bluuebunny/crossref_metadata_2025 huggingface dataset:
Preserved unfamiliar face identity discrimination ability in Alzheimer’s disease: electrophysiological evidence
Authors: David Justine , Quenon Lisa , Hanseeuw Bernard J , Ivanoiu Adrian , Koessler Laurent , Rossion Bruno
Published: January 2025

Background

While Alzheimer Disease (AD) patients’ difficulty to recognize face identity (Werheid & Clare, 2007) has been mainly attributed to episodic and semantic memory impairments, these patients can also show abnormal difficulties at matching of unfamiliar faces for their identity, suggesting impaired perceptual function (Lavallée et al., 2016). However, since this latter evidence is based on explicit behavioural measures, the difficulties of AD patients can be due to many factors (e.g., task understanding, stress, motivation, attention, decision making…).

Methods

To obtain an objective and implicit measure of face identity discrimination ability we coupled electroencephalographic (EEG) recordings and fast periodic visual stimulation (FPVS). FPVS consists in the presentation of visual stimuli at a defined frequency that produces EEG responses at the exact same stimulated frequency. 22 diagnosed AD patients (CSF‐positive for AD, MMSE ≤27) and 22 healthy controls matched in sex and age (Fig.1) were tested with a well‐validated FPVS paradigm (>30 published studies) consisting in the presentation of a same identity face 6 times per second (base frequency: 6Hz) with variable other identities presented every fifth image (i.e., oddball frequency: 6/5 = 1.2Hz)(Fig.2). EEG responses at 1.2 Hz reflect an individual’s identity discrimination ability (e.g., Liu‐Shuang et al. 2014, Neuropsychologia; Rossion et al., 2020, Eur. J. Neurosci.).

Results

At the 1.2 Hz oddball frequency and harmonics, a highly significant amplitude response was found at bilateral occipito‐temporal site for both groups (Fig.3; AD: 0.43 µV, p <.001; CTR: 0.58 µV, p <.001). Since this response becomes negligible when the same faces images are presented upside down (AD: 0.02 µV, p>.05; CTR:0.0009 µV, p >.05), the 1.2 Hz response reflect high‐level cognitive processes. ANOVA analyses revealed a significant effect of Condition (i.e., upright vs. inverted; p<.001). However, despite a lower response overall in AD patients (Fig.3), there was no significant effect of Group (p = .53) or interaction (p = .07).

Conclusion

These results provide evidence with an implicit and objective neural measure that unfamiliar face identity discrimination ability is largely preserved in AD, suggesting that abnormal difficulties at matching pictures of unfamiliar faces for their identity in this population is due to other factors than visual discrimination.
NLRP3 genetic polymorphisms are associated with the onset of mild cognitive impairment in Chinese
Authors: Gao Ruonan , Ma Suk Ling
Published: January 2025

Background

Nucleotide‐binding domain and leucine‐rich repeat (LRR)‐containing family protein 3 (NLRP3) is involved in neuroinflammation in Alzheimer’s Disease (AD). Single nucleotide polymorphisms (SNPs) in the NLRP3 gene are associated with the risk of AD in different populations, however the relationship between NLRP3 SNPs and Hong Kong population has not been studied.

Method

In this study,12 intron SNPs and 2 exon SNPs were genotyped in 233 healthy controls and 323 mild cognitive impairments (MCI) patients from Hong Kong. Gene expression levels of NLRP3 and other inflammation‐related genes were evaluated in peripheral blood mononuclear cells (PBMC) from the subjects by quantitative PCR (qPCR).

Result

Our results showed that rs10754558 (C/T) and rs7525979 (G/C) were associated with an increased risk of MCI. The T allele of rs12564791 was associated with higher gene expression level of NLRP3 (p<0.001), IL18 (p<0.001) and IL1beta (p = 0.044) in PBMC. The G allele of rs3806268 was negatively correlated with NLRP3 gene expression (p = 0.048). Functional studies by dual‐luciferase assay showed that rs10754558 G to C mutation and rs10754555 G to C mutation led to a lower relative luciferase activity.

Conclusion

These results suggested that genetic variations of NLRP3 were associated with the cognitive decline. In addition, NLRP3 SNPs might be associated to the gene expression of NLRP3.
Autophagy Deficits Underly Selective Neuronal Vulnerability to Alpha Synuclein Fibrils in Alzheimer’s and Parkinson’s iPSC Derived Neurons
Authors: Abey Ajantha S , Ng Bryan , Heon‐Roberts Rachel , Carlyle Becky C. , Bengoa‐Vergniory Nora , Wade‐Martins Richard
Published: January 2025

Background

Alzheimer’s (AD) and Parkinson’s disease (PD) feature progressive neurodegeneration in a remarkably regionally selective manner. Post mortem studies have posited a role for cell autonomous mechanisms driving this, so we aimed to examine a live human induced pluripotent stem cell (iPSC) model to see whether it can replicate the phenomenon of selective neuronal vulnerability, so to better determine disease mechanisms and therapeutic targets.

Method

iPSC‐derived neurons offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD‐related presenilin‐1 mutations (n = 6), PD‐related leucine rich repeat kinase 2 mutations (n = 6), and isogenic corrected (n = 4) and healthy controls (n = 4) have been differentiated into both cortical and midbrain dopaminergic neurons to enable comparison of pre‐formed fibril induced pathology in different neuronal subtypes from the same patient. We then examined lysosomal number, morphology, degradation, pH, and calcium using live imaging assays, alongside mitochondrial biology, and electrophysiology to understand underlying drivers of vulnerability in the cell types.

Result

Upon insult with alpha‐synuclein PFFs, AD and PD dopaminergic neurons produce substantial Lewy‐like pathology, whereas cortical neurons remain relatively resilient to alpha‐synuclein aggregation, suggesting cell‐type vulnerability. PSEN1‐Intron‐4‐Deletion cortical neurons, however, had significantly elevated pathology. These lines displayed hyperactivity on microelectrode arrays and abnormal lysosomal biology, including increased LAMP1 and dysregulated calcium. PFF‐insulted AD cortical neurons also have impaired neurite outgrowth, while PD cortical neurons are resilient.

Conclusion

These preliminary results show relative vulnerability of AD against PD cortical neurons, and dopaminergic against cortical neurons to alpha‐synuclein aggregates for the first time. These suggest the selective vulnerability to proteinopathy in these diseases is reflected by the iPSC neuronal model and support the notion that cell intrinsic factors like autophagy drive vulnerability.
Crocetin inhibits Aβ aggregation in vitro and reduces ROS production and Aβ mediate cellular toxicity in neuronal SHSY5Y cells
Authors: GK Pratap , Priyadarshini CG Poornima
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by senile plaques, amyloid‐beta (Aβ), and neuroinflammation. The key targets in the treatment of AD are inhibiting the production of amyloid‐beta (Aβ), sphingomyelinase, and inflammation. Among the mechanisms, sphingolipids (specifically Ceramides) are recognized as distinctive mediators associated with the pathology of AD. Reportedly, alterations in sphingolipid metabolism and their metabolites result in mitochondrial dysfunction, autophagy impairment, dysregulation of amyloid‐beta, and disruption of neuronal homeostasis. This leads to increased production of reactive oxygen species (ROS), cytochrome c release, Bcl‐2 depletion, and caspase‐3 activation, primarily through modulation of intracellular signaling pathways, particularly those related to Akt/PKB kinase and mitogen‐activated protein kinases (MAPKs), exacerbating the progression of AD. Several natural compounds such as alkaloids, flavonoids, terpenoids, and phenolics have been reported to exhibit neuroprotective effects targeting various biomarkers including Aβ.

Method

The present study investigates the inhibition of amyloid‐β aggregation, oxidative stress markers (ROS), CD spectra, sphingomyelinase and amyloidogenic activity in vitro of Crocetin, a carotenoid isolated from Gardenia gummifera fruit.

Result

Our results show that crocetin was shown to inhibit aggregation of Aβ1‐40 up to>60%. Compared to Galantamine. Further, attenuation of Aβ1‐40‐induced neuronal toxicity in SH‐SY5Y cells by up to 50% was also observed along with the prevention of reactive oxygen species accumulation.

Conclusion

Overall, these findings suggest that Crocetin may be a promising candidate for the management of AD
Intranasal insulin administration reduces oxidative stress‐induced damage and improves mitochondrial bioenergetics in Alzheimer disease
Authors: Tramutola Antonella , Pagnotta Sara , Domenico Fabio Di , Rolfi Lucrezia Romana , Perluigi Marzia , Barone Eugenio
Published: January 2025

Background

Brain insulin resistance (bIR) heavily impacts on the core pathological processes of aging and Alzheimer disease (AD) since insulin regulates brain metabolism and cognitive functions. A close link among bIR, oxidative stress (OS) and mitochondrial defects exists, that contributes to brain dysfunctions observed in AD. Intriguingly, several studies suggest that intranasal insulin treatment (INI) enhances cognitive performance and reduced AD neuropathology both in humans and murine models of AD. We focused on the interplay between OS and bIR, by testing the hypothesis that rescuing brain insulin signaling activation by INI results in improved mitochondrial functions and reduced OS‐induced damage to proteins in a mouse model of AD (3xTg‐AD).

Method

12‐month‐old 3 × Tg‐AD and wild‐type (non‐Tg) mice were treated with INI (2 UI) or vehicle (saline) every other day for 2 months. Insulin signaling pathway and OS marker levels, i.e., PC, 4‐HNE and 3‐NT were evaluated in the frontal cortex. Then, due to the link between bIR and nitrosative stress, a redox proteomics approach was used to identify specific protein targets of 3‐NT modifications. Mitochondrial functions were evaluated by measuring mitochondrial complexes (OXPHOS) and activities in all experimental groups.

Result

INI administration improved insulin signaling and reduced OS levels in 3xTg‐AD mice. In particular, a consistent reduction of 3‐NT levels was observed. Redox proteomics allowed to identify several proteins with reduced 3‐NT modifications, that belong to key pathways, such as protein degradation and energy metabolism, known to be involved in the progression of AD. Remarkably, reduced 3‐NT levels on mitochondrial proteins were responsible for an improvement of mitochondrial activity and brain energy metabolism.

Conclusion

We propose that INI represents a promising approach to reduce OS‐induced damage to proteins and restore mitochondrial bioenergetics in AD brain.
Pluripotent stem cell based and crispr engineered models of neurodegeneration to assess neuronal networks
Authors: Ahlenius Henrik
Published: January 2025

Background

Stem cell based models of neurodegeneration are emerging as valuable tools to study neuronal networks as well as for drug discovery and testing. Drugs identified using stem cell based models are now entering clinical trials.

Method

We have generated CHMP2B, APP, PSEN and Tau‐mutated and transgenic human embryonic and induced pluripotent stem cell lines, using CRISPR genome editing, with the purpose to create human in vitro disease models. To date, most studies have focused on neuronal alterations; however, we have developed co‐culture systems in which neurons and glia are independently generated from human pluripotent stem cells and combined in vitro. We are now using these models to study neuronal networks and the involvement of astrocytes in FTD and AD.

Result

With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development.

Conclusion

Here we present our improved and updated strategy and results of combining pluripotent stem cells, CRISPR genome engineering and forward programming to generate complex co‐culture models to study neuronal network alterations in cardinal neurodegenerative disorders.
Clinical Phenotypes of Alzheimer’s Disease: Atrophy Patterns and their Pathological Correlates
Authors: Reijner Niels , Frigerio Irene , Bouwman Maud M.A. , Boon Baayla D.C. , Guizard Nicolas , Jubault Thomas , Hoozemans Jeroen J.M. , Rozemuller Annemieke J.M. , Bouwman Femke H. , Barkhof Frederik , Gordon Elizabeth , van de Berg Wilma D.J. , Jonkman Laura E.
Published: January 2025

Background

Recent studies highlight distinct patterns of cortical atrophy between amnestic (typical) and non‐amnestic (atypical, with subtypes: behavioural, dysexecutive, logopenic and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional MRI patterns of cortical atrophy across AD phenotypes, and their association with amyloid‐beta (Aβ), phosphorylated tau (pTau), axonal degeneration (NfL) and microvascular deterioration (COLIV).

Method

Postmortem In‐situ 3DT1 3T‐MRI data was collected for 33 AD (17 typical, 16 atypical) and 16 control brain donors. Images were segmented and AAL3 atlas regional volumes were obtained using QyScore®. At subsequent autopsy, eight brain regions were selected, immunostained for Aβ (4G8), pTau (AT8), Neurofilament‐light (NFL), and Collagen‐IV (COLIV), and quantified using qupath. Group comparisons and volume‐pathology associations were analyzed using linear models and partial correlations with covariates age, sex, postmortem delay, and intracranial volume.

Results

Compared to controls, AD phenotype groups showed overall lower cortical volume, while only minor volume differences were observed between AD phenotype groups, observed primarily in limbic regions (Fig. 1). Across pathological markers, AD phenotype groups showed consistently higher immunoreactivity than controls, while atypical AD showed consistently higher immunoreactivity than typical AD (Fig. 2). Moreover, different patterns of pathology could be observed between atypical subtypes (e.g. distinctly higher pTau load in the occipital gyrus of the visuospatial subtype). In typical AD, global volume loss was associated with lower Aβ and higher pTau, NFL and COLIV immunoreactivity, while in atypical AD, global volume loss was primarily associated with higher NFL immunoreactivity (Fig. 3a). Regionally, AD phenotype differences in atrophy‐pathology association were most pronounced in the (para) hippocampal regions. This distinction was mainly characterized by negative associations for NFL and COLIV, which was only observed in typical AD (Fig. 3b‐c).

Conclusion

Atrophy patterns between AD phenotypes showed only minor differences, potentially attributable to the on average later disease stage of the study cohort. The higher immunoreactivity for pathological markers found in atypical AD might suggest a more severe disease burden. (Para) hippocampal volume decline was associated with axonal and microvascular deterioration in typical AD, but not in the higher pathologically burdened atypical AD group, suggesting a differential susceptibility between AD phenotypes.
SNX19 contributes to neurodegeneration by disrupting the endolysosomal system in neurons
Authors: Ma Liang , Aguirre Luis , Holstein Debroah , Estevez Vanesa , Lechleiter James , Hsieh Jenny , Seshadri Sudha
Published: January 2025

Background

SNX19 is a key player in endolysosomal and autophagy pathways, which have been extensively reported in neuronal dysfunction and neurodegenerative diseases. Although genetic and cellular evidence suggests SNX19 contributes to neuropathology, the underlying mechanisms remain unknown. Here, we propose to study the mechanism in aging postmortem brain tissue at single cell level and model SNX19 in human induced pluripotent stem cell (hiPSCs) derived brain organoids.

Method

We collected human postmortem brain dorsolateral prefrontal cortex (DLPFC) single‐cell RNA‐seq data from Religious Orders Study/Memory and Aging Project (ROSMAP N = 48). We obtained two human induced pluripotent stem cells (hiPSCs).

Result

Single‐molecule in situ hybridization experiments found that SNX19 is highly expressed in neurons, particularly excitatory neurons, compared to glia in human postmortem brains. Our single‐cell RNA‐seq data further demonstrated that SNX19 gene expression is significantly associated with neuritic plaques in excitatory neurons in postmortem brains.

Cerebral organoid technology has made it possible to model human neurophysiology and disease with increasing accuracy in human‐derived tissue cultures. We performed advanced CRISPR gene editing in hiPSCs to knockout SNX19. We then differentiated them into 2D neurons and 3D cerebral organoids to evaluate the SNX19 impact. Our preliminary data has shown that SNX19 knockout can increase synaptic markers’ expression in hiPSC‐derived neurons. We observed morphological changes in SNX19 knockout organoids and replicated the synaptic markers’ change in the SNX19 knockout brain organoids.

Conclusion

Our study identified novel AD factors at SNX19 in human postmortem brains and will define its role in AD using human‐derived tissue cultures.
Copy number variation of whole genome sequence in 1519 patients with Alzheimer’s disease in China
Authors: Shen Lu , Yang Qijie , Xiao Xuewen , Xu Tianyan , Zhu Yuan , Jiao Bin
Published: January 2025

Background

Single nucleotide polymorphism (SNP)‐based genetic studies have identified many risk genes for Alzheimer’s disease (AD), but only explain part of the heritability. Structural variation (SVs) may account for some of this otherwise unexplained heritability. In this study, we sequenced 1,519 AD patients and 2,010 controls using 30X whole‐genome sequencing (WGS).

Method

Using six complementary CNV callers, we generated a high‐confidence CNV set. We reviewed rare variants within the reported 117 causal genes for dementia in our cohort. We also assessed the linkage disequilibrium (LD) between single nucleotide variants (SNVs) and copy number variants (CNVs).

Result

We identified 66990 deletions and 10906 duplications. On dementia genes, we observed the a total of 28 AD patients carried with rare CNVs in APP (duplication, 1 EOAD, Known pathogenicity), OPTN (deletion, 6 AD and 2 control), PRKAR1B (duplication, 1 EOAD), VPS13A (deletion, 1 EOAD), and et al. LD Analysis revealed that a 5.2 Kb deletion in NBEAL1 intron highly LD (R2 = 0.95) with rs139643391 (chr2:202878716) and a 291bp deletion in TMEM106B highly LD (R2 = 0.97) with rs5011436 (chr7: 12229132).

Conclusion

Overall, our findings suggest that the occurrence of APP locus duplication appears to be less common in the Chinese population. Other rare CNV variants in dementia genes may have potentially pathogenic and further validation of their pathogenicity is needed.
Aberrant XIST beyond the inactivated X chromosome modulates the intracellular dysregulation in Alzheimer’s disease
Authors: Sen Somenath , Mukhopadhyay Debashis
Published: January 2025

Background

Recent advances in understanding the regulatory networks implicated in Alzheimer’s Disease (AD) evinces the involvement of long non‐coding RNAs (lncRNAs) as crucial regulatory players. The present study explores the role played by maternally imprinted lncRNA XIST in regulating the sex‐biased prevalence of AD.

Method

With whole transcriptomic sequencing data from the hippocampal RNA of post‐mortem AD brains from humans and APP/PS1 mice, the altered expression of XIST in AD was studied. The data was further validated in an in vitro AD cell model. RNA FISH and subcellular fractionation‐qPCR studies were then performed to trace and quantitate the distribution of XIST in nuclear and cytoplasmic compartments. The nuclear XIST in AD was studied for its altered dynamics with H3K27me3 levels using RNA Immunoprecipitation (RIP)‐qPCR. The fate of the cytosolic XIST was further explored using RIP and miRNA‐lncRNA pull‐down experiments using antibody against RBPMS and biotinylated mimic of miR‐186‐5p.

Result

XIST was found to be significantly upregulated in AD. RNA FISH experiments revealed that XIST from the inactivated X chromosome (Xi) was getting translocated to the cytoplasmic compartment in AD. Upon quantification of the transcript by subcellular fractionation/qPCR, it was found that the heightened XIST expression in AD was due to the ectopic upregulation of the lncRNA in cytoplasm relative to the nucleus. Nuclear XIST on the other hand showed downregulation in AD compared to the control sets. ICC+FISH and RIP studies showed altered dynamics between H3K27me3 levels and XIST in the nucleus in AD. The ectopic XIST was found to be interacting with RBPMS and miR‐186 and knocking down XIST showed opposing effects in the expression levels of RBPMS and miR‐186 in AD. Moreover, RBPMS mRNA was found to be regulated by miR‐186 forming a competitive endogenous RNA (ceRNA) triad modulated by the lncRNA XIST in AD.

Conclusion

This study reports the presence of XIST in cytoplasm in AD for the first time and sheds light on its downstream mechanisms mediated by this aberrant translocation. Studying XIST from the context of AD further allows us to establish the role of this imprinted lncRNA on the gender specific prevalence of AD.
Whole genome methylation sequencing identifies sex‐specific DNA methylation levels in late onset dementia due to Alzheimer’s disease
Authors: Bergmann Phillip E , Madrid Andy , Papale Ligia A , Breen Coleman , Clark Lindsay R. , Asthana Sanjay , Johnson Sterling C. , Keles Sündüz , Hogan Kirk J. , Alisch Reid S
Published: January 2025

Background

Late onset dementia due to Alzheimer’s disease (AD) has a sex‐biased incidence with females comprising nearly two thirds of all cases. Females have a more rapid progression in cognitive decline and higher levels of known AD biomarker pathology compared to men. Genetic sequence variation does not account for the sex‐biased incidence of AD, directing attention to the emerging role of epigenetics in AD. Using whole genome methylation sequencing (WGMS), we previously reported 28,038 differentially methylated position (DMPs) within 2,707 genes between persons with and without AD. Here we report sex‐specific DNA methylation levels in AD.

Method

WGMS data quantified DNA methylation levels at 25,406,945 CpG loci in 281 blood samples from 109 AD (47 female, 62 male) and 174 cognitively unimpaired (CU) individuals (90 female, 84 male) in the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention cohorts. Beta‐binomial regression models were developed to test for significant sex‐specific DNA methylation levels between CU and AD accounting for batch effects, estimated white blood cell proportions, BMI, and age. P‐values were corrected and local false discovery rates (lFDRs) were calculated.

Result

13,293 DMPs were identified in females and 20,719 DMPs were identified in males (Figure 1) when comparing CU and AD (lFDR < 0.05; mean methylation difference > 2.5%). Approximately 2% (280) of the DMPs overlap between sexes with 87 having opposite mean methylation differences. The majority of DMPs annotate to introns (55.9% females; 54.8% males) with most of the remainder intergenic (37.0% females; 37.9% males). Annotation of DMPs to genes identified 1,498 genes that are only differentially methylated in females, and 2,183 genes that are only differentially methylated in males, with 1,365 differentially methylated genes shared between females and males (Figure 2). Gene ontological analyses identified significant enrichment of pathways related to glutamate receptor and ion channel activity in shared gene sets (Figure 3).

Conclusion

33,732 unique, sex‐specific DMPs in AD were identified with more than 60% annotated to one of 5,067 genes. DMP‐associated genes have sex‐specific DNA methylation levels suggesting that these DMPs may play a role in the biased pathogenesis of AD.
A Novel platform for precision quantitative analyses of neuropathology in Alzheimer’s disease
Authors: Keene C Dirk
Published: January 2025

Background

The BRAIN Initiative has stimulated development of novel single cell and spatial molecular approaches to understand human brain structure and function. However, traditional methods for human brain specimen collection, including retrospective archival tissues, have not been optimized for these latest methods. A modernized approach that optimizes tissue quality, anatomical precision, and comprehensive, quantitative neuropathological assessments is needed to maximize the impact of the tremendous investment and remarkable technological advances in human neuroscience research.

Method

We developed a modernized methodology that incorporates rapid neuroimaging, hemibrain embedding in dental alginate, consistently thin (4mm) coronal slicing, and alternating fixation or freezing in supercooled isopentane. Fixed tissues are comprehensively sampled using functionally‐informed, network‐based approach. Traditional neuropathological examination is combined with quantitative neuropathological analysis of digital images of pathologic peptides and markers of neurons, glia, and neuroinflammation. We developed a temporally‐based case series (all donor brains collected during a certain time frame, excluding frontotemporal lobar degeneration) from participants in the UW ADRC Clinical Core and the Kaiser Adult Changes in Thought (ACT) study. Brain regions for examination were chosen to model the temporal progression of AD neuropathology; samples for molecular studies we from adjacent frozen slices.

Result

Eighty‐four brains were included in this study from donors (∼60% female) ranging from no cognitive impairment to dementia. Tissue quality metrics (RIN, pH, PMI) were high, nuclear yields for single cell omics were robust (with rare exceptions), and spatial transcriptomics performed well, with minimal tissue freezing artifact. Traditional neuropathological examination confirmed a spectrum of not to high AD neuropathologic change (ADNC), with a subset of the cohort exhibiting some level of one or more age‐related comorbid pathologies. HALO‐based analysis of digital pathology of beta amyloid, pTau, pTDP‐43, alpha‐synuclein, NeuN, GFAP, and Iba‐1 across cortical layers resulted in an array of quantitative variables which were used to generate continuous pseudo progression scores for the cohort that informed molecular omics analyses.

Conclusion

Development and implementation of improved methods for tissue collection, characterization, and preservation, combined with enhanced sampling and integrated neuropathology, resulted in a robust tissue and data resource to support modern molecular cell‐types and pathway‐based analyses.
The Potential of Non‐invasive Neurostimulation, tDCS for Cognitive Decline in Alzheimer’s Disease: Through the Lens of an Ongoing Clinical Trial
Authors: Vanzyl Jordan , Zhen Ivan , Ha Kevin , Flores Itzel , Taranto Melany , Melecio‐Vazquez Mairim , Ayers Emmeline , Weiss Erica , Zwerling Jessica L , Blumen Helena M , Verghese Joe , Knotkova Helena
Published: January 2025

Background

Transcranial direct current stimulation (tDCS) is a non‐invasive neuromodulation method. Short‐term tDCS protocols have shown positive effects on cognitive outcomes in Alzheimer’s Disease (AD) populations1‐5. Less is known about the long‐term benefits of tDCS on cognition in AD. Here, we discuss the evidence on efficacy of tDCS in AD and the potential of this novel technique applied in home settings6‐8 through the lens of our ongoing long‐term, large‐scale (N = 100) randomized controlled clinical trial in patients with mild‐to‐moderate AD. This RCT aims to determine the effects of tDCS on cognition, mood, quality of life and functional/structural brain connectivity, and to explore the durability of these effects after 9‐months.

Method

Participants age ≥60 years with mild‐to‐moderate stage AD and the ability to provide informed consent are eligible. Participants receiving/have received monoclonal antibody treatment for AD or have history or head trauma or seizures are excluded. Participants are randomized to receive active tDCS at 2mA or sham delivered with two saline‐soaked electrodes placed over the dorsolateral prefrontal cortex for 30 minutes/day, 5 days/week for 6‐months at home.

Result

The study protocol has been developed and approved by the IRB. It includes 6 study visits (V1‐6) over 9 months. Eligible participants undergo in‐person tDCS training (V2), followed by a refresh training and the first tDCS session under supervision of study personnel (V3). Daily tDCS sessions proceed at home for 6 months, with a daily remote supervision via phone/video. Outcome assessments post‐intervention occur at 6, 7 and 9‐months (V4‐6). Our team developed and implemented an enhanced remote monitoring procedure (ERMP) that promotes safety and protocol adherence by monitoring skin condition and allowing for quality checks of electrode placement. The study protocol has been successfully implemented and is ongoing. To date, 101 participants have been consented/screened; of those, 62 were eligible and randomized to apply tDCS at‐home for 6‐months. Enrollment will continue until 2025.

Conclusion

There is preliminary evidence on the potential of tDCS for symptom management in AD. Our study will expand the understanding of the long‐term benefits of tDCS in AD. If effective, this non‐pharmacological intervention could become an important strategy for symptom management in AD patients.
Cellular and molecular changes in a unified and integrated single cell atlas of Alzheimer’s disease across community datasets
Authors: Travaglini Kyle J
Published: January 2025

Background

Numerous studies have identified AD‐associated molecular and cellular changes to the cortex using single nucleus RNA sequencing (snRNA‐seq) and, to a lesser extent, single nucleus ATAC‐seq (snATAC‐seq), applied to millions of cells across hundreds of donors. It has proven challenging, however, to determine whether changes are consistent because of differences in cohort selection, reported clinical metadata, data pre‐processing, cellular taxonomy construction/mapping, and analytical strategies across studies.

Method

We uniformly re‐processed 10 publicly available datasets (Table 1) that had applied snRNA‐seq to 4.3 million cells from the dorsolateral pre‐frontal cortex (DLPFC) of 780 donors. We integrated each of them with SEA‐AD’s multi‐modal, single cell atlas of AD, which contains 4.5 million cells from the middle temporal gyrus (MTG) and DLPFC that were profiled with snRNA‐seq, snATAC‐seq, snMulitome or spatial transcriptomics (MERFISH). We then harmonized clinical data across donors and mapped all cells to the same 139 fine‐grained cell supertypes in SEA‐AD’s shared MTG and DLPFC cellular taxonomy. With common clinical data and cellular labels, we then compared cohorts and data quality across studies as well as identified cellular changes consistently associated with AD.

Result

Cohorts from nearly every study sampled across the spectrum of plaque and tangle pathology, even in those that performed case‐control analyses. With rare exception, the fraction of donors in each cohort with an APOE4 allele, clinically diagnosed dementia, and severe co‐morbidities were also similar. Comparing datasets, SEA‐AD was uniquely successful in profiling both many donors and many nuclei per donor, while deeply sequencing libraries to drive high gene detection. Most importantly though, of the 34 supertypes that were significantly changed in the DLPFC in SEA‐AD, 8 were also significantly changed across external studies with large enough cohorts to power discovery. This included 5 selectively vulnerable Sst interneuron supertypes and 1 Microglia supertype that were changed early in AD in SEA‐AD.

Conclusion

Consistent and early selective loss of Sst interneurons and increase in disease associated Microglia underscore their importance to AD progression. Our integrated dataset provides a valuable common starting point for future comparative analyses from the community and, we hope, will accelerate discovery of novel therapeutic targets.
ADSP Whole Genome Sequencing (WGS) Release 5 data update from Genome Center for Alzheimer’s Disease
Authors: Carter Luke , Leung Yuk Yee , Lee Wan‐Ping , Kuzma Amanda B , Gangadharan Prabhakaran , Nicaretta Heather Issen , Qu Liming , Ren Youli , Valladares Otto , Zhao Yi , Iqbal Taha , Schmidt Michael A. , Mena Pedro R. ,   The Alzheimer’s Disease Sequencing Project (ADSP), Dalgard Clifton L. , Kunkle Brian W. , Bush William S. , Martin Eden R. , Naj Adam C. , Haines Johnathan L , Pericak‐Vance Margaret A. A , Wang Li‐San , Schellenberg Gerald D. ,   Alzheimer’s Disease Sequencing Project
Published: January 2025

Background

The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration and meta‐analysis of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data to facilitate the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated via the collaboration of scientists from the Alzheimer’s Disease Sequencing Project (ADSP) and GCAD. To minimize data heterogeneity introduced by different sequencing protocols and machines, GCAD processes all samples using identical pipelines.

Methods

The raw sequencing data are first mapped to GRCh38/hg38 and variants (SNVs and indels) are called using GATK. Additionally, compact VCF and GDS formatted files are generated to facilitate researchers who want to use smaller pVCFs. SNVs and indels are annotated using the ADSP annotation pipeline. Lastly, structural variants (SV) are called using Smoove and Manta and joint genotyped using GraphTyper2.

Results

The dataset (ADSP Release 5, R5, 2024) includes ∼60,000 genomes from >50 diverse cohorts with 4 major ancestries: 47% Non‐Hispanic White, 29% Hispanic or Latino, 16% Black or African American and 8% Asian. Data are deeply sequenced (average genome coverage: >30x). CRAMs, gVCFs from GATK, and SV VCFs of a subset of the R5 samples (n = 36,361) were deposited into NIAGADS Data Sharing Service (DSS) (https://dss.niagads.org/) for public distribution in 2022, and similarly, the new samples in R5 will be released after the joint call is complete. In addition, joint‐genotype VCFs on SNVs, indels, and SVs will be available. These will undergo full quality control and annotation process.

Conclusion

The ADSP and GCAD generate high quality genotype and SV calls. Currently the project is processing ∼60,000 WGS samples sequenced primarily through the ADSP Follow‐Up Study, which will contain a more ancestrally diverse set of populations. We anticipate this 2024 release will continue to benefit the research community studying AD genetics.
Spatial Transcriptomics Analysis Identifies Glial Signatures Spatially Associated with Neuritic Plaques in Human Post‐Mortem Brains
Authors: Karaahmet Berke , Duquesne Laurine , Sigalov Alina , Yung Christina J , Kroshilina Alexandra , Zhang Ya , Taga Mariko , Klein Hans‐Ulrich
Published: January 2025

Background

Glial cells exhibit distinct transcriptional responses to β‐amyloid pathology in Alzheimer’s disease (AD). While sophisticated single‐cell based methods have revealed heterogeneous glial subpopulations in the human AD brain, the histological localization of these multicellular responses to AD pathology has not been fully characterized due to the loss of spatial information. Here, we combined spatial transcriptomics (ST) with immunohistochemistry to explore the molecular mechanisms in the neuritic plaque niche.

Methods

32 sections from the prefrontal cortices of 15 AD and 2 control cases were applied to ST arrays with spatially barcoded probes (spots) of 55µm diameter. Each of the 59,588 tissue‐covering spots in our dataset detected a median of 2,202 genes and included a median of 4 nuclei. Amyloid plaques were stained with Thioflavin S (ThioS) and astrocytes were stained using GFAP in the same ST tissue section. The immunohistochemistry data were then projected onto the ST profiles.

Results

Clustering the spots reconstructed the cortical layer structure. We detected 263 ThioS+ amyloid plaques, and spots within 150µm of plaques were compared to distant spots (≥500µm), adjusted for cortical layer and donor. This approach identified 182 plaque‐associated genes and confirmed genes previously reported in mice, such as GFAP, CLU, MBP and MOBP. Interestingly, the AD‐related gene SERPINA3 was found to be upregulated at neuritic plaques. SERPINA3 is a marker of an inflammatory astrocyte subpopulation, resembling previously discovered disease‐associated astrocytes in mice. Indeed, computationally deconvoluting this astrocyte subpopulation from the ST data confirmed its enrichment at plaques. Further, we found a downregulation of metallothioneins, expressed by astrocytes, indicating a potential dysfunction of metal ion homeostasis. We validate these results using immunohistochemistry and in situ hybridization.

Conclusions

Here, we demonstrate the heterogeneity in glial communities within the amyloid plaque microenvironment. We show evidence suggesting a spatial enrichment of SERPINA3+ astrocytes at neuritic plaques. Furthermore, the identification of the 182 plaque‐proximal genes suggests involvement of processes related to inflammation, and ion transport and homeostasis. The role of these subtypes and molecular signatures in AD pathophysiology remains to be elucidated.
Predisposition to Alzheimer’s Disease in First‐Degree Relatives: Cognitive Decline, Personality Traits, and Prodromal Neuropsychiatric Symptoms
Authors: Cezar Giovana Benassi , Dias Marcos Josué Costa , Costa Adriana Oliveira , Ferreira Diego Alves , Foss Maria Paula
Published: January 2025

Background

Families with a history of Alzheimer’s Disease (AD) may have a genetic predisposition that raises the risk of developing the condition. However, not all members of these families can undergo genetic testing. Thus, this study aims to evaluate specific cognitive changes, neuropsychiatric symptoms (NPS), and personality traits that may act as early indicators of AD in family members compared to controls.

Method

Fifty participants were divided into two groups for this study: cognitively healthy controls (CG; n = 25) and individuals with first‐degree relatives of AD (GP; n = 25). The education was represented as primary education (PE) from 1 to 9 years, secondary education (SE) from 10 to 12 years, and higher education (HE) from more than 13 years. Both groups underwent a neuropsychological battery (Adapted Background Questionnaire, Subjective Memory Assessment Clinics questionnaire (MAC‐Q), Addeenbroke’s cognitive examination revised (ACE‐R), Personality Factor Battery (PFB) and Mild Behavioral Impairment Checklist (MBI‐C)). Subsequently, the collected data was subjected to statistical analysis using a t‐test, MANOVA, and chi‐square, with a significance level of p≤0.05.

Result

No significant differences between groups were found in age (p = 0.23), sex (p = 1.0), and education (p = 0.45) (Table 1). Except for alcohol consumption, there was no difference in medical history (Table 2). However, significant differences were encountered in ACE‐R (CG = 90.68±5.31; GP = 86±5.84; p = 0.005; d = 0.84) and MAC‐Q (GC = 23.4±3.52; GP = 26.68±3.29;p = 0.001;d = 0.96). In addition, no differences were demonstrated in MBI‐C (GC = 7.4±7.81; GP = 7.44±5.62;p = 0.984;d = 0.01) or the interaction between neuroticism (GC = 3.29±1.24;GP = 3.33±0.78) and conscientiousness (GC = 3.29±1.24;GP = 3.33±0.78;p = 0.94) in PFB (Table 3).

Conclusion

Individuals who are first‐degree relatives of Alzheimer’s Disease patients tend to experience more cognitive complaints and show worse cognitive performance than controls. However, the two groups had no significant differences regarding NPS and personality traits. These findings were observed even after pairing the controls by sex, age, and education.
‘Latent’ mild behavioral impairment as a potential diagnostic strategy for preclinical Alzheimer’s disease: an animal model study
Authors: Forlenza Orestes Vicente , Singulani Monique Patricio , Talib Leda Leme , Camarini Rosana , Britto Luiz Roberto
Published: January 2025

Background

In Alzheimer’s disease (AD) the fact that neuropsychiatric symptoms can predate the onset of cognitive symptoms suggests that greater focus on the non‐cognitive behavioral changes in earlier life could be an opportunity to investigate ‘latent’ mild behavioral impairment (MBI) as a possible diagnostic strategy for preclinical AD.

Method

We used 1‐ and 6‐month‐old 3xTg‐AD male mice and age‐matched wild‐type animals (CEUA‐ICB/USP: 127/2015). Two batteries of behavioral tests were performed: (1) open field test (OFT), novel object recognition test (NORT), and rotarod test; (2) elevated zero maze test (EZMT), forced swim test (FST), and sucrose preference test (SPT). The immunohistochemistry method was performed to analyze amyloid‐β (Aβ) accumulation (6E10) in areas of the brain. Statistical analysis was performed through two‐way ANOVA followed by a Bonferroni post‐hoc test and unpaired t‐test (IBM SPSS Statistics® software 23). We considered statistically significant p<0.05.

Result

In both OFT (F(3, 28) = 22.92, p<0.001) and EZMT (F(3, 28) = 41.72, p<0.001), a rise in anxiety‐related responses was detected in 3xTg‐AD versus Controls mice from an early age. We also detected depressive‐like behavior in 1‐ and 6‐month‐old 3xTg‐AD evaluated by FST (F(3, 28) = 40.88, p<0.001). In SPT, 6‐month‐old 3xTg‐AD presented a decrease in sucrose preference versus Controls of the same age and versus 1‐month‐old 3xTg‐AD (F(3, 28) = 8.77, p = 0.006), suggesting signs of anhedonia at a later age. NORT was applied to evaluate cognition, which showed 6‐month‐old 3xTg‐AD mice were not able to discriminate the novel from the familiar object in short‐ (F(3, 28) = 132.14, p<0.001) and long‐term memory (F(3, 28) = 275.86, p<0.001) versus Controls. The immunoreactivity analysis showed that 6‐month‐old 3xTg‐AD exhibited a significant increase in Aβ versus 1‐month‐old 3xTg‐AD (parietal cortex, p<0.001; hippocampal CA1, p<0.001; dentate gyrus, p<0.001), justifying occurrence of memory impairment at a late age. When analyzing the amygdala, 1‐ and 6‐month‐old 3xTg‐AD showed similar Aβ immunoreactivity (p = 0.2), suggesting that premature accumulation of Aβ in amygdala can be contributed to dysfunction in emotional responses.

Conclusion

Taken together, we propose that anxiety‐like and depressive‐like behaviors can be detected at an early age in 3xTg‐AD mice as a ‘latent’ MBI syndrome, positioning it as a possible diagnostic strategy for preclinical AD.
Interactive association of type 2 diabetes and subclinical CeVD markers with cognitive decline and incident dementia: A memory‐clinic study
Authors: Cui Jiangbo , Chen Christopher , Hilal Saima
Published: January 2025

Background

Association of type 2 diabetes with cognitive decline and incident dementia in older adults remains inconsistent. In this study, we aim to investigate whether subclinical cerebrovascular disease (sCeVD) would modify this relationship.

Method

A total of 654 participants underwent brain MRI at baseline, from whom 592 individuals with at least one follow‐up were selected for longitudinal analysis. Cognitive assessments, including Clinical Dementia Rating Sum‐of‐boxes (CDR‐SOB) and detailed neuropsychological tests, were performed annually for up to 5 years. sCeVD markers of interest were lacunes, white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), intracranial stenosis (ICS), and cortical infarcts.

Result

Diabetes was associated with presence of lacunes, WMHs and ICS in multivariate‐adjusted model. Notably, a significant interaction term (diabetes × WMHs × time) was observed, especially among stroke‐free individuals, suggesting an interactive effect on cognition. Subgroup analyses showed association of diabetes with cognitive decline was stronger in participants with high WMHs but not significant in those with low WMHs. Moreover, participants with both diabetes and high WMHs showed the greatest cognitive decline in CDR‐SOB, global cognition, language, and memory, along with the highest risk of dementia.

Conclusion

Older adults with diabetes compared those without had more sCeVD lesions, and the impact of diabetes on cognitive decline is contingent on the presence of high load WMHs. Our findings suggested that WMHs could be used for risk stratification among older adults with diabetes.
Transcriptomic changes preceding neurodegeneration in a C. elegans model of tau and TDP‐43 co‐pathology
Authors: Jadhav Vaishnavi , Eck Randall , Smukowski Samuel , Toscano Laura Garcia , Latimer Caitlin S , Valdmanis Paul N , Kraemer Brian C. , Liachko Nicole F
Published: January 2025

Background

Alzheimer’s disease (AD), the most common aging‐associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP‐43 as a secondary pathology. Clinically, AD patients with secondary TDP‐43 pathology have more severe cognitive impairment, more rapid cognitive decline, worse brain atrophy, and a shorter disease course. TDP‐43 is already implicated in neurodegenerative disease as the major pathological protein aggregate in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD‐TDP), two other devastating neurodegenerative diseases. In patients with mixed Aβ, tau and TDP‐43 pathology, TDP‐43 dysfunction may synergize with neurodegenerative processes in AD, worsening disease. Using C. elegans models of mixed pathology in AD, we have shown that TDP‐43 specifically synergizes with tau but not Aβ, resulting in enhanced neuronal dysfunction, selective neurodegeneration, and increased accumulation of pathological tau.

Method

To identify cellular responses to mixed tau and TDP‐43, we have identified distinct transcriptomic signatures from two disease‐relevant timepoints preceding frank neuronal loss in C. elegans.

Result

We find that early disease associated changes are driven by tau, but a unique gene expression signature characteristic of co‐morbid tau and TDP‐43 emerges during aging. Using gene ontology and differential splicing analyses, we find significant changes in genes and pathways including lysosomal mediated degradation, lipid metabolism. We have characterized novel modifiers of tau and TDP‐43 identified from their responsive gene expression profiles in tau and TDP‐43 co‐expressing C. elegans.

Conclusion

Establishing early cellular responses to co‐morbid tau and TDP‐43 is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP‐43 in AD.