bluuebunny/crossref_metadata_2025 huggingface dataset:
ApoE in brain mitochondria and energetics: From mice to human
Authors: Borkowski Kamil , Liang Nuanyi , Arnold Matthias , Bu Guojun , Kaddurah‐Daouk Rima , Zhao Na , Kanekiyo Takahisa
Published: January 2025

Background

Alzheimer’s disease (AD) risk and progression are significantly influenced by ApoE genotypes, with ApoE4 increasing and ApoE2 decreasing the susceptibility compared to ApoE3. Understanding metabolic pathways affected by ApoE genotypes will help decipher disease development and identify new therapeutic targets.

Method

This study investigates the impact of ApoE genotypes on aging brain metabolic trajectories using human ApoE‐targeted replacement mice. Applying Biocrates P180 targeted metabolomics platform, we analyzed the metabolic impact of ApoE2/2, ApoE3/3, and ApoE4/4 on fatty acid β‐oxidation, amino acids, and phospholipids, which are known to be altered in AD. Furthermore, we compared our rodent model results with human dorsolateral prefrontal cortex data from the Religious Orders Study/Memory and Aging Project (ROS‐MAP).

Result

We found aging mice carrying ApoE2/2 had altered branch‐chain amino acid metabolism and increased C5 acylcarnitine and its ratio to precursor isoleucine, pointing towards increased β‐oxidation and branched‐chain amino acid (BCAA) utilization. Furthermore, ROS‐MAP data revealed the ApoE2 genotype affects similar areas of metabolism in humans. Additionally, our data provide comprehensive insight into age‐related metabolic changes of the current mice model, independent of ApoE genotype, among phospholipids, sphingomyelins, amino acids, and biogenic amines. Many of the observed differences are also known aging markers in humans, with a connection to cognition and Alzheimer’s disease.

Conclusion

Together, these results suggest a potential involvement of ApoE2/2 genotype in energy metabolism and characterize the current mice model for further study of ApoE in AD, brain aging, and brain BCAA utilization for energy.
Naturally occurring human antibodies associated with AD and normal cognition
Authors: Reyes‐Ruiz Jorge Mauricio , Zhang Jizhi , Kumar Ashutosh , Yu Zhaoxia , Glabe Charles G
Published: January 2025

Background

Anti‐ Aβ monoclonal antibodies are the first FDA‐approved treatments for AD that slow cognitive decline and lower Aβ plaques. Our goal is to identify the epitope specificities of antibodies in human blood that are associated with AD and NC and determine the predicted protein targets of these antibodies.

Method

101 AD (MMSE < 27) and 98 NC (MMSE > 27) serum samples were obtained from the UCI tissue repository. Epitomic profiling was conducted on the blood samples to define the epitopes for the antibodies in the samples by immunoselecting random 12 amino acid sequences from a phage display library. The resulting unique sequences are identified and their frequency counted. The 12mer sequences are tiled into tetramers and the resulting antibody‐specific tetramers are compared by Mann‐Whitney U test to identify differentially expressed epitope segments (DEES) that are upregulated in the AD and NC populations.

Result

A large number of DEES (range 300 – 14,000 out of a total of 160,000 tetramers) was observed for AD and NC populations in both samples. Some of the DEES map to amyloids known to occur in AD, such as Aβ, tau, a‐synuclein, TDP43 and Tmem106b, but the actual epitopes are different in AD and NC. Both AD and NC populations’ data was then processed using UMAP for visualization and cluster analysis. Cluster analysis indicates that there are two clusters in the AD population: One large group that partially overlaps with the NC population and includes antibodies against the N‐terminus of Aβ and a well separated minor group that is defined by immunoreactivity to a heptameric linear epitope of currently unknown origin. The NC population includes several groups that contain anti amyloid antibodies.

Conclusion

Human blood contains a large number of antibodies that are differently expressed in AD that recognize distinct amyloid and non‐amyloid epitopes. These antibodies may be protective for disease, predictive for presymptomatic disease onset and progression or antibodies in response to amyloid deposition that could be protective depending on the concentration or predictive of disease subtype. Further work is aimed at determining the significance of the different antibodies and validating their disease association
Agora: An openly available web resource to enable exploration of nascent therapeutic targets for Alzheimer’s disease
Authors: Britton Jessica S , Wiley Jesse C , Beck Jaclyn , Leal Karina , Yi Lawrence , Macdonald Brad , Do Khai , Simon Stockard , Swan Hallie , Grosenbacher Nicholas , Yu Thomas , Hodgson Jay , Greenwood Anna
Published: January 2025

Background

Agora (https://agora.adknowledgeportal.org) is an openly available web resource developed to enable a broad spectrum of Alzheimer’s disease (AD) researchers access to target‐based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora aims to accelerate AD research and maximize therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence.

Method

Agora enables the sharing of information about potential AD therapeutic targets by surfacing data visualizations, summary evidence, and results from targeted validation studies. Agora users can browse a list of over 950 potential therapeutic targets that have been nominated by the NIA’s Accelerating Medicines Partnership in AD (AMP‐AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome‐wide analyses of high‐dimensional human transcriptomic, proteomic, and metabolomic data; use interactive tools designed to enable non‐bioinformaticians to evaluate and compare complex multi‐omic data; and access the underlying data that drives the results and visualizations presented in the application.

Result

Agora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) comparative and per‐target visualizations for SRM proteomic differential expression results and 2) enabling the discovery of TREAT‐AD Target Experimental Resources for supported targets.

Conclusion

The advancement of promising new AD therapeutics requires efforts from research groups and specialties across both academia and industry. Agora enables the AD research community to develop and share target hypotheses that will accelerate the investigation of promising new AD therapeutic targets, pathways and mechanisms.
APOE4 Alters Tau Propagation in Regions Associated with Early Alzheimer’s Disease in a Humanized Mouse Model of Tau Spread
Authors: Arain Hirra A , Idiarte Juan F , Lama Tsering D , Figueroa Helen Y , Guo Jia , Duff Karen E , Nuriel Tal
Published: January 2025

Background

Possession of the APOE4 allele is the strongest genetic risk factor for developing the sporadic form of Alzheimer’s disease (AD). Studies investigating APOE4’s associated AD risk have largely centered on APOE4’s propensity to regulate the deposition of extracellular amyloid beta plaques. More recent attempts to characterize APOE4’s role in AD have brought into question the role APOE4 may possess in modulating the pathogenesis of intracellular tau tangles. However, to date, it remains unclear if APOE4 can alter pathological tau spread and if these effects are dependent on regions associated with early tau accumulation in AD.

Method

To recapitulate tau spread observed early in AD, we developed a novel human APOE mouse that expresses misfolded human tau localizing to the entorhinal cortex (EC). These mice were generated by crossing homozygous mice possessing various humanized APOE alleles to mice harboring the human MAPT P301L mutation. Human MAPT was placed under control of the neuropsin‐tTa promoter to selectively expresses misfolded tau to the EC. Both male and female mice were analyzed at various ages up until 27 months using various in‐vivo and ex‐vivo techniques to measure tau pathology and propagation, spatial memory defects, and neurodegeneration.

Result

We observed differential tau spread and neurodegeneration altered by APOE genotype in both a sex‐dependent and age‐dependent manner. Our results point predominantly to decreased tau pathology in regions associated with early AD in homozygous APOE4 mice. Analysis of the middle‐aged cohort revealed a significant decrease in tau propagation and associated atrophy to the hippocampus and lateral EC in homozygous female APOE4 mice. The observed effect on neurodegeneration and tau burden were attenuated in both male counterparts.

Conclusion

Here we report the generation and characterization of a novel APOE‐tau mouse model that recapitulates the region‐specific tau pathogenesis observed in early AD. Our results offer novel insights into APOE4’s role in AD by altering the sex‐dependent propagation of pathological tau along anatomically connected, vulnerable AD brain regions.
Argonaute 2 in Neurons is essential for healthy Blood Brain Barrier Formation
Authors: Sona Chandan , Yeh Yu‐Te , Ghosh Adhideb , Hinte Laura C. , von Meyenn Ferdinand , Yan Xin , Poy Matthew
Published: January 2025

Background

Argonaute2 (Ago2) plays an essential role in RISC‐mediated silencing of target mRNAs, which are critical for cellular functions. Argonaute2 Syndrome, also known as Ago2 Syndrome, is a rare neurological disorder recently discovered in humans. It has significant implications for brain development, yet it remains unstudied to date

Method

To study this effect, we deleted the Ago2 gene in GABAergic (Slc32a1 cre) and Glutamatergic (Slc17a6 cre) mice. We conducted Western blotting and Immunohistochemistry to analyze the defects in knockouts. Additionally, we performed single‐cell experiments and analysis on the knockouts.

Result

Our study highlights the crucial role of Ago2 in glutamatergic neurons, leading to postnatal lethality due to disruption in the neurovascular unit (NVU) and neuronal positioning in the developing cortex. Surprisingly, the absence of Ago2 only affected postnatal survival when removed from glutamatergic, not GABAergic neurons. Through single‐cell analysis, we found that loss of Ago2 in this specific subset led to impaired synapse formation and endothelial cell connections, resulting in neuroinflammation. Dysregulation of the microRNA pathway and upregulation of Pten were observed, and de‐repression of Pten in Ago2‐deficient mice partially rescued the blood brain barrier (BBB) and increased survival

Conclusion

Our study identifies a vital neuronal population where miRNA function is essential for blood‐brain barrier formation. The loss of functional Ago2 in this neuronal population leads to BBB collapse and neuroinflammation. These observations warrant studies to be conducted in subjects with vascular dementia to investigate if mutations exist in functional Ago2 that correlate with Ago2 syndrome.
5xFAD/Abi3S209F mice display distinct age‐dependent effects on amyloid beta pathology and microglia dynamics
Authors: Butler Claire Ann , O'Gara Katie , Mendoza‐Arvilla Adrian , Milinkeviciute Giedre , Da Cunha Celia , Kawauchi Shimako , Rezaie Narges , Liang Heidi Yahan , Thach Annie , Wang Shuling , Collins Sherilyn , Walker Amber , Shi Kai‐Xuan , Neumann Jonathan , Gomez‐Arboledas Angela , Tenner Andrea J , LaFerla Frank M , Mortazavi Ali , MacGregor Grant R , Green Kim N.
Published: January 2025

Background

In several large genome‐wide association studies (GWAS), genetic polymorphisms of Abi3 have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABI3 along with ABI1 and ABI2, regulate the formation of the WAVE complex which in turn, regulates actin dynamics. ABI3 is highly expressed in microglia in the brain, however, the function of ABI3 in microglia is relatively unknown. In recent studies knock‐out of ABI3 has been shown to exacerbate amyloid beta (Aβ) pathology and associated inflammation. To date, there have been no studies on variant specific effects on amyloid beta pathology.

Methods

To study the effects of ABI3 on the development of Alzheimer’s disease (AD) relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (S212F) into the C57BL/6 mouse genome using CRISPR/Cas9 (S209F). We set out to characterize the Abi3S209F variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, Abi3S209F homozygous, 5xFAD, and 5xFAD/Abi3S209F homozygous. Characterization was performed using histological staining and biochemical approaches at 4‐, 12‐ and 18‐months of age.

Results

5xFAD/Abi3S209F mice displayed an age‐related decrease in dense core‐Aβ plaque burden, characterized by reduced Thioflavin‐S staining, accompanied by changes in fibrillar Aβ (OC) staining, in confocal images of both subiculum and visual cortical regions of 5xFAD/Abi3S209F mice compared to 5xFAD mice. Broadly, microglial numbers mimic plaque load, however by 18‐months of age 5xFAD/Abi3S209F mice display dramatic reductions in IBA1+ microglia number – to levels comparable to WT/Abi3S209F homozygous mice, suggesting a general loss of plaque associated microglia. By 12 months of age, Abi3S209F homozygous and 5xFAD/ Abi3S209F mice displayed increased synaptic density, independent of pathology in visual cortex, subiculum and CA1 regions.

Conclusions

Together, these results characterize the effects of the Abi3S209F missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and synapses. Our data suggests that this mutation may affect microglia dynamics in an age‐dependent manner and may result in dysfunctional microglia at later stages of disease.
Increased fibrin deposition in the brains of individuals with Down syndrome and Alzheimer’s disease
Authors: Du Annie , Flores‐Aguilar Lisi , Edwards Natalie C. , Lao Patrick J. , Ryu Jae Kyu , Akassoglou Katerina , Wilcock Donna M. , Kofler Julia , Ikonomovic Milos D , Lai Florence , Brickman Adam M. , Head Elizabeth
Published: January 2025

Background

Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer’s disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood‐brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma. The blood coagulation factor fibrin promotes immune‐mediated neurodegeneration and is a marker of BBB disruption in a wide range of neurological diseases. This study investigated the severity of fibrin deposition as a measure of BBB integrity in the brains of adults with DS and AD pathology (DSAD). We hypothesized that fibrin deposition is increased in DSAD in comparison to neurotypical controls without DS or AD.

Method

Fibrin immunoreactivity was assessed by free‐floating immunohistochemistry in 30µm tissue sections from the occipital cortex from neurotypical controls (n = 12; 41‐65 years old) and DSAD (n = 12; 46‐66 years old). Using whole slide imaging, brain sections were digitized, and the severity of fibrin deposition was scored using Aperio Imagescope.

Result

Individuals with DSAD display significantly higher fibrin deposition in the white and grey matter of the occipital cortex in comparison to the age‐matched neurotypical controls (p<0.0001).

Conclusion

Neurotypical controls display minimal fibrin deposition in the brain parenchyma and perivascular space. However, compared to neurotypical controls, adults with DS at advanced stages of AD neuropathology display significant fibrin deposition in the occipital cortex, suggesting that the BBB may be compromised in this population.

Funding: NIH U19AG068054, RF1AG079519, P30AG066519 and 23AARFD‐1022715.
Comprehensive Multi‐Neuron Imaging During Aging and Degeneration in C. elegans
Authors: Yadav Dilip , Wirak Gregory , Connor Christopher , Gabel Chritopher
Published: January 2025

Background

Despite the prevalence of Alzheimer’s Disease in the aged human population and advancements in our understanding of the disease at the molecular level, we still lack a fundamental understanding of how cognitive dysfunction stems from alterations in cellular neuron dynamics and how it relates to the normal aging process. To address this gap in knowledge, we measured the breakdown of nervous system function with cellular resolution during normal aging and in an Alzheimer’s Disease model.

Method

Employing comprehensive multi‐neuron florescence microscopy in the nematode worm, C. elegans, a simple yet powerful model animal, we can measure neuron activity across the majority of the animal’s nervous system with single cell resolution. To measure how system‐state dynamics and neuronal connectivity breakdown during normal aging and in the disease model, imaging was performed throughout the animal’s lifespan in wild‐type as well as a transgenic strain in which human amyloid‐β (Aβ) peptide (1‐42) is pan‐neuronally expressed.

Results

During normal aging we measure a breakdown in system‐state dynamics that accompany shifts in activity to higher frequencies and a global loss of inhibitory signaling. In Aβ expressing animals this process is accelerated and includes loss of both inhibitory and excitatory signaling.

Conclusion

Our work is defining the functional degradation of a complete nervous system from single neurons to system‐wide dynamics during normal aging and in the disease model. In doing so we are revealing the specific changes in neuron activity at the cellular level that cause the breakdown of global nervous system dynamics. These results will enable a knowledge‐based approach to novel neurotherapeutic strategies in the treatment and prevention of dementia.
Identification of pathological pathways centered on circRNA dysregulation associated with early pathogenic progression of Alzheimer’s disease
Authors: Wang Feng , Li Yangping , Shen Huifeng , Feng Yue , Yao Bing
Published: January 2025

Background

Circular RNAs (circRNAs) play multifaceted roles to precisely control expression of broad gene networks. These highly stable molecules are often accumulated in the mammalian brain and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the postmortem brains of Alzheimer’s disease (AD). However, whether and how circRNAs dysregulation underlies AD disease progression remain unexplored.

Methods

Poly(A)‐tailing/RNase R digestion was coupled with a recently published computational algorithm called CARP to examine circRNA landscapes alteration and identify functional circRNA‐pathways progressively dysregulated in the cerebral cortex of the 5xFAD mouse model of AD between 5‐ and 7‐month, a critical window for the transition of starting pathology to full manifestation. We have also employed comprehensive biochemical approaches to identify circRNA interactome, as well as short hairpin RNA‐based genetic approaches to manipulate circRNAs and their key regulators to pinpoint their mechanistic contributions to AD.

Results

We discovered genome‐wide alterations of brain circRNAs within the above age window critical for AD progression. Further analysis revealed co‐operation of distinct circRNAs and age‐dependent switch of circRNA isoforms derived from internal alternative splicing and alternative back splicing, which offered new means for regulating miRNA‐mRNA pathways in the 5xFAD cortex. In particular, we focused on conserved circRNAs that were progressively downregulated with increased severity of dementia in human AD brains. During circRNA biogenesis, we identified several previously established AD‐affected splicing factors, such as hnRNPL, regulate the production of AD‐associated circRNAs. Mechanistically, we found these circRNAs contained binding sites for many miRNAs and demonstrated its activity in sponging several AD‐relevant miRNAs to regulate their target mRNAs indicated in AD pathogenesis. Furthermore, we identified multiple circRNA‐interacting RNA binding proteins associated with AD, including the cleavage and polyadenylation factor 6 (CPSF6). In fact, altered polyadenylation efficiency was observed, which results in aberrant upregulation of many known CPSF6 target mRNAs indicated in AD pathogenesis.

Conclusions

Together, our results unveiled pathological brain circRNA landscape alterations within a critical window for phenotypic progression in a mouse model of AD and identified novel molecular mechanisms underlying dysregulation of conserved circRNA pathways that contribute to AD pathogenesis.
Increase the amyloid pathology in meningitis‐induced cognitive impairment: sex differences
Authors: Danielski Lucineia , Giridharan Vijayasree V , Iwunze Ngozi , Catumbela Celso , Morales Rodrigo , Barichello Tatiana
Published: January 2025

Background

Pneumococcal meningitis is a type of meningitis that may face long‐term neurological complications, leading to the hypothesis that it might contribute to the deposition of beta‐amyloid (Aβ) and predispose individuals to Alzheimer’s pathology.

Method

Male and female APP/PS1 mice, 50 days old, were divided into control (n = 5) and meningitis (n = 6). Under anesthesia, an intracisternal injection of either artificial cerebrospinal fluid (CSF) as a placebo or 5 × 109 colony‐forming units (CFU) of S. pneumoniae suspension was injected. Meningitis was confirmed through culture incubation. The Open Field Test (OFT) and Novel Object Recognition (NOR) tasks were conducted when the mice reached 180 days of age; after this, the hippocampus and prefrontal cortex (PFC) were stained to be evaluated by immunofluorescence.

Result

Mice of both sexes experiencing meningitis displayed cognitive impairment (p < 0,001) evaluated for NOR, but the distribution of Aβ burden differed between males and females. Males exhibited elevated Aβ predominantly in the hippocampus (p < 0,05), while females showed heightened Aβ levels exclusively in the PFC (p < 0,05). Interestingly, only females with meningitis showed increased levels of IBA‐1, a marker for microglial reactivity, in both the hippocampus (p = 0,0048) and PFC (p = 0,0023) compared to their controls.

Conclusion

The distinct patterns observed in Aβ distribution and microglial activation between sexes suggest a potential association, indicating that meningitis can induce elevated Aβ deposition, with microglia potentially playing a role in this divergent response.
Cellular overexpression of mutant TDP‐43 results in a decrease in solubility of phosphorylated TDP‐43
Authors: Dopler Matthew B , Cox Keyshawn E , Petersen Tyler L , Abeer Muhammad I , Pressley Juneessa M , Arezoumandan Sanaz , Gitcho Michael A.
Published: January 2025

Background

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by upper and lower motor neuron death that leads to paralysis with the average survival being 3‐5 years after diagnosis. The major pathological protein in ALS is TDP‐43. TDP‐43 becomes hyperphosphorylated and forms inclusions mainly in the cytoplasm. Although only 5‐10% of familial cases are caused by mutations in TDP‐43; over 90% of all sporadic and familial ALS have TDP‐43 pathology. We have developed a cellular over expression model of TDP‐43 aggregation.

Methods

Three familial ALS mutations (A315T, M337V, and S379P) were introduced in the TARDBP gene (3X‐TDP‐43) and cloned into pcDNA 3.1+ then transfected into HEK293 cells. Techniques used: Cell culture, Western blot, immunoprecipitation, immunofluorescence, nuclear/cytoplasmic fractionation, cellular solubility fractionation, and proteomics.

Results

Overexpressing 3X‐TDP‐43 in HEK cells results in an increase in TDP‐43 C‐terminal fragments, time dependent change in TDP‐43 localization from nucleus to the cytoplasm, and an increase in cytoplasmic phosphorylated TDP‐43. We observed reduced solubility of phosphorylated TDP‐43 and a time dependent flux of LC3B and an increase in P62 which may indicate potential autophagy dysfunction. Global shotgun proteomics reveal changes in protein expression in importin subunit alpha‐1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), H2B clustered histone 17 (H2BC17), and protein disulfide‐isomerase A3 (PDIA3). TDP‐43 also interacts in complex with KPNA2 and PDIA3.

Conclusion

This cellular overexpression model shows a change in solubility and aggregation of phosphorylated TDP‐43. Hopefully this model will provide a better understanding of the pathogenesis of TDP‐43 proteinopathies
Polygenic scores for Alzheimer’s disease risk and resilience predict age at onset of amyloid‐β
Authors: O’Brien Eleanor K. , Porter Tenielle , Fernandez Shane , Cox Timothy , Dore Vincent , Bourgeat Pierrick , Goudey Benjamin , Doecke James D. , Masters Colin L. , Rowe Christopher C. , Villemagne Victor L , Cruchaga Carlos , Saykin Andrew J. , Laws Simon M ,   ADOPIC Consortium (AIBL, ADNI, OASIS)
Published: January 2025

Background

Genome‐wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer’s disease (AD) risk, but genetic variation in the onset and progression of AD pathology is less understood. Accumulation of amyloid‐β (Aβ) in the brain is a key pathological hallmark of AD beginning 10 – 20 years prior to cognitive symptoms. We investigated the genetic basis of variation in age at onset (AAO) of brain Aβ by comparing the performance of polygenic scores (PGSs) based on AD risk and resilience with a Aβ‐AAO trait‐specific PGS.

Method

1122 participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) study underwent genome‐wide SNP genotyping and assessment of brain Aβ using positron emission tomography (PET) imaging at two or more timepoints. AAO was the age at which participants were estimated to have crossed the 20 centiloid (CL) threshold for high Aβ. We utilised AD risk and resilience GWAS summary statistics and conducted a GWAS for AAO using a cross‐validation approach (10 test‐validation folds). We used PRSice to identify optimal PGSs for Aβ‐AAO for risk (PGSRisk), resilience (PGSResilience) and Aβ‐AAO (PGSAAO).

Result

PGSRisk and PGSResilience were both significantly associated with Aβ‐AAO, such that higher PGSRisk and lower PGSResilience were associated with an earlier Aβ‐AAO. PGSRisk showed the strongest association and explained more variance in Aβ‐AAO than did PGSAAO. When stratified by APOE ε4 carriage, the strongest genetic risk factor for AD, the association of PGSRisk with Aβ‐AAO was stronger among ε4 non‐carriers, whilst PGSResilience, was more strongly associated with Aβ‐AAO in ε4 carriers.

Conclusion

PGS based on genetic risk and resilience for AD are both significant predictors of the age at which people are estimated to cross the threshold for high brain Aβ burden. Predicting the age at which a person will pass this threshold would enable treatment at an earlier stage, when it may more effectively delay or prevent symptom onset.
Utility of Embic digital cognitive biomarkers in predicting dementia conversion, brain volumetrics, and AD biomarkers in ADNI
Authors: Chen Michelle H. , Hu William T.
Published: January 2025

Background

Early identification of preclinical Alzheimer’s disease (AD) is key to timely interventions. However, existing neuropsychological test scores are not sensitive to subtle cognitive decline during preclinical AD. There is a need to develop cognitive measures that are more sensitive to early stages of decline. Embic digital cognitive biomarkers (DCBs) apply hierarchical Bayesian cognitive processing model to item‐level data of word list memory measures and attempt to delineate latent processes of memory encoding and retrieval, which may be more sensitive to subtle cognitive decline. The current study examined the utility of Embic DCBs in predicting dementia conversion and changes in brain volumetrics, as well as the relationship between AD biomarkers and Embic DCB trajectories.

Method

A total of 2,425 participants (596 were cognitively normal [CN] at baseline, 874 had mild cognitive impairment [MCI] at baseline, and 298 had dementia at baseline) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with at least 3 visits were included in the current study. Cox proportional hazards models were conducted to determine conversion from CN to MCI and from MCI to dementia based on Embic DCB performance. Linear mixed effects models were performed to examine cross‐sectional and longitudinal associations between Embic DCBs and volumes of brain regions involved in memory, as well as Embic DCB trajectories based on cerebrospinal fluid (CSF)‐based AD biomarker profile.

Result

Higher encoding and retrieval performances based on Embic DCBs were associated with increased risks of conversion from CN to MCI and from MCI to dementia. Specifically, measures related to encoding to and retrieval from long‐term “durable storage” were most predictive of conversion. Higher Embic DCB scores were associated with greater hippocampus and entorhinal cortex volumes at baseline, and those with lower Embic DCB scores exhibited greater decline in hippocampus and entorhinal cortex volumes over time. Participants with positive CSF‐based AD biomarkers showed steeper decline in Embic DCBs compared to those who were AD biomarker negative.

Conclusion

The current study provided initial validation of Embic DCBs in predicting MCI/dementia conversion, brain volumetrics, and AD biomarkers in the ADNI sample. Future studies should examine the utility of Embic DCBs in predicting early stages of cognitive decline.
Impact of severe systemic infections on neuroimmune interactions in neurodegenerative diseases
Authors: Villareal Jonathan Anthony B. , Bathe Tim , Phillips Jennifer L , Prokop Stefan
Published: January 2025

Background

Severe systemic infections can trigger cognitive decline, but the underlying mechanisms and their impact on the manifestation and progression of Alzheimer’s disease and other neurodegenerative diseases are poorly understood. The current COVID‐19 pandemic has brought a surge of severe viral illness and highlights the importance of understanding the impact of acute infections on cognition and the manifestation of neurodegenerative disease in survivors. A wealth of observational and clinical data suggests major short‐ and long‐term effects of severe infections on cognition, but detailed and systematic analyses of neuropathological changes after acute infections are scarce. In order to bridge this gap and to provide insight into the cellular and molecular effects of severe systemic inflammation on hallmarks of neurodegenerative diseases, we performed immune profiling on the brains of recovered COVID‐19 patients and of patients without a history of severe systemic infection.

Method

Immunohistochemical profiling of microglial, astrocytic, and oligodendrocytic morphological biomarkers was performed in human post‐mortem tissue sourced from various brain regions. Glial coverage was directly quantified using immunohistochemical analysis software QuPath with custom parameters designed to adapt the program for detecting the different cell types. Multiplexed gene expression analysis of immune and neuroglia‐related genes in human post‐mortem tissue was performed using the Nanostring nCounter platform.

Result

Immunohistochemical profiling of glial cells in COVID‐19 patients revealed a subtle but distinct difference in microglial activation, as well as differences in coverage of other glial sub‐types, as compared to non‐COVID patients, while no significant differences in disease‐associated protein pathologies were observed. Multiplexed gene expression analysis corroborated these findings and also revealed significant shifts in oligodendrocyte and myelination‐related transcriptomic profiles in COVID patients. A spatial component of COVID‐19 was also observed, with a difference in severity of glial population shifts existing between brain regions.

Conclusion

These findings demonstrate a subtle, but distinct and long‐lasting effect of severe systemic infections on the brain’s innate immune system which may impact the onset and progression of neurodegenerative diseases. Gene expression analyses of patients suffering from COVID‐19 also indicate significant alterations in the transcriptome of oligodendrocytes, and further investigation into the cross‐talk between these cells and microglia should be performed.
Large‐scale discovery of novel shared genetic etiology between stroke and neurodegenerative diseases like Dementia, Multiple sclerosis, Parkinson’s Disease, Amyotrophic Lateral Sclerosis
Authors: Khamkar Akhilesh Shailendra , Chauhan Ganesh
Published: January 2025

Background

Stroke, a cerebrovascular condition, and neurodegenerative diseases (ND) like Dementia, Multiple sclerosis, Parkinson’s Disease, Amyotrophic Lateral Sclerosis are major types of neurological disorders, which are associated with increasing global morbidity and mortality burden. But to what extent shared genetic architecture is involved between stroke and ND is unknown.

Method

We investigated shared genetics between stroke (10 subtypes) and ND (6 diseases) using large scale Genome‐Wide Association Study (GWAS) summary statistics data for Cross‐Ancestry, European and South Asian samples including Indians. We used largest GWAS results for AD from EADB and for stroke subtypes from GIGASTROKE consortium. Different computational approaches ‐ LDSC, PLACO, COLOC was used to assess genetic overlap between stroke and ND. Functional annotation and gene‐set enrichment analysis (FUMA) was executed to identify genes and molecular pathways to get detailed insight into shared disease mechanisms between stroke and ND. We performed genetic risk score (GRS) analysis to estimate combined effect of stroke associated genetic variants on ND.

Result

We found negative genetic correlation between Alzheimer’s disease and stroke subtypes (all, ischemic & cardioembolic) at genome‐wide level (correlation coefficient (rg): ‐0.12 to ‐0.26, P value: 0.028 to 0.038) (Table‐1). 23 genetic variations showed association with ND (Alzheimer’s disease, Multiple sclerosis) and stroke subtypes (lacunar, ischemic) at genome‐wide significance level (P<5 × 10‐8). We found 184 causal lead pleiotropic SNPs for stroke‐ND trait pairs (Figure‐1). Biological pathway analysis shows that shared genes are highly enriched in pathways related to immune system, protein catabolism, phagocytosis. Genetic risk scores of stroke subtypes for South Asians including Indian samples shows association with neurodegenerative diseases (beta: ‐0.005 to 0.003, P value: 2.23 × 10‐8 to 0.021) (Table‐2).

Conclusion

This is first study which shows extensive pleiotropy present between stroke and neurodegenerative diseases at genome‐wide level. We found GRS of stroke subtypes for South Asian samples also associated with neurodegenerative diseases which suggest that applicability of GIGASTROKE GWAS data of Indians in prediction of neurodegenerative diseases; despite smaller sample size compared to other ancestries in world. These research findings have strong implication for future development of early diagnosis, prevention and treatment strategies for both cerebrovascular and neurodegenerative diseases.
Brain Connectome Graphs based Machine Learning for Diagnosis of Alzheimer’s Disease
Authors: CHEN Ke , Weng Ying , Dening Tom , Hosseini Akram A. , Zuo Guokun
Published: January 2025

Background

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Early and accurate diagnosis of AD is crucial for patient information, advance planning, and potentially effective intervention and treatment. The integration of machine learning techniques with brain connectome graphs, encompassing both structural and functional brain connectomes, can enhance the accuracy and efficiency of AD diagnosis.

Method

We propose a framework for AD diagnosis using both structural and functional brain connectome graphs with machine learning techniques. Our framework comprises three stages: image pre‐processing, brain connectome graph construction, and machine learning‐based AD diagnosis. We use PANDA and fMRIPrep for image pre‐processing and brain connectome graph construction. The two types of derived graphs, namely brain structural and functional connectome graphs, are then used as joint inputs for graph neural network (GNN)‐based models for AD prediction, including its early stage, and mild cognitive impairment (MCI).

Result

The experiments are performed on diffusion magnetic resonance imaging (dMRI) and functional MRI (fMRI) obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) datasets, displaying promising results with high performance in identifying AD, (MCI), and cognitively normal (CN) patients. Explainable artificial intelligence algorithms are also applied to the model’s predictions for visualizing decision strategies.

Conclusion

The findings of our research contribute to the burgeoning field of neuroinformatics by offering a novel and effective approach to AD diagnosis. The integration of machine learning with brain connectome graphs has potential to provide early and accurate identification of individuals at risk of AD, and pave the way for timely interventions and personalized treatment strategies. Moreover, this study sheds light on the intricate connectome‐level changes associated with AD and fosters a deeper understanding of the disease’s pathophysiology. Ultimately, this research has established a significant step towards leveraging advanced computational techniques to enhance our ability to diagnose and manage AD.
A novel coumarin derivative treatment ameliorates neuroinflammation and cognitive functions in the ICV‐STZ‐induced rat model of Alzheimer’s disease
Authors: SHARMA PRAJJWAL
Published: January 2025

Background

Neuroinflammation has gained substantial attention for its involvement in the progression of Alzheimer’s disease (AD).

Method

Recently, it was discovered that platelets, which make up 90% of the circulatory Aβ, encourage the development of AD. Therefore, we hypothesized to use a novel coumarin derivative PS21HKR, which is believed to possess anti‐platelet and anti‐inflammatory properties for the treatment of AD. We investigated the effects of PS21HKR on STZ induced cognitive decline and neuroinflammation. Intra‐cerebroventricular streptozotocin (ICV‐STZ) (3mg/Kg) induced Wistar rat models of AD were used in the study. Rats were divided into 3 groups including sham, STZ and PS21HKR group.

Result

Behavioural studies revealed that PS21HKR mitigates the cognitive deficit associated with STZ. Anti‐platelet effect of PS21HKR was confirmed by tail vein bleeding assay. Further, in‐vitro studies were performed on BV2 cells including the MTT assay and determination of expression of inflammatory markers. The results suggested that PS21HKR potentially regulated the expression of pro‐ and anti‐inflammatory cytokines.

Conclusion

Therefore, findings of this study indicate that PS21HKR has a potent neuroprotective effect by virtue of its anti‐platelet and anti‐inflammatory activity.
Anti‐saccadic task can distinguish between patients at risk of developing Alzheimer’s disease and cognitively unimpaired patients in a memory clinic
Authors: Ištvánfyová Zuzana Wallin , Nilsson Mattias , Hagman Göran , Kivipelto Miia
Published: January 2025

Background

Early detection is crucial for alleviating Alzheimer’s disease (AD) burden. At present, assessment for early detection of AD is time‐consuming, costly, and often invasive. In recent years, various eye‐tracking methodologies have emerged, and they show promising results in detecting persons at risk of developing AD dementia (ADD). This study aims at identifying suitable anti‐saccadic measures to detect people with early AD.

Method

Preliminary data from 21 cognitively impaired and 45 cognitively unimpaired individuals was collected from a memory clinic (Karolinska University Hospital, Sweden). The data included results from an anti‐saccadic task, neuropsychological tests battery, demographic information, cerebrospinal fluid markers (CSF), and AI‐computed volumetry from magnetic resonance imaging. Median values were calculated on anti‐saccadic measures with the strongest associations to cognition, CSF, and volumetry. The identified measures were proportion of errors (PoE) and latency of a correction saccade (LoCS). Subsequently, the clusters of high and low performers were compared using the Mann‐Whitney U test.

Result

Both PoE and LoCS were able to distinguish between high and low atrophy grade in all cortical brain regions with the highest effect size found in the right cerebral lobe for PoE (U = 266.00, d = 1.36, p < .001) and the right parietal lobe for LoCS (U = 227.50, d = 1.234, p < .002). PoE and LoCS could also distinguish between high and low cognitive function, with the highest effect size for LoCS in verbal delayed recall (U = 210.50, d = 1.061, p < .001) and visual immediate recall (U = 217.00, d = 1.027, p < .001). We did not find any significant differences in the CSF between the clusters.

Conclusion

A brief anti‐saccadic task was able to distinguish between individuals with and without brain atrophies, with PoE capturing atrophy grade with largest effect size. Similarly, the task distinguished individuals with better and worse cognition, with LoCS resulting in largest effect sizes. Our results indicate that both PoE and LoCS have a potential to distinguish individuals at risk of ADD from cognitively unimpaired individuals. Furthermore, the lack of CSF association raises questions about chronology of pathological processes involved in AD.
Lithium as a pharmacological approach to treat behavioral complications in Alzheimer’s disease: a preclinical study
Authors: Singulani Monique Patricio , Camarini Rosana , Talib Leda Leme , Britto Luiz Roberto , Forlenza Orestes Vicente
Published: January 2025

Background

Nearly all individuals with Alzheimer’s disease (AD) develop neuropsychiatric symptoms (NPS). Lithium is a mood‐stabilizer and is efficient in reducing disruptive behaviors in bipolar‐disorder; this characteristic could be an opportunity to investigate the use of lithium in treating behavioral changes in AD.

Method

We tested lithium carbonate treatment in 3xTg‐AD and age‐matched Wild‐type male mice (CEUA/PROCESS: 1605/2020; 4127240122). The drug was administered ad libitum via lithium‐supplemented chow (1.0g Li2CO3/kg of chow; 12‐weeks) from 9‐ to 12‐month‐old. Two behavioral test batteries were performed: (1) open‐field test (OFT), novel‐object recognition test (NORT), elevated zero‐maze test (EZMT), and rotarod test; (2) tail‐suspension test (TST), forced‐swim test (FST), and sucrose preference test (SPT). Immunohistochemistry method was performed to analyze amyloid‐β (Aβ) accumulation (6E10) in areas of the brain. Statistical analysis was performed using two‐way ANOVA followed by Bonferroni post‐hoc test and unpaired t‐test (IBM_SPSS Statistics® software 23). We considered statistically significant p<0.05.

Result

Our results demonstrated that lithium had a significant rescue/prevention effect on anxiety‐ and depression‐related behaviors in AD. In both OFT (F(1, 28) = 37.15; p<0.001) and EZMT (F(1, 28) = 19.44; p<0.001), a suppression in anxiety‐related responses was detected in 3xTg‐AD+Lithium mice versus 3xTg‐AD. Similar results were found in TST (F(1, 28) = 11.70; p<0.01) and FST (F(1, 28) = 7.96; p<0.01) with reduction of depressive‐related behavior. In SPT (F(1, 24) = 17.86; p<0.001), 3xTg‐AD+Lithium mice presented an increase in sucrose preference versus 3xTg‐AD, suggesting benefice effects of lithium on anhedonia signs detected in AD. In NORT, 3xTg‐AD+Lithium mice demonstrated greater index in recognition memory parameter versus 3xTg‐AD, suggesting prevention of short‐ (F(1, 28) = 8.37; p<0.01) and long‐term memory (F(1, 28) = 7.99; p<0.01) in AD. We also reported reduction of nearly 50% in Aβ immunoreactivity in areas such as parietal cortex (F(1, 21) = 571.90; p<0.001), CA1 (F(1, 20) = 357.28; p<0.001), dentate gyrus (F(1, 20) = 417.74; p<0.001), subiculum (F(1, 20) = 7073.19; p<0.001), entorhinal cortex (F(1, 21) = 1562.86; p<0.001), and amygdala (F(1, 22) = 419.79; p<0.001), in 3xTg‐AD+Lithium mice versus 3xtg‐AD; suggesting the neuroprotective action of lithium, which partially explains the positive cognitive and non‐cognitive behavioral changes observed with chronic lithium treatment.

Conclusion

The efficacy of a low‐dose lithium treatment in improving cognitive loss and NPS suggest it as therapeutic potential to treat AD.
Enhancing Single‐Domain Antibody‐Based Protein Degradation for Synucleinopathies
Authors: Jiang Yixiang
Published: January 2025

Background

Synucleinopathies lack cures. Antibody therapies targeting α‐synuclein aim to inhibit aggregation and enhance degradation, but have limited brain entry because of size (150kDa). Smaller single‐domain antibodies (sdAbs, 15kDa) have substantially improved brain uptake. Previously, we developed sdAb‐based probes (2D10 and 2D8) enabling specific α‐synuclein imaging in mice post i.v. injection, correlating with lesion burden, indicating therapeutic and diagnostic potential (Jiang Y et al Sci Adv 2023).

Method

To enhance sdAbs’ efficacy, we developed 2D8‐PEGn‐T (n = 2,4,6), linking 2D8 sdAb and thalidomide (T) with different PEG linkers to promote proteasomal degradation (sdAb‐PROTAC). We assessed sdAb binding affinity to α‐synuclein preparations by biolayer interferometry, examined α‐synuclein degradation in M83‐mouse primary culture, and evaluated therapeutic efficacy in M83‐synucleinopathy mouse model (n = 17). Using 2D10 sdAb linked to a near‐infrared‐tag and In‐Vivo‐Imaging‐System, we assessed brain α‐synuclein burden pre‐treatment. Mice with similar burden received 3 i.v. sdAb injections (molar equivalent: 100 µg of 2D8) 3 days apart, with re‐imaging after 3 days, followed by brain extraction for analyses of α‐synuclein clearance and potential toxicity.

Result

2D8‐PEGn‐T’s affinity after conjugation was comparable to 2D8’s affinity. 2D8‐PEG4‐T targeted α‐synuclein and Cereblon, inducing ubiquitination and proteasomal degradation. In the culture, 2D8‐PEG4‐T prevented α‐synuclein‐induced toxicity and reduced α‐synuclein levels via lysosomal‐ and proteasomal‐pathways, outperforming unmodified 2D8 sdAb that mainly cleared α‐synuclein via the lysosomal‐pathway. In the M83‐synucleinopathy mouse model, 2D8‐PEG4‐T significantly (81%, p = 0.0049) reduced α‐synuclein brain signal, surpassing 32% for 2D8 (p = 0.3195) vs PBS control. Western blots showed 2D8‐PEG4‐T to be more efficacious (89‐93% reduction, p<0.0001) in reducing insoluble total and pS129 α‐synuclein, compared to 2D8 (59‐69% reduction, p = 0.0015 and 0.0016) vs PBS control. Additionally, 2D8‐PEG4‐T decreased soluble total and pS129 α‐synuclein levels by 70% (p = 0.0072) and 90% (p = 0.0001), surpassing 2D8 that did not significantly reduce soluble total (p = 0.8643) or pS129 α‐synuclein (reduced by 34%, p = 0.1018), compared to PBS control.

Conclusion

2D8‐PEG4‐T enhances α‐synuclein proteasomal degradation while maintaining 2D8’s lysosomal clearance. Its superior α‐synuclein clearance, compared to unmodified 2D8 sdAb in vitro and in vivo, highlights its therapeutic potential for synucleinopathies. Small sdAbs with improved brain entry and potency may enhance clinical benefits in antibody‐based therapies.