bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐cell spatial transcriptomic and proteomic characterization of a novel mouse model of late‐onset AD
Authors: Kwang Nellie , Green Kim N. , Swarup Vivek
Published: January 2025

Background

Late‐onset Alzheimer’s disease (LOAD) represents the majority of human AD cases, yet the availability of animal models that accurately reflect LOAD progression and pathology is limited. Traditional transgenic mouse models including 3xTg‐AD and 5xFAD rely on supraphysiological overexpression of familial AD risk genes, failing to adequately replicate the disease progression observed in LOAD. Here, we present the first characterization of MODEL‐AD1 (MAD1), a platform mouse developed by the Model Organism Development and Evaluation for Late‐onset Alzheimer’s Disease (MODEL‐AD) Consortium. MAD1 features replacements of murine Aβ (App), Mapt, and Apoe alleles with their human counterparts hAβ, hMAPT (H2), and hAPOE4. These humanized alleles are regulated similarly to their murine equivalents and expressed at physiological levels.

Method

Brain sections from 4‐month‐old (mo) MAD1 and B6J (WT) (n = 3/sex/group) mice were analyzed using NanoString CosMx single‐cell hybridization‐based spatial transcriptomics and antibody‐based spatial proteomics to probe region‐specific differences in gene expression and protein distribution. Further, to examine the role of demyelination in AD pathology, snRNA‐seq analysis was performed on hippocampal and cortical samples of 8‐mo MAD1 mice treated with cuprizone (n = 3M,2F/group), a copper chelator that causes oligodendrocyte degeneration and myelin loss. Finally, snRNA‐seq findings were validated with immunohistochemistry by staining for glial and AD markers.

Result

Spatial transcriptomic and proteomic analyses revealed distinct differences in gene expression and protein distribution between MAD1 and WT mice. Key genes involved in neuroinflammation, synaptic function, and neuronal survival showed altered expression in MAD1 mice, indicating a shift towards an AD‐like state. Congruent with our spatial analyses, snRNA‐seq analysis revealed increased glial cell activation in MAD1 compared to WT. Additionally, 8‐mo MAD1 mice treated with cuprizone exhibited marked microgliosis and astrogliosis compared to MAD1 controls, as demonstrated by immunohistochemistry and snRNA‐seq. These pronounced glial changes were not sufficient to induce Aβ or tau formation at this stage.

Conclusion

These exciting preliminary findings establish MAD1 as a novel platform model for testing various interventions in AD research, including demyelination. Future studies will explore the effects of aging, diet, remyelination, and other factors on MAD1 mice to elucidate the mechanisms of LOAD.
The involvement of human CD33 in the pathogenesis of Alzheimer’s disease mouse model
Authors: Su Tzu‐Ching , Hung Wei‐Chien , Cheng Irene Han‐Juo
Published: January 2025

Background

Genome‐wide association studies demonstrated that immune suppressive receptor CD33 variants are associated with high susceptibility to developing Alzheimer’s disease (AD). Human CD33 (hCD33) regulates microglial immune response and clearance ability. However, the differential regulation of phagocytosis by human and mouse CD33 imposes constraints on utilizing the mouse model for investigating the role of CD33 in AD. Therefore, we investigate the pathogenesis progression of the AD mouse model with hCD33 knockin.

Method

We generated conditional hCD33 knock‐in mice on microglia in the J20 AD mouse model. At 6 months, Morris water maze and Barnes maze were applied to examine their spatial learning and memory. The ELISA and immunohistochemistry were used to examine the accumulation of soluble and insoluble Aβ, microglial activation, in‐vivo Aβ uptake, and synaptic dysregulation.

Result

In the presence of hCD33, Aβ accumulation was decreased in the AD mouse. Conversely, a more diffuse and less condensed plaque structure was observed. In hCD33 knock‐in mice, microglia failed to form a compact barrier covering plaque deposits. Under hCD33 expression, AD mice had more neurotoxic dystrophic neurite around plaques, suggesting a higher plaque‐associated neurotoxicity. However, spatial learning and memory retention had no significant differences between the control AD mice and hCD33 knock‐in AD mice in the Morris water maze.

Conclusion

Our findings suggested that the presence of the AD risk gene human CD33 incurred neurotoxicity and altered the structure of Aβ deposition by manipulating microglial barrier formation against AD stress.
Dissecting the mechanisms of CASK deficiency on the clearance of Aβ in microglia
Authors: Chang Jacky , Cho Yen Ting , Lin Yu Yi , Cheng Irene Han‐Juo
Published: January 2025

Background

Amyloid‐beta (Aβ) deposition is a key pathological characteristic of Alzheimer’s disease (AD). Microglia serves as a crucial system responsible for clearing Aβ. Activated microglia migrate towards Aβ deposits, engulf them, and breakdown Aβ through cathepsins within the lysosome. Calcium/calmodulin‐dependent serine protein kinase (CASK) regulates microglia’s migration and phagocytic activity. Notably, our findings revealed a reduction in the expression of microglial CASK upon Aβ treatment. Nevertheless, the specific function of CASK in activated microglia remains undiscovered.

Method

The chemotaxis and migration of CASK KO BV2 microglia were examined via transwell and wound healing assays with Aβ presence variations. Focal adhesion kinase (FAK) protein levels were assessed through western blotting. Phagocytic capacity will be tested by using fluorescence‐labeled Aβ and microbeads after activated by LPS and Aβ. Vinculin, CD68 or lysosome associated membrane (LAMP1) were visualized using immunostaining. Actin was stained with phalloidin. The colocalization was measured by ImageJ. Expression of cathepsin B, D, and S, and Aβ‐degrading enzymes in CASK KO microglia were measured via qPCR. Lysosome morphology was tracked using lysotracker.

Result

The expression of microglial CASK was reduced upon Aβ treatment. The chemotaxis and migration capabilities of CASK KO microglia are notably inferior to WT microglia. After Aβ treatment, FAK protein levels were significantly higher in WT but not CASK KO microglia. Moreover, CASK KO microglia had lower vinculin‐lamellipodia colocalization and lamellipodia area than WT microglia. Conversely, CASK deficiency in microglia increased Aβ engulfment and the number of lysosomes. In addition, LAMP1‐Aβ colocalization was diminished in CASK KO microglia. CASK KO microglia had higher levels of cathepsin B, D, and S, as well as and Aβ‐degrading enzymes than WT microglia.

Conclusion

Our investigation revealed the critical roles of CASK in regulating microglial migration and phagocytic functions, particularly in the context of Aβ treatment. These findings necessitate further exploration into the nuanced functions of CASK in activated microglia, potentially offering insights into novel therapeutic avenues for AD.
Shared Genetic Risk Factors Contribute to the High Comorbility between Alzheimer’s Disease and COVID‐19 in European and African Populations
Authors: Chen Jingchun
Published: January 2025

Background

The global outbreak of COVID‐19, caused by the SARS‐CoV‐2 virus, has been linked to long‐term neurological complications, including Alzheimer’s disease (AD) among seniors. However, the precise genetic impact of COVID‐19 on long‐term AD development remains unclear.

Method

This study leveraged genome‐wide association study (GWAS) data and genotype data to explore the genetic correlation between AD and various COVID‐19 phenotypes across European ancestry (EA) and African ancestry (AA). We first calculated the polygenic risk scores (PRSs) of three COVID‐19 phenotypes in AD cases and controls from both EA and AA populations, then determined the genetic correlations between COVID‐19 PRSs and AD by logistic regression analyses with or without adjusting for age, sex, and APOE genotypes. Furthermore, shared SNPs and genes were identified through variant mapping and gene annotation from the large GWAS data of both diseases.

Result

Our study identified significant positive correlations between AD diagnosis and COVID‐19 in both populations. Notably, correlations were stronger from AA as compared to the EA population. In addition, significant shared variants and genes were identified in the chr17q21.31 region, suggesting common biological mechanisms may contribute to the high comorbidity between AD and COVID‐19.

Conclusion

Further functional studies are required to understand their causal relationships, leading to enhanced prevention and treatments for both conditions.
Investigating the Interplay between Air Pollution and APOE Clusters in Taiwan: Implications for Alzheimer’s Disease Susceptibility
Authors: Fuh Jong‐Ling , Lo Yen‐Li , Lin Yung‐Shuan , Lee Wei‐Ju , Fann Cathy SJ
Published: January 2025

Background

There is a strong genetic component to Alzheimer’s disease (AD), as evidenced in genome‐wide association studies (GWASs) that have identified new variants associated with the disease. This is particularly true for the apolipoprotein E (APOE) gene and its neighboring genes on chromosome 19q13.3. In addition, air pollution was linked to aggravating the development of AD. A significant gap remains in the understanding of gene‐environment interactions influencing AD susceptibility. The purpose of this study is to examine how air pollution interacts with APOE clusters in Taiwan.

Method

We conducted a district‐matched case‐control study involving 3,229 AD patients and 12,916 controls aged 65 to 71 years old using data from the Taiwan Precision Medicine Initiative and the Taiwan Biobank. From 2005 to 2014, air pollutants with a size up to 2.5 micrometers (PM2.5) were sampled at one‐day intervals and assigned according to home addresses according to the Taiwan Administrative Region Map. When the PM2.5 concentration exceeded 35 g/m3, it was considered a high PM2.5 day. Logistic regression models were used to assess the association of air pollution, categorized into tertiles as low, moderate, and high exposure, with the risk of AD.

Result

The role of single nucleotide polymorphisms (SNPs) in air pollution has been demonstrated, especially for SNP rs147466807 (NECTIN2), when compared to PM2.5 (p = 0.005). A significant increase in AD risk was found among individuals living in high PM2.5 areas (more than 165 days exposed to high PM2.5 per year) who had one NECTIN2 risk allele compared to those without (adjusted odds ratio, 3.54; 95% confidence interval, 1.60‐7.03). Additionally, NECTIN2 6‐SNP haplotypes exhibited a similar gene‐environment interaction.

Conclusion

We found a possible interaction between NECTIN gene polymorphisms and outdoor air pollution, emphasizing the importance of including environmental exposures in genetic etiological studies of AD.
Increasing cerebral blood flow reduces neural activity derangement in mouse models of Alzheimer’s disease
Authors: Zirkel Rick T , Isaacson Matthew , Lamont Michael , Nishimura Nozomi , Schaffer Chris B
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by progressive, irreversible neurodegeneration, leading to memory loss and cognitive decline. In mouse models of AD, global decreases in cerebral blood flow (CBF) are brought on by the plugging of capillaries by arrested neutrophils, and the administration of the neutrophil‐specific antibody against Ly6G (anti‐Ly6G) reduces these capillary stalls in minutes and improves cognitive function within hours. This suggests that at least some aspects of neural activity impairment are reversible, but the mechanism of this recovery – and what specific neural activity is normalized – is not yet known. In agreement with prior studies, we found orientation tuning selectivity to drifting gratings in primary visual cortex neurons to be broadened in mouse models of AD. Here, we hypothesized that the impaired neural response can be modified by blood flow improvement with anti‐Ly6G treatment (4 mg/kg) in the APP/PS1 mouse model of AD.

Method

We transfected neurons in layer 2/3 of the primary visual cortex (V1) of mice with a fluorescent calcium indicator using AAV9 vectors (pAAV.Syn.GCaMP6s.WPRE.SV40, 10^12 vg/mL). We also injected the fluorescent labels methoxy‐X04 to detect amyloid plaques and Texas‐red‐dextran in the vasculature to detect blocked capillaries. Drifting grating visual stimuli were presented to anesthetized mice with using MouseGoggles during recording with two‐photon microscopy before and one day after anti‐Ly6G or isotype control antibody administration (Fig. 1).

Result

One day after anti‐Ly6G administration to reduce stalls and increase CBF, we observed a significant sharpening of orientation tuning relative to baseline in the same animals, as well as a trend toward increased spontaneous activity in V1 neurons (Fig. 2). Such normalization of neural activity patterns likely underlies the improved cognitive function that is seen within hours of blood flow increase in AD mouse models.

Conclusion

Our data suggests some aspects of the neural and behavioral deficits in AD are acutely recoverable by increasing CBF. Such recovery demonstrates a promising avenue for future therapeutic targets to combat the symptoms of AD in humans.
Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub‐haplotypes
Authors: Wang Hui , Chang Timothy S , Dombroski Beth A. , Cheng Po‐Liang , Si Ya‐Qin , Tucci Albert A , Wang Li‐San , Tzeng Jung‐Ying , Geschwind Daniel H. , Schellenberg Gerald D. , Lee Wan‐Ping
Published: January 2025

Background

The H1/H2 haplotype on 17q21.31 represent the foremost genetic factor contributing to the risk of progressive supranuclear palsy (PSP). Various structural forms of 17q21.31 characterized by the number of copies of α, β, and γ duplications have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study.

Method

Whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects were obtained from the Alzheimer’s Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Copy numbers of α, β and γ were called by CNVpyter (Version 1.3.1). Expectation‐maximization algorithm was used to infer the sturctural forms of 17q21.31 for each individual. Then, a case‐control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP.

Result

The copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04‐1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10‐1.33, P = 5.47 × 10‐5) for H1β1γ1 to 1.29 (95%CI 1.16‐1.43, P = 1.35 × 10‐6) for H1β1γ2, 1.45 (95%CI 1.27‐1.65, P = 3.94 × 10‐8) for H1β1γ3, and 1.57 (95%CI 1.10‐2.26, P = 1.35 × 10‐2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub‐haplotype associated with increased risk of PSP. The proportion of MAPT sub‐haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increase from 34% in H1β1γ1 to 77% in H1β1γ4.

Conclusion

This study identified that the copy number of γ was associated with the risk of PSP. H1 haplotypes with more γ duplication showed a higher odds ratio and were associated with MAPT sub‐haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure of H1/H2 affect the risk of PSP.
Cortico‐hippocampal dysfunction in APP‐KI and PS1 mouse models
Authors: Hernández‐Frausto Melissa , Chinea Francesca , Basu Jayeeta
Published: January 2025

Background

Lateral entorhinal cortex (LEC), medial entorhinal cortex (MEC), and hippocampal area exhibit cell damage due to B‐Amyloid depositions, intracellular tau aggregates, and neurofibrillay tangles. AD mouse models allow us to investigate how AD neurodegeneration affects specific brains circuits and resulting behaviors. Specifically, the PS1 and APP NL‐G‐F knock in (APP‐KI) mouse models are relevant due to their genetic modifications, episodic memory impairment, early AD pathophysiology, and novelty designed for study. Nevertheless, the circuit mapping of entorhinal cortex in the medial and lateral portion within the hippocampal area during the progression of AD remains elusive.

Method

By using anatomical tracing and cognitive freely moving behaviors we compared the progression of cognitive deficits in the PS1 and APP‐KI mouse models. First, with AAV viral infection we expressed a green fluorophore in excitatory cell bodies in LEC and MEC, we examined through confocal microscopy the density of the projections in hippocampal area. Then, we compared with the behavioral performance in two cognitive tasks involved in the cortico‐hippocampal function; Novel Object Recognition (NOR) and Novel Object Location (NOL).

Result

Our confocal imaging show a reduced density of the excitatory projections from LEC and MEC neurons in hippocampus compared to controls. Likewise, when evaluated the cognitive performance in NOR and NOL tasks, mice have a cognitive impairment performance in NOR and NOL.

Conclusion

Our findings suggest that during an age period when Alzheimer’s disease phenotypes are already established, there is a markedly reduction in the connectivity between LEC, MEC and hippocampus with an episodic memory performance impaired. Current analysis to determine the precise period of the cortico‐hippocampal dysfunction appears during the disease progression are underway.
Effects of brain microRNAs in cognitive trajectory and Alzheimer’s disease
Authors: Vattathil Selina M. , Bennett David A. , Schneider Julie A. , Wingo Aliza P. , Wingo Thomas S.
Published: January 2025

Background

microRNAs (miRNAs) are small RNAs involved in regulating gene expression by repressing target protein‐coding genes. Hundreds of miRNAs are expressed in human brain, but our understanding of their role in Alzheimer’s disease (AD) and cognitive decline is limited.

Method

We performed miRNA differential expression analysis using small RNA sequencing data generated from dorsolateral prefrontal cortex samples from 641 participants of the Religious Orders Study (ROS) and Memory and Aging Project (MAP). After quality control, 528 miRNAs were available to test for differential expression in cognitive trajectory (for five cognitive subdomains and global cognition), amyloid, tangles, and AD clinical diagnosis. Initial analyses were performed using association models that included adjustment for technical and demographic covariates. To identify miRNAs associated with AD‐related outcomes independently of co‐occurring age‐related cerebral pathologies, secondary analyses were conducted using models augmented to also adjust for the pathologies. Sex interaction analyses were performed to identify sex‐biased miRNAs, and Mendelian randomization was conducted to assess the evidence that genetically‐regulated miRNA abundance mediates the observed trait associations.

Result

We identified 311 differentially expressed miRNAs for AD, its hallmark pathologies, or cognitive trajectory. Our secondary analysis identified 137 miRNAs that were associated with AD‐related outcomes independently of up to ten age‐related cerebral pathologies. The protein‐coding genes predicted to be repressed by the differentially expressed miRNAs were enriched in lipoproteins, transcription, postsynaptic signaling, and cellular senescence. Sex interaction analysis identified 5 miRNAs with different observed associations in males and females. Finally, Mendelian randomization identified 15 miRNAs with evidence that their expression roles play a causal role in the associated trait.

Conclusion

We find evidence for some miRNAs being associated with AD‐related traits and cognitive trajectory through age‐related cerebral pathologies while other miRNAs are independently associated with AD‐related outcomes. The miRNAs consistent with a causal role are promising candidates for future studies in model systems to understand how miRNAs contribute to AD and cognitive decline.
Alzheimer’s disease‐associated gut microbes shape neuroinflammatory tone and disease outcomes in mouse models
Authors: Blackmer‐Raynolds Lisa , Sampson Maureen , Hamilton Adam M , Yang Aimee , Kozlov Anna , Lipson Lyndsey , Chang Jianjun , Kelly Sean D , Sloan Steven A , Sampson Timothy R.
Published: January 2025

Background

Changes in neuroinflammatory tone have been shown to modulate neuroimmune responses to Alzheimer’s disease (AD) pathology and shape disease outcomes, however, extrinsic factors that modify neuroimmune activation remain poorly understood. The gut microbiome is one such factor, with the ability to shape peripheral and central immune activation, as well as AD pathologies. AD patients display unique changes in microbiome composition, however, the link between specific AD‐associated gut bacteria, neuroinflammatory tone, and AD outcomes remains to be elucidated.

Method

To identify AD‐associated bacteria that modify neuroinflammatory tone, wildtype germ‐free mice were mono‐colonized with type strains of bacteria species of interest (Escherichia coli, Bacteroides thetaiotaomicron, Clostridium celatum, and Lactobacillus johnsonii) for 2 weeks. Further evaluation of the effect of E. coli—an identified neuroimmune modulatory bacteria—on AD outcomes was performed by exposing conventional 5xFAD mice to E. coli via oral gavage for one month. Neuroinflammatory outcomes were assessed by bulk and single cell RNA‐seq and protein analysis. In addition, AD outcomes including cognitive and pathological markers were evaluated in E. coli exposed 5xFAD mice.

Result

AD‐associated bacteria induced bacteria‐ and sex‐specific changes in cytokine levels as well as myeloid cell gene expression within the brains of mono‐colonized mice. In particular, E. coli was shown to induce a distinct, AD‐associated neuroinflammatory phenotype that was characterized by increased MHC II antigen presentation and changes in boarder associated macrophage and endothelial cell gene expression. Further, E. coli‐exposed 5xFAD mice displayed accelerated cognitive decline compared to vehicle controls. Neuroinflammatory and pathological markers in the brains of E. coli‐exposed 5xFAD mice were also evaluated to further explore the effects of E. coli on AD pathophysiology.

Conclusion

Together, these results highlight the neuroimmune modulatory potential of AD‐associated gut bacteria. In particular, the present study demonstrates how increased intestinal exposure to non‐pathogenic E. coli is sufficient to modify neuroinflammatory tone, cognition, and pathology in 5xFAD mice, highlighting the potential importance of this microbe for AD.
Dyadic patterns of subjective cognitive decline and longitudinal cognitive outcomes
Authors: Houston Michelle L. , Zhang Panpan , Liu Dandan , Pechman Kimberly R. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A.
Published: January 2025

Background

Subjective cognitive decline (SCD) may provide an early indicator of Alzheimer’s disease. Dyadic SCD, the self/patient’s in relation to an informant/loved one’s endorsement of SCD, may better reflect underlying Alzheimer’s pathology. We related dyadic SCD discrepancies to longitudinal changes of cognitive aging.

Methods

Vanderbilt Memory and Aging Project participants (cognitively unimpaired 71%, n = 537, 69.3±10.1 years, mean follow‐up time 5.9±2.8 years) and their informants completed the Everyday Cognition (ECog) questionnaire and Cognitive Complaint Questionnaire (CCQ). Dyadic discrepancy (self‐reported score minus informant‐reported score) was calculated and split into 3 levels (i.e., self>informant, informant>self, and dyadic concordance). Participants completed a diagnostic interview, neuropsychological testing, and multimodal brain MRI at each timepoint. Linear mixed‐effects regression models related baseline dyadic category to diagnostic conversion and longitudinal neuropsychological and neuroimaging outcomes. Models were adjusted for age, sex, self‐reported race/ethnicity, baseline diagnosis, APOE‐ε4 status, depression symptoms (Geriatric Depression Scale), and follow‐up time. A false discovery rate (FDR) correction for multiple comparisons was applied.

Results

Dyadic discrepancy on the ECog did not relate to diagnostic conversion. Compared to dyadic concordance, individuals with greater self‐SCD on the CCQ related to diagnostic conversion (β = 2.96, p = 0.04). In secondary models stratified by diagnosis, cognitively unimpaired participants with greater self‐SCD were more likely to diagnostically convert (β = 6.48, p = 0.02). Compared to dyadic concordance, individuals with greater informant‐SCD on the ECog were associated with worsening executive functioning (β = ‐0.06, pFDR = 0.02), Boston Naming Test (BNT) (β = ‐0.42, pFDR<.001), and animal naming (β = ‐0.44, pFDR = 0.01). Compared to dyadic concordance, individuals with greater informant‐SCD on the CCQ were associated with worsening executive functioning (β = ‐0.08, pFDR = 0.01), memory (β = ‐0.07, pFDR = 0.01), and BNT (β = ‐0.53, pFDR<.001), with stronger associations in the mild cognitive impairment subgroup. Neither ECog nor CCQ dyadic discrepancy related to neuroimaging markers (pFDR>0.10).

Conclusions

The direction of dyadic discrepancy related differently to diagnostic conversion and cognitive performance. Greater self‐reported SCD related to greater likelihood of diagnostic conversion in cognitively unimpaired participants. However, greater informant‐reported SCD related to worsening cognitive performance. Results highlight that dyadic patterns of SCD differentially predict prognosis and incorporation of an informant provides important information. Further analyses will examine dyadic discrepancy and longitudinal biomarker patterns.
Loss of Alzheimer’s disease risk factor BIN1 from inhibitory neurons induces network hyperexcitability
Authors: Voskobiynyk Yuliya , Cochran J. Nicholas , Davis M. Natalie , Carullo Nancy VN , Day Jeremy J , Roberson Erik D
Published: January 2025

Background

Genome‐wide association studies have identified genetic risk factors for AD, including a single nucleotide polymorphism in the bridging integrator 1 (BIN1) gene that is present in approximately 40% of the population and has the largest effect size of the common AD genetic risk factors. While the association between BIN1 and AD has been established, the mechanisms by which BIN1 contributes to AD remain understudied. We previously showed that increasing BIN1 expression in primary hippocampal neurons increases neuronal excitability (Voskobiynyk & Roth et al., 2020). However, expression of the primary neuronal isoform of BIN1 is reduced in AD patients compared to healthy age‐matched controls. We thus set out to explore the mechanism of BIN1’s contribution to network hyperexcitability in vivo.

Methods

We used conditional knockout mice to selectively reduce murine Bin1 from all neurons (Nestin‐Cre‐driven), excitatory neurons (CaMKIIα‐Cre‐driven), and inhibitory neurons (Viaat‐Cre‐driven). We then examined network hyperexcitability through a pentylenetetrazole‐induced seizure susceptibility assay; transcriptomic effects through bulk RNA sequencing, and behavioral effects through a battery of tests.

Results

Pan‐neuronal loss of Bin1 increased seizure susceptibility in a gene‐dose‐dependent manner. Bin1 loss from excitatory neurons decreased seizure susceptibility, while Bin1 loss from inhibitory neurons increased seizure susceptibility. Bin1 loss from inhibitory neurons induced learning deficits and increased mortality of adult mice.

Conclusion

Bin1 loss from inhibitory neurons led to increased seizure susceptibility, similar to the pan‐neuronal loss of Bin1, suggesting that loss of Bin1 from inhibitory neurons drives the effect of global loss of Bin1. Overall, this study contributes to our understanding of how BIN1 regulates network hyperexcitability at a cell‐type‐specific level.
Agreement between self‐ and informant‐reports of cognitive complaints in predicting time to an objective cognitive worsening in Cognitively Unimpaired (CU) and with Subjective Cognitive Decline (SCD) participants: Results from the CompAS longitudinal study
Authors: Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Lojo‐Seoane Cristina , Spuch Carlos , Aldrey Jose M. , Juncos‐Rabadán Onésimo , Rozas Arturo X. Pereiro
Published: January 2025

Background

The importance of coincidence of cognitive complaints between participants without objective impairment and their informants in predicting progression remains unclear (Nosheny et al, 2022). Our objective was to determine whether agreement in dyadic reporting at baseline can predict survival time to progression to MCI or dementia.

Method

A sample of 145 participants from the CompAS Study was included in a survival analysis. They were identified at baseline as CU (N = 115) and SCD (N = 30) and re‐diagnosed as CU, SCD, MCI, or dementia from 17 to 76 months of follow‐up. ‘Agreement’ in the presence of complaints was computed depending on the informant and participant QAM scores (range: 7‐35) at baseline were above or below a cut‐off point (i.e., 10‐11): 1) Overreport by participant (i.e., QAM scores above the established cut‐off for participant and below for informant); 2) Agreement in presence of complaints (i.e., QAM total scores of both coincide in being above the established cut‐off point). The other two categories (i.e., Overreport by informant; Agreement in absence of complaints) were discarded because there were almost no cases. We performed a Cox proportional hazards regression model (no cases censored). The event was defined as stability when the baseline diagnosis remained stable over the follow‐ups and worsening when a change to MCI or dementia. ‘Agreement’ was introduced as a covariate. Two groups (CU; SCD) identified at baseline entered the model as strata.

Result

The model was statistically significant [model fit: ‐2 Log Likelihood = 1029.810, χ2 = 9.721, df = 1, p<.002]. ‘Agreement’ significantly predicts time survival [β = ‐.471, SE = .161, Wald = 8.569, p < .003] and HR = .575 (95% CI = .404‐.817) indicated that the risk of worsening per month was 42.5% (1‐.575 = .425) smaller for the ‘Agreement in presence of complaints’ than for the ‘Overreport by participant’ in both CU and SCD groups (Figures 1 and 2).

Conclusion

Our results suggest that compared to the ‘Overreport by participant’, the dyadic agreement in the presence of complaints decreases the risk of worsening over time. These results could have to do either with a greater awareness of one’s own difficulties or with the beneficial effect of agreeing on its detection with informants in pre‐symptomatic stages.
Microglial expression of Alzheimer’s risk factor BIN1 regulates tau pathology in PS19 mice
Authors: Sudwarts Ari , Hansen Mitchell , Wang Shuai , Smirnou Stanislau , Skorobovenko Vlada , Delozier Michaela , Thinakaran Gopal
Published: January 2025

Background

Microglia play significant roles in Alzheimer’s disease (AD) pathophysiology. Current evidence suggests microglia may function in both protective and degenerative capacities, which has received little clarity from transcriptionally‐characterised phenotypes uncovered from transgenic pathologies alone. BIN1 ‐ the second‐most significant risk gene for the development of late‐onset AD (LOAD) ‐ is expressed at high levels in neurons, oligodendrocytes and microglia. We examined microglial BIN1 expression and function and previously demonstrated that BIN1 regulates proinflammatory and disease‐associated activation responses in microglia in vitro and in vivo (PMID 35526014). However it’s role in AD‐specific pathologies is as yet unknown.

Method

We used a reverse‐genetic approach to conditionally delete Bin1 in microglia of the PS19 mouse model of tauopathy. We used histology, biochemistry and RNAseq analyses to determine the effects of Bin1‐cKO on tau pathology and microglial responses.

Result

Our data demonstrate that microglial BIN1 facilitates levels of pathologically phosphorylated tau (p‐tau), specifically in female PS19 mice. RNAseq analysis identified cell ‐autonomous and non‐autonomous effects for microglial BIN1 during tau pathogenesis in the PS19 model. Weighted gene co‐expression analyses revealed complex networks of genes regulated by microglial gene expression during tau pathogenesis. We also identified gene networks correlated with levels of formic acid‐soluble p‐tau, irrespective of microglial Bin1 gene manipulation.

Conclusion

These gene networks offer novel insight into microglial genes involved in responses to tau pathology, and the potential impact of BIN1 as a LOAD risk gene.
Impact of sex, ancestry, and local ancestry on Apolipoprotein E (APOE) for Alzheimer’s disease (AD): a pooled case‐control analysis of Alzheimer’s Disease Genetics Consortium (ADGC)
Authors: Rodriguez Omar Garcia , Wang Lily , Young Juan I ,   Alzheimer’s Disease Genetics Consortium (ADGC), Pericak‐Vance Margaret A , Martin Eden R. , Kunkle Brian W.
Published: January 2025

Background

Previous studies have reported that non‐Hispanic white (NHW) females carrying the APOE ε4 allele differ in risk of developing Alzheimer’s disease (AD) when compared to men. Recent studies suggest the association between APOE ε4 and AD risk may be modified by age and its local ancestry in admixed populations. However, there is still scant evidence on how sex could interact with these factors. We aimed to investigate the association of sex, ancestry, APOE, and local ancestry with AD in multiple cohorts.

Methods

A pooled case‐control study was undertaken from 50 independent datasets (n = 30,539;age≥55years) in the Alzheimer’s Disease Genetics Consortium. Logistic regression models were used to study the associations between disease status and independent variables including age, sex, reported race (as a proxy of ancestry), and APOE genotype. Additionally, mixed models were implemented for the local ancestry APOE haplotype analyses among different ethnicities. A p‐value less than 0.05 was considered statistically significant.

Results

Regardless of ancestry, men and women with APOE ε3/ε4 or ε4/ε4 genotypes showed no significant difference in the risk of developing AD. When comparing subjects with APOE ε3/ε4 or ε4/ε4 (vs. ε3/ε3), East‐Asian (EA) males (OR,5.56; 95% CI:4.26‐7.60) and females(OR,5.46:4.34‐6.86) had the strongest ORs; whilst the weakest risk was for South‐Asian (SA) men(OR,1.14:0.99‐2.57) among all races/ethnicities. Age‐stratified analyses showed that NHW females(OR,5.36:4.74‐6.07 vs. males: OR,4.72:4.10‐5.60) had a higher risk of developing AD between ages 66‐75; whereas African American (AA), EA and SA exhibited this pattern at 55‐64. In Hispanics, the relationship is reversed, with males aged 55‐65 years carrying APOE ε3/ε4 or ε4/ε4(OR,4.53:1.67‐12.30: vs. females: OR,3.03:1.59‐5.78) having a stronger association with AD risk than their counterpart. No differences were found when stratified by sex and age for APOE ε2 and AD. Local ancestry (European ‐EU‐; African ‐AF‐; Amerindian ‐AI‐; and EA) analyses are being conducted by ancestry and sex.

Preliminary analyses suggest differences by sex and local ancestry for APOE ε4.

Conclusions

Our findings suggest differences by sex and reported ancestry in the risk for developing AD in carriers of APOE ε4. Global, local ancestry and sex should be considered in predicting risk due to APOE alleles.
Sex‐stratified GWAS for Alzheimer’s Disease Reveals African Ancestry Risk variants in Men
Authors: Belloy Michael E. , Reid Danielle M. , Guen Yann Le , Napolioni Valerio , Greicius Michael D
Published: January 2025

Background

Several studies have indicated sex‐specific genetic risk for Alzheimer’s disease (AD), but these were centered on non‐Hispanic White individuals of European ancestry. We sought to identify sex‐specific genetic variants for AD in non‐Hispanic and Hispanic subjects of admixed African ancestry.

Method

Participants were ages 60+, of African ancestry (≥25%), 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, sex, and Hispanic/non‐Hispanic status (Table‐1), requiring genotyping rate ≥80% and minor allele frequency ≥1%, followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). A sex‐by‐SNP interaction model was also evaluated. GWAS performed multiple linear regression on an AD‐age score (Le Guen & Belloy et al. 2021; Figure‐1), 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.

Result

We found 3 genome‐wide significant loci in men (Figure‐2) with lead variants 1) rs74853649 ∼85kb downstream of FHIT, 2) rs73411425 in the PILRA/ZCWPW1/NYAP1 AD risk locus, and 3) rs3736450 intronic on WWOX. Despite that rs73411425 is within a known locus, the variant is novel. Notably, all three variants showed significant sex‐by‐SNP interactions and were specific to African rather than European ancestry (Table‐2). Further, in men, we also observed a suggestive association intronic on RBFOX1, which was previously implicated as a risk gene harboring variants associated with higher amyloid burden in brain (Raghavan et al. 2020), with strongest effect sizes in African‐American individuals (those samples were independent of the current data).

Conclusion

The study is an initial exploration of sex‐specific genetic effects in African ancestry individuals and warrants replication in larger data. Importantly, we show the relevance of expanding beyond non‐Hispanic white samples for sex dimorphism research, identifying male‐specific risk variants that have elevated frequencies in African ancestry, while being rare in other ancestries. In ongoing work, we are performing cross‐ancestry meta‐analyses of sex‐stratified GWAS followed by sex‐stratified omics integration to increase power to uncover sex‐specific genes relevant to AD.
Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer’s disease
Authors: De Jager Philip L.
Published: January 2025

Background

Recent studies have revealed diverse Alzheimer’s disease (AD)‐associated cell states, yet when and how they impact the causal chain leading to AD remains unknown.

Method

To reconstruct the dynamics of the brain’s cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single‐nucleus RNA‐seq profiles. We associated glial, vascular and neuronal subpopulations with AD‐related traits for 437 aged individuals and aligned them along the disease cascade using causal modeling.

Result

We identified two distinct lipid‐associated microglial subpopulations, one associated with amyloid‐β proteinopathy while the other mediated the effect of amyloid‐β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment, we devised the BEYOND methodology, which uncovered two distinct trajectories of brain aging defined by differing sequences of changes in cellular communities. Our set of prospectively autopsied older individuals is separated into one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with either (1) AD dementia or (2) alternative brain aging.

Conclusion

We provide a cellular foundation for a new perspective on AD pathophysiology that could inform the development and personalization of new therapeutic interventions targeting cellular communities while personalizing clinical management for those individuals on the path to AD or to alternative brain aging.
Synaptic plasticity dysregulation driven by pathogenic tau
Authors: Pareja‐Navarro Kristeen A. , King Christina D. , Kauwe Grant , Lokitiyakul Doyle , Sharma Mahima , Wong Ivy , Ngwala Yani , Schiling Birgit , Tracy Tara E.
Published: January 2025

Background

Synapses can modify their strength in response to activity, and the unique properties of synapses that regulate their plasticity are essential for memory. Long‐term potentiation (LTP) is considered the physiological basis for how neurons encode new memories. A complex series of postsynaptic signaling events in LTP is associated with memory deficits in tauopathy models, but the mechanism by which pathogenic tau inhibits plasticity at synapses is unknown. Here, our objective was to delineate the postsynaptic mechanisms by which pathogenic tau inhibits LTP in neurons.

Method

We used human induced pluripotent stem cell (iPSC)‐derived neurons with mutations on tau that cause frontotemporal dementia or we treated human iPSC‐derived neurons with tau oligomers to model tau‐related pathogenesis. We induced NMDA receptor‐dependent LTP in the neurons and monitored trafficking of AMPA receptors (AMPARs) to the postsynaptic surface. To identify the mechanisms underlying synapse dysregulation, we designed an approach to detect changes in the postsynaptic proteome with high temporal resolution using APEX‐mediated proximity labeling and mass spectrometry.

Result

Pathogenic tau inhibited the delivery of AMPARs to the postsynaptic surface and blocked LTP expression in human iPSC‐derived neurons. The postsynaptically‐targeted APEX platform mapped the dynamic changes in the postsynaptic proteome of neurons with pathogenic tau.

Conclusion

Our findings reveal new mechanistic insights into how pathogenic tau alters the postsynaptic proteome and inhibits synaptic plasticity.
Single cell nuclei transcriptomics of human brains identify a role for homeostatic microglia in cellular senescence in Alzheimer’s disease
Authors: Yassine Hussein N , Li Boyang , Wang Shaowei , Ebright Brandon , Duro Marlon Vincent V. , Kerman Bilal Ersen , Asante Isaac , Arvanitakis Zoe , Louie Stan G
Published: January 2025

Background

Cellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer’s disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so‐called “senescence‐associated secretory phenotype” (SASP) characterized by increased secretion of pro‐inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.

Method

In this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models. Bulk (n = 632) and single‐cell nuclei transcriptomic profiling (n = 427) of the human dorsolateral prefrontal cortex (DLPFC) from the Religious Order Study/Memory Aging Project (ROSMAP). Lipidomic profiling was performed on a subset of 200 brains from the midfrontal cortex of ROS.

Result

Our findings revealed upregulation of cellular senescence signatures in postmortem AD brain tissues across different cell types in comparison with controls. We identified a strong correlation between SASP and arachidonic acid (AA) metabolism (P<0.001) in bulk RNA. In single cell nuclei transcriptomics, AA Activation was strongly correlated with P2RY12 (homeostatic) microglia (P<0.0001), and was associated with worse performance on all cognitive domains (p<0.001) and AD neuropathology (P<0.001) as shown in the figure. Lipidomic analysis of postmortem brain tissues confirmed activation of AA derived eicosanoids. Pathway analysis implicated the activation of calcium dependent phospholipase A2 (cPLA2). Inhibiting cPLA2 by treatment with ASB14780 reduced senescence‐associated eicosanoids in APOE4 mouse models.

Conclusion

This work implicates the sustained activation of homeostatic microglia as an underlying mechanism of cellular senescence in the AD brain.
Using anti‐Aβ antibodies to modulate the multi‐pronged human microglia response to Aβ pathology
Authors: Albertini Giulia , Zielonka Magdalena , Cuypers Marie‐Lynn , van Lieshout Veerle , Snellinx An , Pasciuto Emanuela , Wolfs Leen , Craessaerts Katleen , Horré Katrien , Jaspers Tom , Fiers Mark , Dewilde Maarten , De Strooper Bart
Published: January 2025

Background

While social and medical debate about the efficacy and safety of anti‐Aβ immunotherapy is ongoing, one thing that emerged is that we have little understanding of the working mechanisms of these antibodies and this lack of knowledge complicates the interpretation of the clinical results. Here, we aimed to establish if microglia are required for the efficacy of Lecanemab, one of the most promising FDA‐approved disease‐modifying therapy for AD (Van Dyck et al. N Engl J Med 2023).

Method

To do so, we crossed AppNL‐G‐F mice with Csf1rΔFIRE/ΔFIRE mice (Rojo et al. Nat Commun 2019) to generate mice that show key features of Aβ pathology but genetically lack mouse microglia. We then assessed the effect of Lecanemab treatment on Aβ load and neuritic dystrophy.

Result

We demonstrate that Lecanemab lacks efficacy in the absence of microglia. On the other hand, when we xenotransplant human microglia into the brain of these mice (as described in Mancuso et al. Nat Neurosci 2019), we show that Lecanemab treatment significantly ameliorates both Aβ load and neuritic dystrophy. Furthermore, by employing scRNAseq on sorted human microglia, we demonstrate that Lecanemab treatment affects the transcriptome of the microglia by inducing a number of genes related phagocytosis, interferon response and immune activation. Functionally, we also established that Lecanemab‐treated human microglia ingest more amyloid‐β in vivo.

Conclusion

Overall, we provide the first evidence that microglia are crucial for the efficacy of anti‐Aβ immunotherapy and provide real insight into the working mechanisms of this first disease‐modifying therapy for AD.