio , Greicius Michael D 
Published: January 2025

AbstractBackgroundAPOE*4 is the strongest genetic risk for late‐onset Alzheimer’s disease (AD), but other genetic loci may counter its detrimental effect, providing therapeutic avenues. Expanding beyond non‐Hispanic White subjects, we sought to additionally leverage genetic data from non‐Hispanic and Hispanic subjects of admixed African ancestry to perform trans‐ancestry APOE*4‐stratified GWAS, anticipating that allele frequency differences across populations would boost power for gene discovery.MethodParticipants were ages 60+, of European (EU; ≥75%) or admixed African (AFR; ≥25%) ancestry, and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed or whole genome sequencing (WGS). Genome‐wide association studies (GWAS) were performed per data type, APOE*4 status, and Hispanic/non‐Hispanic status (Figure‐1A), requiring genotyping rate ≥80% and minor allele frequency ≥0.1% in EU and ≥1% in AFR, followed by random effects meta‐analysis (Plink v2.0; GWAMA v2.2.2). An APOE*4‐by‐SNP interaction model was also evaluated. GWAS performed multiple linear regression on an AD‐age score (Le Guen & Belloy et al. 2021; Figure‐1B), adjusting for APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Variants were filtered to be covered on at least half of the individuals per stratum and on both EU as well as AFR ancestry datasets.ResultWe found 1 novel genome‐wide significant locus in the APOE*4‐by‐SNP interaction GWAS (Figure‐2), with lead variant rs17042744 located intronic on a long non‐coding RNA (ENSG00000233005) and 558kb away from APOB. This variant showed disparate allele frequencies across the studied populations, yet was consistently protective in APOE*4 carriers and risk‐increasing in APOE*4 non‐carriers (Figure‐3).ConclusionWe show the relevance of expanding beyond non‐Hispanic white samples to identify genetic risk variants that may modulate the effect of APOE*4 on AD risk, identifying a risk locus with substantially elevated frequencies in African compared to European ancestry. The locus harbored APOB, a ligand for the LDL receptor, regulator of plasma cholesterol levels, and known to have mutations in its regulatory region that cause hypobetalipoproteinemia and hypercholesterolemia. Ongoing work is exploring replication and computational functional genomics follow‐up work.
Deciphering the molecular and cellular underpinnings of cognitive resilience in Alzheimer’s disease
Authors: Castanho Isabel , Yeganeh Pourya Naderi , Boix Carles A , Mathys Hansruedi , Prokopenko Dmitry , White Bartholomew , Morgan Sarah , Lange Christoph , Bennett David A. , Bertram Lars , Tanzi Rudolph E. , Tsai Li‐Huei , Kellis Manolis , Hide Winston 
Published: January 2025

AbstractBackgroundA significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer’s disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD.MethodWe integrated multi‐modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi‐regional single nucleus (n = 48) RNA sequencing. Subjects were categorized into AD, Resilient, and Control based on Aβ and tau pathologies, and cognitive status. We investigated genetic risk and transcriptomic changes in resilience and prioritized protected cell populations using genetic enrichment and cellular distribution estimation. We further characterized these populations using multiplex immunofluorescence.ResultResilient individuals exhibited an intermediate genetic risk profile between AD and Control. Remarkably, only GFAP and KLF4 were differentially expressed between Resilient and Control subjects in bulk tissue. GFAP was upregulated in Resilient astrocytes in the dorsolateral prefrontal cortex compared to AD and Control. Inhibitory and excitatory neurons displayed distinct brain region‐specific phenotypes in cognitive resilience. Somatostatin‐positive interneurons were enriched for genes linked to protective rare genetic variants and showed vulnerability in AD but not in Resilient individuals. Specific excitatory neuronal populations in the entorhinal cortex exhibited resilience‐like behavior and expressed genes previously associated with cognitive resilience.ConclusionOur findings suggest that at the bulk tissue transcriptome level, cognitive resilience does not exhibit marked gene expression differences from healthy aging, despite significant Aβ and tau neuropathology. At the cellular level, specialized excitatory neuronal populations may drive cognitive resilience, while a specific subset of interneurons may play a crucial role in other forms of protection against AD‐associated neuronal vulnerability. This systematic study provides direct insight into the molecular basis of cognitive resilience, yielding targets offering the potential to convert natural protective systems into effective therapeutic interventions for AD.
“I feel happy, I can remember things because my family is supportive of me.” Patient’s experiences of Alzheimer’s disease in Nairobi, Kenya
Authors: Bosire Edna N , Kamau Lucy Wambui 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia globally and is the fifth leading cause of death and disability. About half of all people suffering from the disease are living in sub‐Saharan African Countries including Kenya. However, research on dementia has been almost exclusively focused on the Global North societies. In Kenya, little is known about patients’ lived experiences with AD. Objective: To explore patient’s experiences living with and managing Alzheimer’s disease in Kenya.MethodWe employed ethnographic methods encompassing clinical and home observations and lengthy interviews among people with early‐stage Alzheimer’s disease (n = 30) in Kenya. Patients were purposively recruited from the neurology clinic at the Aga Khan University Hospital in Nairobi. We also conducted 10 home visits to understand existing social support systems and self‐management practices. Field notes and qualitative interviews were transcribed and analyzed verbatim with use of QSR NVivo 12 software.ResultTwo‐thirds of the patients were aged 50 years and above, had low education levels and fully depended on close family members for support. Patients experienced challenges such as higher cost of hospital care and treatment, comorbidities (e.g., depression, diabetes and hypertension), language barrier, forgetfulness, being misunderstood and conflicts with loved ones. These challenges made managing their AD difficult. Social connectedness – which entailed: (i) Self‐connectedness – including active participation in self‐care, relaxation and having personal time; and (ii) Connectedness with others (e.g., relationships with family, friends to prevent loneliness and isolation) were found to be key on how patients managed and coped with their Alzheimer’s disease.ConclusionPeople living with AD in Kenya cannot be understood without knowing about their inner lives, other people around them and the background where they belong. Alzheimer’s disease can transform people’s self‐identities but with good social support system, patients can live quality lives. There is a need to train family members and other informal caregivers to improve care and foster a sense of belonging amongst the patients. More research on Alzheimer’s disease in Kenya is needed as well as increased public awareness and community sensitization regarding dementias.
The effect of estrogen signaling modulation on female‐specific microglial heterogeneity in the mouse hippocampus
Authors: Ko Sunghwan 
Published: January 2025

AbstractBackgroundEstrogens, such as 17β‐estradiol, are the primary female sex hormones predominantly synthesized by mature ovarian follicular cells. The natural exhaustion of ovarian follicular cells during menopause causes a rapid decline in endogenous estrogen levels. This decline in estrogen levels is associated with an increase in chronic, age‐related pathologies, including inflammation in the brain. Studies suggest that estrogens can temper inflammatory processes in the brain by activating estrogen receptor α (ERα), a nuclear transcription factor expressed by microglia, the brain’s primary resident macrophage. However, the pathways responsible for estrogens’ anti‐inflammatory effects in microglia remain unresolved. Here, we hypothesize that estrogen signaling through microglial ERα suppresses pro‐inflammatory signaling pathways. We believe that ablation of endogenous estrogens during menopause induces neuroinflammation and promotes the transition of microglia to activated phenotypes, contributing to various brain diseases, including Alzheimer’s disease (AD).MethodTo test the effect of estrogenic depletion on microglial heterogeneity in mice, we: 1) knocked out ERα, 2) depleted endogenous estrogens with 4‐vinylcyclohexene diepoxide (VCD) treatment, and 3) compared to untreated female C57BL/6 controls. We then examined the changes in hippocampal microglial phenotypic states using 10X single‐cell transcriptomic sequencing (scRNA‐seq).ResultscRNA‐seq data were quality filtered, and unbiased clustering analyses (i.e., UMAP) identified five hippocampal microglial subtypes. Interestingly, the expression of specific microglial phenotypic state (stage 1 disease‐associated microglia) was increased upon ablation of endogenous estrogen production by VCD or knockout of ERα.ConclusionSuch skewing of microglia towards reactive phenotype suggests that loss of estrogen‐ ERα signaling may encourage “priming” of microglia to transition to the stage 1 DAM phenotype, which is then more susceptible to becoming “reactive” DAMs (stage 2 DAMs).
A Transport Vehicle‐enabled TREM2 agonist antibody induces putative transcription factor activation in microglia
Authors: Monroe Kathryn M. 
Published: January 2025

AbstractBackgroundLoss‐of‐function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. We’ve previously described a high‐affinity mouse TREM2‐activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), ATV:4D9. Single‐cell RNA sequencing and morphometry revealed that ATV:4D9 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. However, the factors mediating ATV:4D9‐induced transcriptional responses in microglia is not known.MethodWe performed fluorescence‐activated nuclei sorting (FANS) to isolate PU.1+ microglial nuclei from frozen brain tissue followed by assaying for transposase‐accessible chromatin with sequencing (ATAC‐Seq) to determine regions of accessible chromatin in the microglial genome.ResultWe identified changes in chromatin accessibility that are observed in microglia dosed with ATV:4D9 compared to isotype control antibody. Bioinformatic analysis identified motifs for putative regulatory transcription factors in ATV:4D9‐activated enhancers.ConclusionOur data provide insights into putative transcription factors that mediate microglial state changes in response to ATV:4D9, which further elucidates mechanisms of TREM2 agonism.
Genetic Risks of AD and Associated Health Conditions are Linked with the Dynamic Patterns of AD’s Clinical and Physiological Course
Authors: Fournier Nemo , Durrleman Stanley 
Published: January 2025

AbstractBackgroundOver‐representation of several health conditions (such as diabetes, hearing loss, etc) have been identified up to 15 years before Alzheimer’s Disease (AD) diagnosis through the study of electronic health records [1]. Mechanisms underlying these associations remain elusive. We propose to study the associations between these co‐pathologies (proxied by genetic risk scores), and the physiological and clinical evolution of AD patients.MethodLongitudinal and genetic data was obtained on 1120 AD patients from the ADNI cohort. Genetic risks for AD and selected health conditions (type 2 diabetes, hypertension, hearing loss, depression, ldl cholesterol, and colon cancer) are computed using state‐of‐the‐art Polygenic Risk Scores. We utilize a non‐linear mixed‐effects model [2] to estimate a multimodal progression profile of the disease (jointly modelling structural and PET imaging biomarkers as well as cognitive scores — fig. 1). Interpretable parameters describing each patient’s progression are estimated (Fig. 2). Pearson correlations between random‐effects and genetic risk scores were computed, with presented P‐values Bonferroni‐corrected for multiple testing. Conditioning the fixed‐effects of the model by the genetic risk scores (as introduced in [2]) allows studying associations between these genetic risks and the disease dynamics at a biomarker‐by‐biomarker level.ResultHigher AD genetic risk is associated with all longitudinal aspects of the disease: earlier onset (P<0.001), faster disease pace (P<0.001), and inter‐marker patterns (P = 0.042). Elevated type‐II diabetes genetic risk is associated with earlier onset of AD (p = 0.031). Increased hypertension genetic risk is associated with a faster progression pace (P = 0.012). We then exhibit (Fig. 3) finer links between these genetic risks and the progression patterns of the disease.ConclusionThis study unveils the relationship between genetic risk scores for health conditions and nuanced aspects of AD progression. We show that despite being established on case/control cohorts, these genetic risk scores offer valuable insights into the finer dynamics of disease progression.References:[1] Nedelec et al., Identifying health conditions associated with Alzheimer’s disease up to 15 years before diagnosis: an agnostic study of French and British health records, in Lancet Digital Health, 2022[2] Fournier and Durrleman, A Multimodal Disease Progression Model for Genetic Associations with Disease Dynamics, in MICCAI 2023
Phenotypic characterization of a novel Spi1*rs1377416 mouse model of Alzheimer’s Disease
Authors: Milinkeviciute Giedre , Da Cunha Celia , Mendoza‐Arvilla Adrian , Butler Claire Ann , Kawauchi Shimako , Neumann Jonathan , Walker Amber , Tenner Andrea J , LaFerla Frank M , MacGregor Grant R , Green Kim N. 
Published: January 2025

AbstractBackgroundGenome‐Wide Association Studies (GWAS) implicate SPI1 (PU.1) as a risk factor for late‐onset Alzheimer’s Disease (LOAD). Within the brain, SPI1 encodes a microglia‐specific transcription factor, necessary for microglial proliferation and activation. SPI1 rs1377416 has been identified as a non‐coding GWAS risk variant for AD. We have developed a novel mouse model with the SPI1 rs1377416 variant to explore its impacts on AD pathogenesis.MethodBy using CRISPR/Cas9, we have generated SPI1*rs1377416 mice that carry a non‐coding mutation corresponding to the rs1377416 SNP found in human SPI1. We crossed the SPI1 mice with the 5xFAD mouse model of AD and aged them to 4 and 12 months of age. Coronal brain sections were then obtained and immunolabeled with several markers to visualize amyloid plaques, glial cells and assess axonal and neuritic damage. Confocal images were then obtained and quantified in subiculum and cortex.ResultWe found an age‐related increase in dense core plaque number and size in the subiculum of 5xFAD;SPI1 mice. Microglial volume as well as astrocytic activation were reduced in 5xFAD;SPI1 compared to 5xFAD mice in both brain areas at 12 months. Correspondingly, neuritic dystrophy and axonal damage were also diminished. Significant sex difference was observed in different analyses with males being affected less than females (with the exception of plaque deposition), and mainly detected in subiculum.ConclusionOur results indicate that the rs1377416 variant of SPI1 induces an age‐dependent increase in amyloid deposition in the 5xFAD model of AD. Moreover, this SPI1 variant exerts a protective effect by suppressing astrocytic response and preventing neuritic and axonal damage. There is a strong sex difference observed between males and females when the variant is present and requires further investigation.
Sex Modulates the Influence of APOE Genotype on Sleep and Sleep‐Dependent Memory Consolidation in Older Adults
Authors: Sattari Negin , Mander Bryce A , Dave Abhishek , Lui Kitty K. , Sprecher Kate E , Chappel‐Farley Miranda G. , Riedner Brady A , Bendlin Barbara B. , Benca Ruth M 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a world‐wide healthcare crisis among older adults. Sex, aging, and apolipoprotein E (APOE) genotype are among the most impactful risk factors for AD. Sleep is beneficial for memory and changes with age. We aimed to test whether sex and APOE (ε4‐carriers/non‐carriers) interact to impact sleep‐dependent memory consolidation (SDMC).MethodsWe tested 67 older adults (41 women, 25 ε4‐carriers, mean±SD; 61.8±6.1 years). Participants encoded word‐pairs in the evening, were tested immediately, then underwent overnight in‐lab polysomnography, and performed a delayed test in the morning. SDMC was computed as a difference score (morning‐evening). Time spent in non‐rapid eye movement (NREM) sleep stages, and electroencephalography (EEG) spectral power in frontal canonical frequency bands during NREM sleep, were quantified. ANOVA, independent t‐tests, and bivariate correlation analyses were employed in the study.ResultsA sex × APOE interaction predicted SDMC (p = 0.02). Post hoc analysis revealed no difference between male ε4‐carriers and non‐carriers (p = 0.36), but among women, ε4‐non‐carriers exhibited increased deterioration (more forgetting) compared to ε4‐carriers (p = 0.02). Additionally, male ε4‐carriers had worse memory retention than female ε4‐carriers (p = 0.01). Further analysis showed that female ε4‐carriers spent more time in N3 sleep (p = 0.01), correlating with better SDMC (r = 0.72, p = 0.02), while male ε4‐carriers spent more time in N2 sleep (p = 0.04), also linked to better SDMC (r = 0.68, p = 0.03). Fisher r‐to‐z transformation indicated significant differences in these associations (p = 0.01). Regardless of sex, among ε4 non‐carriers, no significant associations were found between theta, alpha, slow‐sigma, fast‐sigma during NREM sleep and memory (all ps>0.17). Among ε4‐carriers, male participants showed no significant associations (all ps>0.54), whereas females exhibited positive associations between memory and theta (r = 0.80, p = 0.005), alpha (r = 0.82, p = 0.004), slow‐sigma (r = 0.85, p = 0.002), and fast‐sigma (r = 0.77, p = 0.009).ConclusionOur study reveals that the interplay of sex and APOE affects sleep patterns and memory consolidation in older adults. Notably, distinct non‐rapid eye movement (NREM) sleep stages impact Slow Delta and Theta Modulation (SDMC) differently in male and female APOE ε4‐carriers. While enhanced sleep quality may mitigate APOE and sex‐related cognitive decline in later life, considering sex‐related differences in memory benefits from sleep is crucial for older adults at high risk for AD.