bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contextual discrimination and representation in APP NL‐G‐F knockin mice
Authors: Hopkins Maya D , Oleru Amarachi , Basu Jayeeta 
Published: January 2025

AbstractBackgroundThe entorhinal cortex and hippocampus are loci of early vulnerability in AD. These areas are crucial for episodic memory processing for space and contexts. The majority of AD model mouse imaging and electrode studies utilize simple tasks such open field and linear track. During these paradigms, place cells in hippocampal CA1 remain functionally intact and only demonstrate perturbations later in disease progression. However, restricting behavior to these low cognitive load tasks may mask more nuanced changes in place cell activity that occur earlier in the disease. We have selected cognitively demanding tasks that recruit both episodic memory and/or odor context discrimination to reveal early‐stage deficits in task acquisition and recall.MethodIn APP NL‐G‐F knock‐in homozygotes, we examined hippocampal CA1 activity through 2‐photon calcium imaging and head‐fixed behavior. Mice were aged to a “young” group (3‐5 months) or an “old” group (7‐9 months). Mice underwent two behavioral paradigms to probe episodic context discrimination. (1) A low cognitive load task where mice were exposed to new physical environments and trained to navigate to two different reward zones or (2) a high cognitive load task where mice were exposed to the same physical environment, but different contexts were established using olfactory cues and reward zones. CA1 cell bodies were imaged through viral GCaMP6f expression in excitatory cells and tracked longitudinally throughout learning. We examined the quality, flexibility, and stability of CA1 place cells in these task regimes. Finally, by targeting neuromodulatory systems that modulate GABAergic circuits, we are testing potential pharmacological rescue of functional and behavioral deficits.ResultPreliminary findings suggest an impairment in the learning rate of the high cognitive load task in homozygotes compared to wild‐type controls. Analysis is ongoing for the functional imaging of place cell activity including the stability of cells across days, the ability to remap between contexts, calcium event rate, and the proportion of reward cells.ConclusionAPP KI model mice can learn head‐fixed navigational tasks of varying cognitive loads, but learning acquisition may be impaired. We predict impairment of contextual representation within CA1 for both task regimes in the APP mice.
Cognitive resilience to Alzheimer’s disease characterized by cell‐type abundance estimates
Authors: O'Neill Nicholas K , Stein Thor D. , Olayinka Oluwatosin A , Empawi Jenny A , Hu Junming , Tong Tong , Zhang Xiaoling , Farrer Lindsay A. 
Published: January 2025

AbstractBackgroundSome subjects exhibit AD pathology but remain cognitively intact. This resilience has been associated with cell‐type abundance changes, particularly in neurons. We investigated the molecular basis of cognitive resilience by deconvoluting bulk RNA sequencing (RNA‐seq) data into multiple brain cell types derived from three brain regions.MethodsCell‐type abundance in human brain bulk RNA‐seq data from 2,457 samples among three brain regions (744 anterior caudate (AC), 1,141 dorsolateral prefrontal cortex (DLPFC), and 572 posterior cingulate cortex (PCC)) obtained from ROSMAP Study participants (434 AD cases, 318 cognitively resistant (CR) AD cases and 188 controls (CT) was estimated by deconvolution using snRNA‐seq cell‐type signatures and DeTREM software. Abundance of six major cell types and eight neuronal subtypes were compared between pairs of diagnostic groups and for three AD clinicopathological traits (amyloid‐β burden and neurofibrillary tangles quantified by immunohistochemistry, and MMSE score) using a generalized linear model including covariates for cell‐fraction, age, sex, and post‐mortem interval. We also conducted a genome‐wide association study (GWAS) for abundance of each cell‐type and brain region using a model that included a polygenic random effect, genetic relationship matrix, and the covariates listed above.ResultsParvalbumin positive (PVALB+) inhibitory neuron abundance was negatively associated with cognitive status and tau pathology in DLPFC and PCC (all comparisons padj<0.001, Figure 1) and the most reduced neuronal subtype in AD cases compared to controls in the DLPFC (padj = 8.4 × 10‐7) and PCC (padj = 0.0015) regions (Figure 2). The proportions of astrocytes and RORB expressing neurons in the PCC were significantly increased (padj = 0.047) and decreased (padj = 0.024), respectively, in CR AD cases compared to non‐CR AD cases. We also identified a genome‐wide significant association of neuron abundance with TMEM106B SNP rs13237518 in PCC (p = 6.08 × 10‐12). This variant was also associated with levels of amyloid‐β (p = 0.0085) and tangles (p = 0.0073) in the same region (Figure 3).ConclusionHigh abundance of PVALB+ neurons and lack of astrocytosis may be markers of cognitive resilience among persons with a pathological diagnosis of AD. Variants in TMEM106B are associated with neuron abundance and, hence, may specifically influence resilience to cognitive decline independent of AD pathology.
Identification of genetic risk loci and prediction for β‐amyloid deposition in the East Asian population
Authors: Kim Jun Pyo , Jung Sang‐Hyuk , Ali Muhammad , Cruchaga Carlos , Jang Beomjin , Raj Towfique , Won Hong‐Hee , Seo Sang Won 
Published: January 2025

AbstractBackgroundPrevious Alzheimer’s disease GWAS studies were mostly based on the European population, and the β‐amyloid (Aβ) status was not considered. We performed a meta‐GWAS using East Asian and European genomics data and performed prediction of Aβ status using the identified variant. We utilized single‐cell transcriptome data to identify the differentially expressed gene that is affected by the variant.MethodIn our discovery dataset, genotype data of 3,387 participants from Korea‐Registries to Overcome and Accelerate Dementia research cohort, who underwent amyloid PET were included in our analysis. Additionally, we utilized summary statistics from a recent multi‐ethnic amyloid PET GWAS using genome data from 13 cohorts. We performed a meta‐analysis to identify risk loci for cerebral Aβ deposition. We used 606 independent Korean participants for replication and prediction of Aβ positivity. Finally, post GWAS analysis was performed using Columbia ROSMAP(N = 402) and Samsung Hospital Brain Bank (N = 9) single‐cell transcriptome data.ResultIn our meta‐GWAS analysis, we identified 16 SNPs showing genome‐wide significant associations near SORL1. The SNP rs76490923 (MAF in East Asians = 0.21) showed the most significant association (p = 3.12⨉10‐11). This SNP was associated with Aβ positivity in the replication samples (OR(95% CI) = 0.71(0.52‐0.96), p = 0.025). When we stratified the replication dataset by APOE e4 carrier status and SNP rs76490923, the risk of Aβ positivity was significantly impacted in e4 carriers. (OR = 2.30 in rs76490923 homozygotes, OR = 8.41 in rs76490923 non‐carriers). The single‐cell eQTL results from Columbia ROSMAP database showed that rs76490923 was associated with the expression level of SORL1 in microglia (p = 3.86⨉10‐6). Furthermore, in SMC Brain Bank autopsy cases, SORL1 was differentially expressed in microglia (logFC = ‐1.335, FDR = 3.81⨉10‐83) between Aβ positive and negative individuals.ConclusionWhile variants related to SORL1 have not been identified in a recent multi‐ethnic amyloid PET GWAS, our analysis including greater proportion of East Asian population identified significant SNPs near SORL1. This association might have been undetected in previous studies due to Europeans' low minor allele frequency (0.023). Our finding supports the importance ethnic diversity, which has been increasingly recognized recently in AD genomics studies.
Characterization of the A1527G variant of ABCA7 in an animal model for late‐onset Alzheimer’s disease
Authors: Bernabe Cristian S , Kotredes Kevin P , Pandey Ravi S , Carter Gregory W , Sasner Michael , Oblak Adrian L , Howell Gareth R , Lamb Bruce T. , Territo Paul R ,   MODEL‐AD consortium
Published: January 2025

AbstractBackgroundGenome‐wide association studies (GWAS) identified the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer’s disease (AD). ABC proteins transport various molecules across extra and intra‐cellular membranes. ABCA7 is part of the ABC1 subfamily and is expressed in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes. However, the mechanisms by which variations in ABCA7 increase risk for AD are not known.MethodThe IU/JAX/PITT MODEL‐AD Center identified the A1527G variant in ABCA7 (ABCA7*A1527G) as a putative LOAD risk factor. CRISPR/CAS9 was first used to introduce Abca7*A1527G variant to B6.APOE4.Trem2*R47H (LOAD1) mice to assess the transcriptional profiling on brain hemispheres from different ages. The Abca7*A1527G was then incorporated into B6.APOE4.Trem2*R47H.hAb (LOAD2) mice to further evaluate its contribution to LOAD. Female and male LOAD2.Abca7*A1527G and LOAD2 mice were characterized at 4, 12, and 24 months using the following phenotyping pipeline: behavior, PET/CT, multi‐omics, fluid biomarkers, electrophysiology, cognition, and neuropathology.ResultBrain transcriptional profiling showed that Abca7*A1527G induced changes in gene expression that are similar to some of those observed in human AD (e.g., granulocyte/neutrophil migration, and insulin receptor signaling). LOAD2.Abca7*A1527G showed no aging cognitive deficit but did show significant sex‐ and region‐dependent increases in brain glycolysis paralleled by reduced tissue perfusion yielding progressive age‐related uncoupled phenotypes between 4‐12 and 4‐24 months. While multi‐resolution consensus clustering of regional covariance matrices revealed an increase in cluster number and organization in LOAD2.Abca7*A1527G over LOAD2 for both sexes at 4 months, the cluster number and complexity were reduced by 24 months. Importantly, LOAD2.Abca7*A1527G, but not LOAD2, displayed a similar age‐dependent reduction in cluster number for both sexes. Consistent with the uncoupled phenotype, IL6, IL10, and TNFα were elevated in plasma with genotype, but were not age dependent. Conversely, brain levels of IL4, IL12, TNFα, and CXCL1 were decreased, whereas IL2 and IL10 were elevated in LOAD2.Abca7*A1527G relative to LOAD2. Lastly, assessment of plasma levels of Ab40‐Ab42 revealed an age‐dependent increase in both genotypes.ConclusionData collected to date support a model whereby variations in ABCA7 exert risk for AD through interactions between cerebrovasculature, microglia, and peripheral immune cells.
Identifying genetic risk factors driving cerebral amyloid angiopathy using novel mouse models
Authors: Marola Olivia J , Onos Kristen D , Diemler Cory , Keezer Kelly J , Sasner Michael , Howell Gareth R ,   the IU/JAX/PITT MODEL‐AD Center
Published: January 2025

AbstractBackgroundCerebral amyloid angiopathy (CAA) co‐occurs with neurodegeneration in Alzheimer’s disease (AD). CAA is absent in many AD mouse models, rendering CAA difficult to study. Previous work has shown wild‐derived WSB/EiJ (WSB) mice over‐expressing APP/PS1 had increased CAA, and thus may be useful in investigating CAA‐causing mechanisms. Here, genetic backgrounds with CAA susceptibility (WSB.APP/PS1) and resilience (B6.APP/PS1) are leveraged to map CAA‐susceptibility loci.Furthermore, blood brain barrier (BBB) compromise has been hypothesized to impair amyloid clearance and promote vascular deposition. Endothelial TIE2 deactivation was shown to weaken BBB integrity in other models, and therefore may drive CAA. TIE2 activation (pTIE2) is inhibited by endogenous antagonists ANGPT2 and PTPRB, which can be manipulated to bolster pTIE2. Here, the efficacy of pTIE2 elevation in preventing CAA in AD is investigated.MethodsTo determine the onset and therapeutic window of CAA, WSB.APP/PS1 mice (n≥3/sex) were aged to 4, 6, 8, 14, and 18M. CAA was assessed using immunohistochemistry (X34+ plaques within CD31+ vessels). To map CAA‐susceptibility loci, B6.APP/PS1 and WSB mice were crossed, generating BXW.APP/PS1 (F1) offspring. To determine haplosufficiency of these alleles, CAA was evaluated in BXW.APP/PS1 mice (n = 6/sex). F1 mice were intercrossed to generate heterogeneous F2 progeny (n = 50/sex), which were assessed for CAA.To elevate pTIE2 in models of CAA/AD, Angpt2 heterozygous (Angpt2±) and Ptprb loss‐of‐function (PtprbD57N) alleles were bred to generate CAA‐susceptible mice with TIE2 modulation. Western blot analysis is employed to confirm elevated pTIE2, and CAA amelioration will be evaluated.ResultsWSB.APP/PS1 mice developed significant CAA by 8M. CAA was significantly more advanced in BXW.APP/PS1 compared to founder strains at 8M, and F2 mice had varying CAA severity. Late‐onset AD mice (LOAD2, JAX #033867) with PtprbD57N/D57N exhibited pTIE2 elevation at 12M.ConclusionsRobust BXW.APP/PS1 CAA suggests heterozygous loci promote CAA. F2 CAA variability suggests CAA‐susceptibility loci are likely mappable. F2 SNP analysis and R/qtl2 software is being employed to identify candidate loci corresponding with CAA. Furthermore, BXW.APP/PS1 is a novel CAA model to study the therapeutic potential of pTIE2 enhancement. To this end, BXW.Angpt2±APP/PS1 and BXW.Ptprb+/D57NAPP/PS1 mice are aging and will be evaluated for pTIE2 elevation and CAA attenuation.
Differential patient selection for amyloid‐targeting immunotherapies in Alzheimer’s disease
Authors: Rosen Jurij , Jessen Frank 
Published: January 2025

AbstractBackgroundAnti‐amyloid beta (Aβ) immunotherapies have recently evolved as promising treatment options in patients with early symptomatic Alzheimer’s disease (AD). Meanwhile, accurate patient selection for these treatments might be challenging mirrored by strict selection criteria of the hitherto published clinical trials. Based on a real‐world tertiary care sample of post‐mortem validated cases, we aimed to identify the patients matching these selection criteria and their proportion showing post‐mortem AD pathology.MethodThis study is based on data from The National Alzheimer‘s Coordinating Center‐Uniform and Neuropathology Data Set. Patients with available post‐mortem report of AD pathology were selected by the published selection criteria of clinical trials evaluating efficacy and safety of aducanumab, lecanemab and donanemab. The resulting samples were scrutinized for a potential overlap and their proportion showing post‐mortem AD pathology.ResultOf 44359 patients in the dataset, 3343 had an available report of post‐mortem AD pathology. Of these, 887 patients were potential candidates for an anti‐Aβ immunotherapy as they presented an amnestic AD syndrome at the baseline visit. Applying selection criteria of clinical trials on these patients resulted in 91, 306, and 192 patients that would be suitable for immunotherapy with aducanumab, lecanemab and donanemab, respectively. These patient samples showed a partial overlap. In these samples, 83, 288, and 184 patients showed post‐mortem AD pathology.ConclusionThe present results might influence both differential patient selection for upcoming anti‐Aβ immunotherapies and interpretability of potential differences of clinical trial results.
Sex Specific Association of Apolipoprotein E Alleles with Autopsy Measures of Arteriolosclerosis and Atherosclerosis among Older Adults
Authors: Gomez Melisa Lara , Beecham Gary , Montine Thomas J. , Cuccaro Michael L. , Toga Arthur W. , Keene C Dirk , Crane Paul K. , Mukherjee Shubhabrata , Panizzon Matthew S. , Biber Sarah A , Kukull Walter A. , Bennett David A. , Barnes Lisa L. , Schneider Julie A. , De Jager Philip L. , Menon Vilas , Hohman Timothy J. , Dumitrescu Logan C. 
Published: January 2025

AbstractBackgroundCerebrovascular disease (CVD) is a major cause of mortality in females, while two‐thirds of Alzheimer’s disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well‐established; it is unclear if associations between APOE and CVD are sex‐specific.MethodAutopsy data (females = 3,464; males = 3,130) from three AD cohorts included measures of arteriolosclerosis and atherosclerosis (levels for each: none [0], mild [1], moderate [2], and severe [3]) harmonized as part of the AD Sequencing Project Phenotype Harmonization Consortium. Non‐Hispanic White (NHW) individuals >60 years at age of death were included (average age at death = 85±9; 58% AD dementia). Linear analyses assessed sex‐stratified and APOE*sex interactions on CVD outcomes covarying for age at death. APOE‐ε4 and APOE‐ε2 were modeled additively and dominantly, respectively.ResultFemales were older on average and included more APOE‐ε2 and less APOE‐ε4 carriers when compared to males. Among males and females, APOE‐ε2 was not related to arteriolosclerosis (p = 0.90) or atherosclerosis (p = 0.30), while APOE‐ε4 related to higher arteriolosclerosis (β = 0.07 p<0.001) and atherosclerosis (β = 0.04, p = 0.03). There was a significant APOE‐ε2*sex interaction on arteriolosclerosis (p = 0.02) whereby the ε2 allele was associated with less arteriolosclerosis among females (β = ‐0.05, p = 0.27) and more arteriolosclerosis among males (β = 0.08, p = 0.13), although neither stratified effect reached statistical significance. Similarly, the ε4 allele was associated with more arteriolosclerosis among females (β = 0.11, p<0.001), but not among males (β = 0.04, p = 0.16), although the APOE‐ε4*sex interaction did not reach statistical significance (interaction‐p = 0.052). The ε4 allele was associated with more atherosclerosis among females (β = 0.07, p = 0.01), but not males (β = 0.01, p = 0.56), but again the APOE‐ε4*sex interaction did not reach statistical significance (p = 0.28).ConclusionWe provide evidence that the ε4 allele is related to higher levels of arteriolosclerosis and atherosclerosis, while providing modest evidence of a sex difference in the association between the ε2 allele and arteriolosclerosis. Future work will seek to better characterize these sex‐specific effects within the context of other neurodegenerative pathologies in the aging brain, and more fully characterize sex‐specific clinical consequences of APOE and CVD.
African origin haplotype protective for AD in APOEe4 carriers: exploring potential mechanisms
Authors: Nasciben Luciana Bertholim , Nuytemans Karen , Vasquez Marina Lipkin , Rajabli Farid , Young Juan I , Dykxhoorn Derek M. , Wang Liyong , Scott William K. , Davis David A. , Vontell Regina T , Pericak‐Vance Margaret A , Griswold Anthony J. , Vance Jeffery M. 
Published: January 2025

AbstractBackgroundThe effect size of APOE4 varies across genetic ancestries with African (AFR) local ancestry conferring a lower risk when compared to other ancestries. Recently, we identified a strong effect of the A allele of rs10423769 (with a minor allele frequency of 0.12 in AFR and 0.003 in Europeans), which lowers the risk of AD by 71% in APOE4 carriers. rs10423769 is 2 MB from APOEe4 in a region of segmental duplications (SD) containing a cluster of pregnancy specific beta‐1 glycoprotein genes (PSGs) and a lncRNA. To gain insights into the mechanism of protection, we characterized the haplotype harboring the variant and investigated differences in methylation and structural variation (SV) between haplotypes.MethodWe used the Alzheimer’s Disease Sequencing Project (ADSP) short read sequencing database to fine map and extend the protective haplotype using Haploview 4.2. In addition, long read sequencing (LRS) with the Oxford Nanopore PromethION was performed on 16 samples of individuals carrying one or two copies of rs10423769_A. LRS was used for SV calling with Sniffles2 and differential methylation analysis using Nanomethphase.ResultThe minimum shared haplotype harboring rs10423769_A allele was ∼21kbp (chr19:43099521‐ 43120243). Though the region is rich in SDs, high quality LRS reads mapped uniquely to the region around the A allele confirming that the haplotype is unique and not duplicated elsewhere in the genome of the sequenced individuals. Moreover, the rs10423769_A haplotype harbors 23 differential CpG sites (fdr<0.05) compared to rs10423769_G, although no differential methylated region was identified. LRS revealed a 140bp insertion of repetitive MEF2 binding motifs. Initial examination demonstrated that the insertion was present in 80% of the A allele carriers.ConclusionWe have identified an AF‐specific haplotype protective against AD risk conferred by APOE ε4. Considering the distance from APOE and the complexity of the highly SD region where the variant is located, we have identified the minimum shared haplotype from AFR origin and are investigating the potential effects of SVs and differential CpG sites. Ongoing analyses include 3D chromatin structure and LRS at higher coverage to assemble and resolve the complex genomic context of the allele.
Effects of chaducanumab‐mediated plaque removal on amyloid‐tau synergy
Authors: Welikovitch Lindsay A , de Gerando Anastasie Mate , Khasnavis Anita , Bhavsar Harshil , Meltzer Jonah C , Buee Luc , Bussière Thierry , Hyman Bradley T. T 
Published: January 2025

AbstractBackgroundAmyloid‐targeting antibodies have been shown to be remarkably effective at clearing amyloid plaques from the Alzheimer’s disease (AD) brain. To date, preclinical assessments have used animal models that develop only amyloid pathology, whereas AD patients present with tau pathology, neuroinflammation, and other concurrent neuropathologies. Deciphering how successful anti‐amyloid therapies impact the synergistic interplay of amyloid and tau will be critical in determining which secondary disease processes can be slowed, interrupted, or reversed by amyloid‐targeting immunotherapies.MethodTo establish whether interrupting Aβ plaque deposition or clearing existing plaques could halt the progression of tau pathology and downstream disease events, we treated APP/PS1xTau22 mice with a murine chimeric analog of Aducanumab (chAdu) targeting human oligomeric and fibrillar Aβ species. Equal concentrations of chAdu and isotype Control IgG were administered weekly for 12 weeks by intraperitoneal injection at a dose of 30mg/kg beginning at 6 months of age.ResultFollowing 3 months of immunotherapy, APP/PS1xTau22 mice treated with chAdu had lower Aβ plaque burden in both the hippocampus and cortex. Although amyloid expression accelerates the formation of tau neurofibrillary tangles as early as 6 months of age in the APP/PS1xTau22 transgenic model, inhibiting further plaque deposition using chAdu had no effect on the abundance of AT8+ or AT100+ neurofibrillary lesions in any brain region analyzed. While regional phospho‐tau deposition was similar between isotype‐IgG and chAdu‐treated animals, we observed a reduction in the number of AT8+and SMI312+ axonal dystrophies in mice that had undergone 3 months of immunotherapy.ConclusionWithin a more‐complex neuropathological environment, amyloid immunotherapy influences plaque‐related secondary disease events, but does not directly impact tau deposition in the APP/PS1xTau22 mouse model. Identifying which aspects of the AD pathology remain resistant to amyloid immunotherapy will provide insight into how mono‐ or combination therapies can be developed or improved.