bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the pathophysiological consequences of TDP‐43 mislocalization in retinal cells
Authors: Sørensen Maja Højvang , Xu Yan , Lee Virginia M.‐Y. , Porta Sílvia
Published: January 2025

Background

Glaucoma is characterized by progressive optic nerve degeneration that results in irreversible blindness, and it can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence suggest that glaucoma shares some common neurodegenerative pathways with Frontotemporal Lobar Degeneration (FTLD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Disease (AD) among others. Interestingly, a recent study revealed the presence of abnormal TAR DNA‐binding protein 43 (TDP‐43) inclusions and aggregates in retinal ganglion cells and other retinal cell types in FTLD‐TDP patients; however, the significance of this pathology and its impact on retinal function and optical nerve integrity is unknown. In these patients, optic nerve degeneration has been linked to the spread of aggregated TDP‐43 beyond the brain. Thus, this study aims to explore the role TDP‐43 mislocalization and aggregation contributes to glaucoma.

Method

The expression of the mutant cytoplasmic human TDP‐43 transgene (hTDP‐43NLSm) in a doxycycline‐regulatable TDP‐43 transgenic mouse line (rNLS8), was induced for 2, 4 and 6 weeks (i.e., Off‐Dox), thus causing a time‐dependent cytoplasmic translocation of TDP‐43 in neurons. rNLS8 mice were euthanized, perfused, and intact eyeballs collected for histological examination. The expression of hTDP‐43 and its phosphorylated form (p409/410) together with cleaved caspase‐3 and p62 was examined by immunohistochemistry in 5 µm paraffin ‐embedded retinal sections.

Result

rNLS8 mice kept Off‐Dox expressed hTDP‐43NLSm in all neuronal layers in the retina, in all the time‐points analyzed. Interestingly, in rNLS8 mice at 6 weeks Off‐Dox, revealed mild phosphorylation of TDP‐43 together with an increase of cleaved caspase‐3 and p62 protein immunoreactivity.

Conclusion

Thus far, this data indicates the activation of apoptotic and autophagy signaling pathways concomitant to the presence of mislocated and phosphorylated TDP‐43. Altogether, this indicates that the rNLS8 transgenic mouse line serves as a good model to evaluate the pathophysiological consequences of TDP‐43 mislocalization in retina cells and its role in optic nerve degeneration.
Co‐methylation network analysis of Psychosis in Alzheimer’s disease
Authors: Kouhsar Morteza P , Weymouth Luke , Smith Adam , Imm Jennifer , Bredemeyer Claudia , Wedatilake Yehani , Torkamani Ali , Bergh Sverre , Selbaek Geir , Mill Jonathan , Ballard Clive G , Sweet Robert , Kofler Julia , Creese Byron , Pishva Ehsan , Lunnon Katie
Published: January 2025

Background

Psychosis (broadly delusions and hallucinations) has a cumulative disease prevalence of around 40% in Alzheimer’s disease (AD). The epigenomic, genomic, and neuropathological data provide powerful evidence that AD+P has a distinct neurobiological profile. Here, we used the weighted gene co‐expression network analysis (WGCNA) method to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 153 post‐mortem brain samples.

Method

Our primary analysis focused on applying WGCNA to the PITT‐ADRC cohort, followed by subsequent replication of its findings in the BDR cohort. The genotype data from PITT‐ADRC and the WGCNA results were further utilized to identify the most significant methylation Quantitative Trait Loci (mQTLs) associated with psychosis. Subsequently, we explored RNA sequencing data from PITT‐ADRC to identify genes affected by the replicated findings uncovered in our primary analysis.

Result

We identified five AD+P‐related modules in the PITT‐ADRC cohort, with one of them being replicated in the BDR cohort. This replicated AD+P‐related module exhibits a high enrichment in the T cell receptor signalling pathway. According to the colocalization analysis results, this module shares significant SNPs in some regions that are also significantly associated with Schizophrenia and Educational Attainment.

Conclusion

Understanding molecular differences between AD and Psychosis at the genetic and epigenetic levels could guide us in discovering appropriate treatments for AD+P cases. To this end, we initiated a comprehensive, large sample‐sized network analysis study based on genetic and epigenetic data.
TA‐RNN: an Attention‐based Time‐aware Recurrent Neural Network Architecture to Predict Progression of Alzheimer’s Disease
Authors: Olaimat Mohammad Al , Bozdag Serdar , Saeed Fahad ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Alzheimer’s Disease (AD) is a widespread neurodegenerative disease with Mild Cognitive Impairment (MCI) acting as an interim phase between normal cognitive state and AD. The irreversible nature of AD and the difficulty in early prediction present significant challenges for patients, caregivers, and the healthcare sector. Deep learning (DL) methods such as Recurrent Neural Networks (RNN) have been utilized to analyze Electronic Health Records (EHR) to model disease progression and predict diagnosis. However, these models do not address some inherent irregularities in EHR data such as irregular time intervals between clinical visits. Furthermore, most DL models are not interpretable. To address these issues, we developed a novel DL architecture called Time‐Aware RNN (TA‐RNN) to predict MCI to AD conversion at the next clinical visit.

Method

TA‐RNN comprises of a time embedding layer, attention‐based RNN, and prediction layer based on multi‐layer perceptron (MLP) (Figure 1). For interpretability, a dual‐level attention mechanism within the RNN identifies significant visits and features impacting predictions. TA‐RNN addresses irregular time intervals by incorporating time embedding into longitudinal cognitive and neuroimaging data based on attention weights to create a patient embedding. The MLP, trained on demographic data and the patient embedding predicts AD conversion. TA‐RNN was evaluated on Alzheimer’s Disease Neuroimaging Initiative (ADNI) and National Alzheimer’s Coordinating Center (NACC) datasets based on F2 score and sensitivity.

Result

Multiple TA‐RNN models were trained with two, three, five, or six visits to predict the diagnosis at the next visit. In one setup, the models were trained and tested on ADNI. In another setup, the models were trained on the entire ADNI dataset and evaluated on the entire NACC dataset. The results indicated superior performance of TA‐RNN compared to state‐of‐the‐art (SOTA) and baseline approaches for both setups (Figure 2A and 2B). Based on attention weights, we also highlighted significant visits (Figure 3A) and features (Figure 3B) and observed that CDRSB and FAQ features and the most recent visit had highest influence in predictions.

Conclusion

We propose TA‐RNN, an interpretable model to predict MCI to AD conversion while handling irregular time intervals. TA‐RNN outperformed SOTA and baseline methods in multiple experiments.
The Ego‐Allo Switching Task for Assessing Visuospatial Memory in Brazilian Old Adults
Authors: Cetraro Victoria Sciascia , Silva Ana Beatriz , Cunha Ana Luiza Nunes , Souza Carolina Pinto , Tumas Vitor , Foss Maria Paula
Published: January 2025

Background

Spatial orientation involves egocentric and allocentric strategies that switch in the brain. Disturbances in switching may indicate Neurocognitive Disorders, which contribute to early detection of Alzheimer’s Disease. The “Ego‐Allo‐Switching Task” (EAST) needs to be adapted for cross‐cultural use in Brazil.

Method

61 participants were divided into Cognitively Healthy Seniors (CHS; n = 21), mild Neurocognitive Disorder (mND; n = 20), and Major Neurocognitive Disorder (MND; n = 20). The EAST was applied to all participants, and CHS individuals were retested within 1‐2 weeks. In this study, we modified the original EAST to better suit Brazilian older adults, considering their unfamiliarity with specific geometric shapes. Thus, we developed an adapted version focused on shape recognition rather than free recall. Before the test, two examiners evaluated all participants using the Clinical Dementia Rating (CDR) to ensure they fit into one of the three groups. The test‐retest reliability was analyzed by intraclass correlation coefficient. Additionally, demographics (age and education) were compared between groups using the Kruskal‐Wallis test, followed by Dunn’s post hoc test and a multivariate linear regression analysis was conducted. All data were analyzed with SPSS 17.0.

Result

The global results of the EAST demonstrated high consistency in the test‐retest comparison (ICCs = 0.84). Initial discrepancies in age and education among CHS, mND, and MND groups (p < 0.001) were corrected using multivariate linear regression. The analysis highlighted distinct EAST performances between groups, as follows: ego‐ego (CHS > mND > MND); alo‐alo (CHS > (mND and MND)); ego‐alo (CHS > (mND e MND)); alo‐ego ((CHS e mND) > MND); EAST total score (CHS > mMD > MND) (Table 1 and 2).

Conclusion

EAST detects changes in spatial orientation skills related to neurodegenerative diseases over time and has temporal reliability. Future research should expand its psychometric properties to Brazilian seniors. This study fills the gap in neuropsychological measures for detecting task‐switching ability.
Current advances in remote and unsupervised digital cognitive assessment in preclinical Alzheimer’s disease
Authors: Polk Sarah E. , Öhman Fredrik , Hassenstab Jason J. , König Alexandra , Papp Kathryn V. , Schöll Michael , Berron David
Published: January 2025

Background

Traditional pen‐and‐paper neuropsychological assessments fail to capture subtle cognitive changes in the early stages of Alzheimer’s disease (AD). Remote and unsupervised digital assessments available on smartphones, tablets, and personal computers may offer a solution to this by increasing the amount and types of data available to researchers and clinicians, while simultaneously improving ecological validity and alleviating patient burden. As these remote and unsupervised digital cognitive assessment tools become more widely available, it is important that they are validated in a systematic way. In this review, we evaluate the validity of available remote tools, focusing on active assessment tools with which the patient interacts with (i.e., cognitive tests, active speech) that have been used to investigate subtle cognitive differences in preclinical AD, defined as clinically unimpaired individuals with biomarkers indicating increased risk of dementia due to AD.

Methods

We performed a systematic literature review on PubMed, Web of Science, and PsycInfo using terms such as “digital,” “remote,” “unsupervised,” “cognition,” “aging,” and “Alzheimer’s,” which resulted in a total of 1,453 unique peer‐reviewed articles and pre‐prints. After filtering for tools that were remotely self‐administered in humans, and excluding papers detailing findings in populations with other diseases than AD (e.g., multiple sclerosis, Parkinson’s disease) or papers reporting findings of intervention studies, 14 papers reporting the use or planned use of 14 tools to detect AD pathology in preclinical AD were selected (as of Jan. 2024).

Results

We evaluate each tool with regards to its use‐case and usability, as well as various types of validity, and suggest a framework with which future tools may also be evaluated. Additionally, we discuss current directions in the field of remote and unsupervised digital cognitive assessment in early AD.

Conclusion

With this review, we hope to show that the systematic and validated use of such tools will increase our understanding of subtle changes in cognition due to AD pathology, as well as make screening for clinical trials and treatment more accessible.
Using polygenic risk scores and APOE e4 to evaluate the risk for Alzheimer’s disease in European ancestry populations
Authors: Lai Dongbing , Zhang Michael , Foroud Tatiana M.
Published: January 2025

Background

APOE e4 has been used to evaluate the risk for Alzheimer’s diseases (AD) but there exist other AD risk genes, and their effects can be collectively measured by polygenic risk scores (PRS). In this study, we sought to use both PRS (APOE excluded) and APOE e4 to evaluate the AD risk.

Method

The discovery dataset was meta‐analysis of three large‐scale European ancestry AD GWAS (Kunkle et al, 2019, the UK Biobank, and the FinnGen consortium). SNPs within 500Kb from transcript starting and ending sites of APOE were excluded. PRS‐CS was used to calculate PRS. Target datasets were European ancestry samples from NIA Alzheimer’s disease centers (ADC, 2,413 cases and 3,423 controls) and All of Us research program (AOU, 1,177 cases and 60,607 controls). Participants having age at onset (cases) or age at the last interview (controls) <60 were excluded. The prevalence of AD were higher in ADC (41.35%) and lower in AOU (1.91%) than those in general populations; therefore, we combined ADC and AOU samples to approximate the PRS distribution in general populations. Then we dichotomized PRS as high (highest 10%) and other (the remaining 90%) based on the PRS distribution of combined sample. Cox proportional hazard model was used to test the effects of dichotomized PRS and e4 genotypes (0, 1, and 2 copies of e4 alleles) by adjusting for sex. Additionally, we performed sex stratified analyses in ADC only as numbers of high PRS and e4/e4 carriers in AOU in either sex were <5.

Result

Results are summarized in Table 1. We used those having other PRS and no e4 as the reference group. In both ADC and AOU, high PRS or e4 were significantly associated with the AD risk (PRS hazard ratios (HRs): 1.31‐1.74, P‐values≤0.01; e4 HRs: 1.39‐8.68, P‐values≤2.80E‐06) but having both substantially increased the AD risk (HRs: 2.07‐14.26, P‐values≤6.80E‐05). In ADC, both high PRS and e4 had larger effects in females than in males.

Conclusion

The effects of PRS were modest and cannot be used alone to evaluate the AD risk; however, PRS can potentially be used with APOE e4 to evaluate the AD risk.
Alzheimer’s Disease patient stratification using iPSC‐derived hindbrain organoids as a novel pre‐clinical tool for drug testing
Authors: Zivko Cristina , Sagar Ram , Xydia Ariadni , Lyketsos Constantine G. , Machairaki Vasiliki
Published: January 2025

Background

By 2050 the number of Alzheimer’s Disease (AD) patients is projected to exceed 150 million worldwide. AD is an incurable, insufficiently understood, and devastating neurodegenerative disease, with high patient heterogeneity in terms of progression, clinical manifestation (including neuropsychiatric symptoms, NPS) and, importantly, responsiveness to treatment options.[1] In the last 20 years, 98% of clinical trials for AD have failed, highlighting the urgent need to drastically change pre‐clinical research to develop better predictors of drug safety and effectiveness.[2]

This is where our precision medicine approach of organoid in vitro models can be a game changer.

Method

Human peripheral blood mononuclear cells from healthy volunteers (n = 6) and AD patient with (n = 12) and without NPS (n = 12) were reprogrammed into induced pluripotent stem cells (iPSCs)[3] and subsequently differentiated into hindbrain organoids, containing serotonin (5‐HT) producing neurons.

Result

Extensive characterization and validation experiments were conducted to assess the quality of the iPSCs and of the 5‐HT‐organoids. These include karyotyping, fluorescent microscopy and flow cytometry to reveal the presence of pluripotency (OCT4, NANOG, TRA‐1‐60) and neuronal markers (TUJ1, TPH2, 5‐HT), real time qPCR, ELISA measurement of 5‐HT levels, size and circularity over 6 weeks of differentiation, for which we developed an in‐house algorithm in Python. The 5‐HT‐organoids were treated with a selective serotonin reuptake inhibitor acutely (1 h) and for 1 week, upon which we could stratify the 30 individuals according to drug responsiveness. Shotgun proteomics analysis was performed on the treated and non‐treated 5‐HT‐organoids from all 30 individuals by LC/MS to reveal distinctive relative abundance profiles. Experiments were run in biologically independent triplicates for 6 cell lines (3 healthy, 3 AD). The results from that training set were used to classify analytical results from the other 24 lines for AD biomarker discovery, as well as for drug responsiveness and effect.

Conclusion

Highly reproducible, people‐specific 5‐HT‐organoids were thus used to study inter‐patient phenotypical variability and drug response diversity in a powerful, novel pre‐clinical tool.

References:

[1] Kim CK et al (2022). J Alzheimers Dis. 2022;87(1):83‐100. https://doi.org/10.3233/JAD‐215699.

[2] Lyketsos CG et al (2011). J. Alzheimers Assoc. 7(5):532‐539. https://doi.org/10.1016/j.jalz.2011.05.2410

[3] Sagar R et al (2023). Cells. 12(15):1990. https://doi.org/10.3390/cells12151990.
Mitochondrial DNA depletion induces AD like phenotypes in neuronal and glial cells
Authors: Molina Carmen Romero , Lysaker Colton R , Roberts Anysja , Gilmore Caleb , See Wen Yi , Liu Yiyuan , Pa Judy , Swerdlow Russell H , Goate Alison M. , Andrews Shea J , Wilkins Heather M
Published: January 2025

Background

Mitochondrial dysfunction is an early and prominent feature of Alzheimer’s disease (AD). We have recently published that lower brain mitochondrial DNA copy number (mtDNAcn) is associated with increased risk of AD neuropathological change and reduced cognitive performance. Here, we addressed how mtDNAcn affects cell‐type specific phenotypes.

Method

iPSC derived neural progenitor cells were infected with a lentivirus encoding a mitochondrial targeted exonuclease under the control of a Tet promoter. mtDNA was depleted with doxycycline and cells were differentiated into neurons or astrocytes using established protocols (StemCell Technologies). iPSC derived astrocyte migration/chemotaxis was measured in the presence of ATP. Microglial BV2 cells were treated with ethidium bromide (etbr) to reduce mtDNAcn. Cells were characterized by RNAseq, ELISAs, Western Blotting, and Seahorse experiments. BV2 cells were challenged with latex beads and zymosan‐pHrodo to analyze phagocytosis. BV2 cells were stimulated with LPS to measure cytokine release. After BV2 stimulation, fresh media was conditioned for 6 hours and collected to treat neurons (SH‐SY5Y) and human primary astrocytes.

Result

mtDNAcn reduction led to reduced oxidative phosphorylation and a mild reduction in proliferation for glial cell types. iPSC derived neurons and astrocytes with mtDNAcn reduction showed increased expression of STING and reduced oxidative phosphorylation. iPSC derived neurons with mtDNAcn reduction showed increased Aβ secretion and changes to tau homeostasis. iPSC derived astrocytes with mtDNAcn reductions had reduced migration/chemotaxis but increased TNFα production. RNAseq data from BV2 cells showed an increase in the hypoxia signature and cellular senescence, coupled with a reduction in biosynthetic process and response to interferon. No changes were observed in phagocytic capacity. However, after LPS stimulation, etbr‐treated cells showed a reduction in the production of IL1B and IL6 cytokines, suggesting an impairment in the response to challenge. Neurons exposed to media from etbr‐treated BV2 cells showed an increase in MAPT and APOE expression.

Conclusion

mtDNAcn reduction can lead to AD pathological hallmarks including changes in Aβ secretion, tau homeostasis, and glial cell phenotypes. mtDNAcn reduction impairs mitochondrial respiration in glial cells, which affects the production of cytokines and leads to cell senescence. Cytokines released by glial cells with reduced mtDNAcn affected neuronal expression of AD‐related genes.
A deep learning‐based deconvolution framework identifies human brain cell‐type specific expression quantitative trait loci (eQTLs) and pathobiology in Alzheimer’s disease
Authors: Dou Lijun , Xu Jielin , Hou Yuan , Cheng Feixiong
Published: January 2025

Background

Cell‐type specific expression quantitative trait loci (eQTLs) can help dissect cellular heterogeneity in the impact of genetic variation on gene expression for Alzheimer’s disease (AD) and AD‐related dementia (ADRD). However, due to the high cost and stringent sample collection criteria, it is challenging to obtain large single‐nuclei RNA sequencing (snRNA‐seq) data with sufficient cohort size to match genotyping data to systematically identify human brain‐specific eQTLs for AD/ADRD.

Method

In this study, we presented a deep learning‐based deconvolution framework on large‐scale bulk RNA sequencing (RNA‐seq) data to infer cell‐type specific eQTLs in the human brains with AD/ADRD. Specifically, we first predicted the brain cell‐type specific gene expression for the harmonized bulk RNA dataset (n = 1,092) from Religious Orders Study and Memory and Aging Project (ROS/MAP). We then incorporated the inferred cell‐type specific gene expression with matched whole genome sequencing (WGS) data from ROS/MAP to identify the brain cell‐type specific eQTLs. These cell‐type specific eQTLs were further colocalized with AD genome‐wide association study (GWAS) findings to discover potential risk genes and druggable targets for AD.

Result

We identified 44,504 genome‐wide significant cell‐type specific cis‐eQTLs (window size = 1Mb, p < 5 × 10‐8) from eight brain cell types, including excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, oligodendrocyte precursor cells, astrocytes, and endothelium. Approximate 2,732 eQTLs in astrocytes and 7,628 in excitatory neurons are identical to the results from a large existing snRNA‐seq data, associated with the regulation of multiple genes (eGenes, e.g., ARL17B, LRRC37A2, ERAP2, PILRB, ZNF266). We illustrated that the GWAS variant rs199456 (AD GWAS: p = 2.57 × 10‐9) co‐localized with its regulatory effect on LRRC37A2, LRRC37A and ARL17B gene expression in excitatory neurons.

Conclusion

In summary, this study presented comprehensive brain cell type‐specific eQTL analysis and identified potential eQTL‐regulated likely causal genes from AD GWAS findings using a deep learning‐based deconvolution framework. It offers an opportunity to efficiently discover the effect of GWAS loci on gene expression at cell type‐specific manners using genotyping data and matched bulk RNA‐seq data instead of costly snRNA‐seq data. Functional validation of candidate eQTLs and associated genes are warranted in the future.
Repurposing drugs that slow down aging for the prevention of Alzheimer’s disease
Authors: Tambaro Simone , Solis Andrea Mosqueda , Tang Bowen , De Oliveira Thais Lopes , Qin Chenxi , Kavsek Alan , Sjölander Arvid , Johnell Kristina , Religa Dorota , Riedel Christian , Nilsson Per , Hägg Sara
Published: January 2025

Background

High age is the biggest risk factor for Alzheimer’s disease (AD). Approved drugs that slow down the aging process have the potential to be repurposed for the primary prevention of AD. The aim of our project was to use a reverse translational approach to identify such drug candidates in epidemiological data followed by validation in cell‐based models and animal models of aging and AD.

Method

Longitudinal samples from a Swedish twin cohort (N = 672) were used to assess the effects of commonly prescribed medications on biological aging. Mendelian Randomization was used to identify associations between genetic variations in the glucagon‐like peptide 1 (GLP‐1) analogues target and the risk of developing AD. The identified classes of compounds were next evaluated in a pipe line of cellular and animal models for their potency of increasing lifespan using C. elegans models expressing amyloidbeta (Aβ) and tau, and for lowering Aβ levels in neuroblastoma SH‐SY5Y cells and AD‐associated pathologies in AppNL‐F knock‐in mice as well as their anti‐aging effects in a novel mouse model of CNS aging.

Result

We found that initiation of calcium channel blockers (CCBs) was associated with about a two‐year decrease in multiple epigenetic clocks (DNA methylation ages) as well as in functional biological ages. Moreover, genetic variants in GLP‐1 targets were associated with lower risk of developing AD. Several of the clinically used CCBs significantly increased the life span in C. elegans Aβ model and decreased levels of secreted Aβ from SH‐SY5Y cells. Several GLP‐1 analogues, similar to the CCBs, demonstrated a positive effect in reducing Aβ42 levels in SH‐SY5Y cell media.

Conclusion

These preliminary data, demonstrating an extension of lifespan and a reduction in Aβ42 production, support the potential repurposing strategy for CCBs and GLP‐1 analogs in slowing down aging and preventing/treating AD. The investigation of these compounds in mouse models of aging and AD will provide a more complete picture of the therapeutic potential and may eventually identify novel preventive measures for AD within CCB and GLP‐1 analogs.
Rare genetic variation in fibronectin 1 (FN1) protects against APOE ɛ4 in Alzheimer’s Disease
Authors: Bhattarai Prabesh , Gunasekaran Tamil Iniyan , Uzrek Bengisu Turgutalp , Reyes‐Dumeyer Dolly , Jülich Dörthe , Lee Annie J. , Yilmaz Elanur , Tayran Huseyin , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Recio Patricia , Flaherty Delaney , Dalgard Clifton L. , Nuriel Tal , Ertekin‐Taner Nilüfer , Dickson Dennis W. , Teich Andrew F , Holley Scott , Mayeux Richard , Kizil Caghan , Vardarajan Badri N.
Published: January 2025

Background

APOEε4 significantly increases the risk of developing Alzheimer’s disease (AD). Cognitively healthy APOEε4‐carriers exist, suggesting potential protective mechanisms against APOEε4. We hypothesized that some APOEε4‐carriers may have genetic variations protecting them from developing APOEε4‐mediated AD pathology. We aim to identify these protective genetic variants.

Methods

Whole genome sequencing (WGS) and cerebrospinal fluid (CSF) proteomics were performed from human cohorts to identify potential protective variants segregating exclusively among APOEε4 carriers. Bioinformatic analyses were performed to select candidate target genes. Immunohistochemistry on postmortem human brain tissues and mouse models expressing human APOE variants were performed along with in‐vivo functional studies in adult zebrafish AD model.

Result

WGS analyses revealed 510 potential gene variants segregating exclusively among APOEε4 carriers, which included rare and loss‐of‐function (LOF) variants. Pathway analysis of these genes showed significant enrichment in extracellular matrix (ECM)‐related processes, suggesting protective effects of LOF in ECM proteins. This was further validated by CSF proteome profiling and subsequent analyses in APOEε4 carriers and non‐carriers. Fibronectin‐1 (FN1) and Collagen‐6A2 (COL6A2) were prioritized as candidate target genes for postmortem validation and in‐vivo functional studies. FN1 protein was increased in APOEε4 carriers resulting in thickened ECM at the basement membrane around the blood vessels, potentially impairing pathology‐induced responses such as clearance and immune system activity. This observation is validated in human brains, mouse models and zebrafish model; therefore, the pathological association of FN1 to AD is evolutionarily conserved. Supporting this hypothesis, in‐vivo functional study in zebrafish model with LOF mutations in fn1b revealed that fibronectin LOF enhanced gliovascular remodeling and microglial activation while reducing astrogliosis, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF.

Conclusion

The vascular deposition of the ECM components FN1 and COL6A2 are increased in APOEε4 carriers. Rare variant in FN1 protect against APOEε4‐mediated pathogenesis in AD. We propose a new disease mechanisms and potential therapeutic intervention targets for vascular contribution to dementia to mitigate the risk of developing AD.
Meningeal and infiltrating T‐cells are associated with neuroinflammation after head injury and with tau pathology in CTE
Authors: Calderazzo Samantha M , Stein Thor D. , Holtzman David M. , McKee Ann C. , Huber Bertrand Russell
Published: January 2025

Background

T‐cell infiltration into the brain parenchyma is associated with hyperphosphorylated tau (p‐tau) accumulation in neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy caused by exposure to repetitive head impacts (RHI). CTE is defined by the perivascular accumulation of p‐tau at the cortical sulcal depths and can be stratified into mild and severe pathological stages. RHI exposure and CTE are associated with progressive microglial inflammation, but the involvement of T cells is unknown.

Method

The dorsolateral frontal cortex from 76 brain donors in the UNITE/ BU ADRC brain bank was analyzed, all men (age 30‐80 yrs), including 19 with mild CTE (stage 1‐2), 24 with severe CTE (stage 3‐4),18 with RHI exposure without CTE, and 19 without RHI exposure or neurodegenerative disease (Table 1). Years of football served as a proxy for the duration of RHI. Multiplex immunofluorescence for T‐cells (CD8 1:20, CD4 1:100), endothelial cells (CD31 1:200), microglia (iba1 1:500, MHC2 1:500), and p‐tau (AT8 1:500) were used. Synaptic markers (PSD95 1:100, Gephyrin 1:200, VGlut 1:1200, VGat 1:1500) were used on adjacent tissue sections to assess synaptic loss. Four regions were annotated: leptomeninges, sulcus (gray matter (gm) in bottom third of gyrus), crest (gm in top third of gyrus), and white matter. Slides were digitally scanned, and HALO software was used to quantify T‐cell numbers and spatial relationships. ANCOVA with posthoc Bonferroni corrections were performed for between group analyses; multivariate linear correlations were utilized for associations between T‐cells and other markers or RHI exposure, all using age as a covariate.

Result

Infiltrating T‐cells were significantly increased at the sulcus in RHI, mild, and severe CTE, with distinct subtypes predominating in RHI and CTE. In addition, T‐cells were correlated with the duration of RHI exposure and synaptic loss. Meningeal and infiltrating T‐cells were notably elevated in p‐tau positive sulci (Fig. 1). Finally, T‐cells were spatially related to CNS‐associated macrophages expressing MHC2, including cortical microglia and meningeal macrophages (Fig. 2).

Conclusion

These data suggest an adaptive immune T‐cell response occurs with RHI exposure, which might be microglia mediated and contribute to tau neurodegeneration in CTE.
The relationship between apoe ε4 and cognitive function and pulvinar medial volume in patients age between 60 to 70 Years
Authors: Wu Jiajing , Wang Jiayu , Li Linlin , Chen Lei , Feng Qiansen , Wang Feiyan , Wang Ziqi
Published: January 2025

Background

To study the morphological characteristics of the thalamus in cognitively normal people with apolipoprotein E epsilon 4 (APOE ε4), and to explore whether it is affected by neuropsychiatric symptoms in patients aged between 60 and 70 years, and to provide evidence for the early brain structural changes in Alzheimer’s disease.

Method

Clinical assessment, neuropsychological assessment, blood text and MRI examination were performed in 101 cognitively normal elderly patients in a tertiary psychiatric memory clinic in Chengdu. The cognitive function and thalamic volume of APOE ε4 carriers (n = 30) and APOE ε4 non‐carriers (n = 71) were compared using an independent sample T‐test. Multiple linear regression was used to analyze the association between thalamic and neuropsychiatric symptoms in APOE ε4 carriers.

Result

The left pulvinar medial and right pulvinar medial volumes were significantly lower in 60 to70 year old APOE ε4 carriers than in non‐carriers (left pulvinar medial P = 0.039, right pulvinar medial P = 0.037). Long delayed recall score was not associated with left pulvinar medial or right pulvinar medial volume in individuals with APOE ε4 carriers (P > 0.05).

Conclusion

The morphological changes of the pulvinar medial structure were associated with APOE epsilon 4 carriers at 60 to 70 years of age. There was no association between neuropsychiatric symptoms and pulvinar medial volume in APOE ε4 carriers.
The effect of non‐pathological aging on behavior, genetics, and epigenetics in mice
Authors: Scheinman Sarah B. , McClarty Bryan , Rodriguez Guadalupe , Carvill Gemma L. , Dong Hongxin
Published: January 2025

Background

Aging is a time‐dependent deterioration of physiological functions that occurs in both humans and animals. Within the brain, aging cells gradually become dysfunctional through a complex interplay of intrinsic and extrinsic factors, ultimately leading to behavioral deficits and enhanced risk of neurodegenerative diseases such as Alzheimer’s disease (AD). The characteristics of normal aging are distinct from those associated with age‐related diseases and it is important to understand the processes that contribute to this pathological divergence. The identification of behavioral, genetic, and epigenetic biomarkers associated with normal aging is key in determining the mechanisms of underlying pathological aging and how these impact AD.

Method

We conducted a comprehensive behavioral assessment of young (3‐month‐old) and aged (18‐month‐old) C57/BL6 mice including locomotion, memory‐relevant, and anxiety‐like behavior to elucidate the cognitive and behavioral phenotypes of aging. We subsequently employed RT‐qPCR to determine synapse‐related gene expression in the prefrontal cortex of mice at both ages, and ChIP to assess age‐related differences in histone acetylation (H3K9ac) at the same genes. Finally, we conducted CUT&RUN sequencing to analyze the relative abundancy of H3K27ac, a histone marker that associates with promoters and enhancers of active genes to determine age‐related changes in epigenomic profiles.

Result

Compared to young mice, aged mice displayed decreased locomotion in the open field (p<0.0001), enhanced anxiety in the elevated plus maze (p = 0.0003), and deficits in the novel object recognition task (p = 0.0011) and novel arm entry task (p = 0.0155). These age‐related behavioral changes occurred in tandem with lower abundancy of H3K9ac at synapse‐related gene promotors nr2a (p = 0.001), glur1 (p<0.0001), glur2 (p<0.0001), and PSD‐95 (p<0.0001), and lower mRNA expression levels of nr2a (p = 0.028), glur1 (p = 0.016), glur2 (p = 0.038), and PSD‐95 (p = 0.0037) in 18‐month‐old mice. CUT&RUN analysis also revealed significant age‐related differences in H3K27ac genome occupancy, including sites associated with synaptic plasticity and neuron function.

Conclusion

These data suggest that non‐pathological aging induces a unique behavioral phenotype that’s associated with alterations in epigenetic markers and gene expression. Future studies will be focused on disentangling epigenetic and behavioral alterations that occur during normal aging from those that occur during pathological aging and aging‐related diseases such as AD.
Elevated amyloid‐ß and tau burden is associated with accelerated cognitive decline on a digital clock drawing test in preclinical AD
Authors: Fu Jessie Fanglu , Robinson Talia L , Alonso Marina Rodriguez , Malave Adela Francis , Jutten Roos J , Healy Brian , Montenegro Grace A Del Carmen , Thibault Emma G , Penney Dana , Davis Randall , Sperling Reisa A , Johnson Keith A , Price Julie C , Rentz Dorene M
Published: January 2025

Background

PET quantifies tau and amyloid‐ß (Aß) pathology in preclinical AD. A 2‐min digital clock‐drawing test (DCTclockTM
) captures clock‐drawing outcomes and processes, potentially more sensitive to cognitive deficits in preclinical AD than pencil‐and‐paper tests. The DCTclock summary score comprised subscores targeting multi‐domain cognitive performance (i.e., Drawing Efficiency, Information Processing, Spatial Reasoning, and Simple Motor). These subscores included unique features reflecting hesitation (pen‐stroke latencies) and speed during the drawing process (Table.1). Previous cross‐sectional study showed worse performance in the Spatial Reasoning domain was associated with high Aß and tau burden in older cognitive normal (CN) participants. This study evaluates whether longitudinal changes in DCTclock performance are associated with Aß and tau burden in preclinical AD, and explores DCTclock features that are most important for such associations.

Methods

A total of 204 CN participants underwent baseline and follow‐up DCTclock assessments, Aß PET ([11C]PiB) and tau PET (Flortaucipir or [18F]MK‐6240, Table.2). Global Aß and regional tau burden were estimated as distribution volume ratios in neocortical aggregate regions and standardized uptake value ratios in entorhinal and inferior temporal using cerebellar gray reference, respectively. Separate linear mixed models examined associations between longitudinal DCTclock and 1) Aß, 2) tau, and 3) Aß and tau burden, adjusted for age, sex, and education. Separate models first examined DCTclock summary scores and domain‐specific subscores. Exploratory analyses then evaluated features within domains showing significant associations.

Results

Elevated baseline Aß or tau is most strongly associated with accelerated decline in DCTclock performance in the Information Processing domain (Fig.1). Evaluating both Aß and tau in a single model, only tau showed significant associations with Information Processing subscores. The associations between DCTclock and Aß or tau were driven by latency features (Information Processing domain), including latency variability, longest latency, and average latency (Table.1). Notably, these features showed improved performance longitudinally in participants without Aß/tau burden, suggesting expected practice effects.

Conclusion

Our results suggest that longitudinal decline in DCTclock performance, especially in information processing or executive function, is related to early Aß/tau burden in older CN adults. Diminished longitudinal DCTclock performance, especially in latency features uniquely captured by digital tools, may reflect greater cognitive efforts in preclinical AD.
The relationship between loneliness, depression and cognition: Evidence from smartphone‐based cross‐sectional and ecological momentary assessment
Authors: Fittipaldi Sol , Teckentrup Vanessa , Rosická Anna M , Lawlor Brian , Gillan Claire M
Published: January 2025

Background

Loneliness is associated with lower cognitive function and may increase dementia risk. However, it is unclear if this effect is mediated by depression. Resolving this issue is important to design effective interventions to promote healthy aging. We adopted a complementary between‐ and within‐person approach, which allowed us to study cross‐sectional relationships as well as the dynamic interactions between loneliness, mood, and cognition in natural environments over time.

Method

A total of 3,416 participants between 18 and 84 years (1,149 male; M age = 45.89±14.55) completed cross‐sectional self‐reported questionnaires of loneliness and depression alongside gamified assessments of memory, processing speed, cognitive flexibility, and planning through a smartphone app, Neureka. A subsample of 286 participants between 18 and 82 years (89 male; M age = 50.14±13.16) also underwent 8‐week ecological momentary assessment (EMA) reporting every 12 hours how lonely and down they felt. We measured cognition at these same timepoints using a recently validated passive measure of cognitive processing speed (digital questionnaire response time, DQRT). Multiple regressions and network analysis were performed to analyze cross‐sectional and EMA data, respectively.

Result

Loneliness and lower cognitive function were associated cross‐sectionally (all ps<.001) except for planning (p = .08). Significant effects did not survive after controlling for depression (all ps>.06). Turning to EMA data, a contemporaneous network analysis showed that within‐person 12‐hour fluctuations in loneliness were related to fluctuations in mood (r = .35, p<.001). However, fluctuations in mood (but not loneliness) were linked to changes in DQRT (r = .13, p<.001). To understand the causal path, we conducted temporal network analysis, which revealed a bi‐directional relationship between loneliness and low mood (β = .08 and β = .06, respectively, both p<.001). In contrast, lower mood predicted slower DQRT 12‐hours later (β = .02, p = 0.03) and not the other way around (β = .005, p = 0.43). In older adults, loneliness and low mood were less related to one‐another, but the relationship between low mood and slower DQRT was stronger.

Conclusion

Depression symptoms mediate the effect of loneliness on cognition, both cross‐sectionally and when assessed within‐person. Older participants show less coupling between loneliness and low mood, but stronger coupling between low mood and slower cognition. Results have implications for differential interventions across the lifespan.
Comparison of Neuro‐cognitive profile of first degree relatives of Alzheimer’s Dementia with other major psychiatric illness
Authors: Singh Arushi , Dayal Pavithra , Bhattacharya Mahashweta , Joseph Mino Susan , Shaktan Alka , Kumar Pramod , Mallappagari Sreenivasulu , Narayana Shruthi , Muthukumaran Moorthy , R Alagarsami A , V Geetha C , Vinod Pratibha , Teotia Vasundhra , Syed Farooq Ali , Utagi Shridhar , Jayasankar Pavithra ,   ADBS Consortium
Published: January 2025

Background

First‐degree relatives of patients suffering from Alzheimer’s Dementia (AD) are at increased risk for developing dementia, yet the associations between family history of AD and cognitive dysfunction remain unclear. Our study aims to understand the intricate interplay between familial risk factors and neurocognitive functioning in AD FDRs versus FDRs of other major psychiatric illnesses by comparing the neuro‐ cognitive functions of unaffected first‐degree relatives (FDR) of patients with AD with unaffected FDR of other major psychiatric illness including Schizophrenia(SCHIZ), Substance use disorders(SUD), Obsessive compulsive disorders(OCD) and Bipolar disorder(BPAD). Subsequently, we also compare the Neuro cognitive performance of FDR’s of AD at baseline and after two years longitudinally.

Method

499 unaffected FDRs (AD‐ 100, SUD – 106, BPAD – 103, OCD ‐94, SCHIZ – 96) were recruited who underwent a comprehensive neuropsychogical battery. The battery includes Digit Span Forward (DSF), Auditory Verbal Learning Test (AVLT), N Back test (NBT) and Color trials (CT) to test for attention, verbal learning, working memory and executive function respectively. Assessments were done twice – at baseline and after two years for FDRs of AD (N = 32). Potential effect modifiers were controlled and generalised linear model was used to compare the neurocognitive functioning of different cohorts. Analysis was adjusted for years of education and gender. Wilcoxon Signed rank test was used to compare the baseline and follow up neurocognitive parameters of AD cohort.

Result

FDRs of AD performed significantly worse in the domains of sustained attention, phonological memory and learning capacity as compared to the other cohorts. However, they performed significantly better in the tests covering verbal working memory, storage capacity and mental flexibility. No significant difference was found when neuro‐ cognitive parameters of FDRs of AD were compared at baseline and 2 years apart.

Conclusion

The current findings provide initial evidence suggesting unsatisfactory performance of the AD FDRs in few domains as compared to others, however the stability of neurocognitive measures longitudinally over a two‐year period suggests the need for further exploration into the complex reciprocity of familial risk factors and cognitive outcomes in at‐risk populations.
Comprehensive aberrations of proteasome complex in Alzheimer’s disease
Authors: Jiang Shan
Published: January 2025

Background

The ubiquitin‐proteasome system (UPS) is the primary protein degrading mechanism in eukaryotes, and is essential for cellular homeostasis. Dysregulation of the UPS has been linked to neurodegeneration through two hallmarks, pathogenic protein aggregation and aberrant proteostasis. However, the molecular changes that alter proteasome functioning in AD are poorly understood. It is also not known whether proteasome dysfunction is a cause or consequence of neurodegeneration. We hypothesized that proteasomes in the AD brain are affected across various levels, including functional attributes, proteomic profile, and transcriptional regulation.

Method

To compare the activities of constitutive proteasome in AD patients samples with confounding factors (such as age and gender) matched controls, we used kinetics assays and native in‐gel activity assays. To compare the abundance changes of constitutive proteasome subunits in AD patients than in controls, we performed proteomics on gel‐isolated and purified proteasomes. To compare the RNA expression changes of constitutive proteasome subunits in AD patients than in controls, we interrogated RNA‐sequencing datasets from brain tissues and iPSC‐derived AD models.

Result

We observed that AD patient samples displayed a decrease in the rate of substrate degradation in kinetics assays compared to the controls. This reduction in activity was further confirmed through native in‐gel activity assays. Proteomics analysis revealed decreased amounts of the proteasome subunits comprising the 20S and 19S particles, accompanied by a considerable proteasomal burden of phosphorylated tau in AD samples. Interrogation of RNA‐seq and snRNA‐seq datasets showed replicable down‐regulation of constitutive proteasome and chaperone genes in brain tissue from early Braak stages. Further analysis attributed this decrease mainly to neurons. Interrogation of RNA‐seq datasets of iPSC‐derived neurons and cerebral organoids showed down‐regulation of constitutive proteasome genes in both Abeta and Tauopathy models than in isogenic controls. Concomitantly, glial cells showed increases in the expression of these genes across Braak stages. The down regulation of assembly chaperones were reflective of the decreased rate of substrate degradation in kinetics assays in AD patients.

Conclusion

Taken together, our results present not only the impairment of the constitutive proteasome in AD, especially in neurons, at RNA and protein expression level, but also the impairment of its functionality.