bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel analysis approach to Mirror Tracing Task performance to detect fine‐grained age‐related differences
Authors: Garrido Pablo F. , Bråthen Anne Cecilie Sjøli , Falch Emilie Sogn , Kransberg Jonas , Sørensen Øystein , Walhovd Kristine B
Published: January 2025

Background

The Mirror Tracing Task (MTT) is a widely known test of motor learning. Participants are required to trace a star looking at their hand as a reflection in a mirror. In this work we introduce a new way of analysis beyond its simplicity.

Method

Three versions of the MTT were employed in this project: paper‐based, online version, and an app version developed in the group, with over 3000 drawn stars and 170 participants. A generalization and standardization of the data is proposed to analyze all the possible stars and regular shapes. The proposed analysis method determines the distance between the drawn path and the mean star (the residuals), and the number of pixels drawn in a certain area (the density). These variables are measured for each unit of angle around the center of the star, providing us richer information about an MTT performance (Figure 1).

Result

Residuals and density were summarized as single values representing the overall MTT performance. The sum of the density for all the angles and the sum of the absolute value of the residuals are used, respectively. They both correlate with the number of times a person draws outside the border, becoming a good alternative to it providing, at the same time, more complex information. Together with task time, these three variables show a clear positive association with age (all p‐values<0.001, see Figure 2). Through the study of the residuals and density as a function of the angle, areas of greatest difficulty for the participants can be identified. Moreover, a more refined analysis indicates that the results obtained in certain areas show a dependence on age (Figure 3).

Conclusion

The proposed analysis provides an innovative approach to a simple task like the MTT. With this method, areas of special difficulty appear with age. These measures could be applied to the study of cognitive decline in aging or dementia, allowing us to look at the evolution of the performance with age and through the different trials.
Structural and functional analysis of TREM2 interactions with amyloid beta reveal molecular mechanisms that drive phagocytosis of oligomeric amyloid beta
Authors: Greven Jessica A , Alexander‐Brett Jennifer M , Brett Thomas J
Published: January 2025

Background

The development of new innovative treatments to prevent and ameliorate Alzheimer’s disease (AD) requires knowledge of molecular mechanisms that are critical to neuronal health. The receptor TREM2 is part of a signaling complex that modulates inflammatory responses, phagocytosis and cell survival in microglia– resident immune cells in the brain that play a critical role in clearing misfolded aggregates such as amyloid beta (Aβ). In recent years, TREM2 has emerged as a promising drug target for AD. Understanding the molecular mechanisms underlying TREM2 signaling in microglia will facilitate the development of specific, safe and efficacious therapies for AD that target TREM2. With this in mind, we set out to determine the structural mechanism for TREM2 phagocytosis of oligomeric Ab (oAb). We utilized comprehensive structural, biophysical, and functional analysis to achieve this goal.

Method

We used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 interactions with oAb42 WT and familial variants. We used X‐ray crystallography to determine the structure of TREM2 in complex with an Ab peptide. We used BLI with structure‐guided TREM2 variants to validate the Ab binding site on TREM2. Finally, we used Ab phagocytosis assays in HMC3 microglia cells for functional investigations.

Result

We found that N‐terminal variants in Ab did not bind TREM2. Using this information, we co‐crystallized a short peptide (Ab 1‐8) in complex with TREM2 and determined the structure. We found that it bound at CDR1 hear the hydrophobic site. This was validated by BLI, and mutations to the TREM2 hydrophobic site ablated binding to oAb42. Finally, we found that the interactions between the N‐terminal region of Ab and TREM2 were critical to drive phagocytosis in HMC3 cells.

Conclusion

Our results indicate that TREM2 uses the hydrophobic site (consisting of the CDR1, CDR2, and CDR3 loops) to engage the N‐terminal region of the Ab42 peptide to drive phagocytosis of oAb42. They also suggest that therapeutics that either directly bind or allosterically alter the hydrophobic site on TREM2 should modulate TREM2 signaling as potential AD treatments.
An AD‐associated variant in TTC3 alters the actin cytoskeleton organization and synaptic function in iPSC‐derived forebrain neurons
Authors: Cukier Holly N. , Duarte Carolina L. , Coombs Lauren , Lambert Caleb Avery , Van Booven Derek , DeRosa Brooke A. , Pericak‐Vance Margaret A , Griswold Anthony J. , Dykxhoorn Derek M.
Published: January 2025

Background

We identified the missense variant Ser1038Cys (rs377155188) in the tetratricopeptide repeat domain 3 (TTC3) gene that segregate in a non‐Hispanic white late onset Alzheimer disease (LOAD) family. This variant is predicted to be deleterious and extremely rare (MAF<0.01%). Expression of TTC3 is decreased in the brains of LOAD patients and negatively correlated with AD neuropathology.

Methods

CRISPR/Cas9 genome editing was used to introduce the TTC3 Ser1038Cys variant into a control iPSC line. induced pluripotent stem cells (iPSCs) were developed that were homozygous for the TTC3 variant and validated for pluripotency. To understand the mechanism(s) by which this TTC3 variant may contribute to LOAD risk, this isogenic pair of edited and unedited iPSCs was differentiated into forebrain neurons and assessed for the cellular, molecular, and transcriptional consequences of this variant, including neuronal morphology, synaptic functionality, and vesicular trafficking.

Results

Neuronal progenitor cells (NPCs) derived from the isogenic iPSC lines showed that TTC3 variant‐bearing cells had elevated migration rates compared to their wild type counterparts as assessed by wound healing assays. Forebrain neurons bearing the Ser1038Cys variant showed elongated neurites and higher numbers of branchpoints compared to the wild type neurons phenocopying the effect of TTC3 loss of function analysis (siRNA‐mediated silencing of TTC3 in mouse neurons). This phenotype could be reversed using small molecule modulators of actin polymerization. Immunoblot analysis showed alterations in the expression of pre‐ and post‐synaptic markers in the TTC3 Ser1038Cys neurons compared to control neurons. RNA‐seq analysis of day 70 neurons identified 978 differentially expressed protein‐coding genes (FDR<0.05), including known AD genes (BACE1, A2M, INPP5F, UNC5C) and genes in AD GWAS loci (ADAMTS1, MAF, NCK2). Pathway analysis identified differential expression in PI3K‐Akt signaling pathway, as well as genes involved in axon guidance, the GABAergic synapse, and the Wnt signaling pathways.

Conclusions

The results of these studies suggest that the TTC3 p.Ser1038Cys variant causes a loss of function leading to alterations in neurite outgrowth, branching, and synapse formation, phenotypes consistent with alterations in actin stability. These studies in iPSC‐derived neurons implicate alterations in actin as potential mechanisms by which TTC3 may contribute to LOAD risk.
Sustained clinically meaningful response in patients with agitation associated with dementia due to Alzheimer’s disease treated with brexpiprazole: post hoc analysis
Authors: Brubaker Malaak , Wang David , Chumki Sanjeda R , Such Pedro , Zhang Zhen , Palma Anton M
Published: January 2025

Background

A reduction in the frequency of agitation behaviors is a clinically meaningful outcome among patients with agitation associated with dementia due to Alzheimer’s disease. This post hoc analysis aimed to determine the percentage of patients treated with brexpiprazole who achieved sustained clinically meaningful response (CMR), over 12 and 24 weeks.

Method

Data for brexpiprazole 2 or 3 mg/day were obtained from two trials of patients with agitation associated with dementia due to Alzheimer’s disease: a 12‐week, randomized, double‐blind, placebo‐controlled trial (ClinicalTrials.gov identifier: NCT03548584) and a 12‐week, active‐treatment extension trial (NCT03594123). According to previous anchor‐ and distribution‐based analyses, a 20‐point reduction from baseline in Cohen‐Mansfield Agitation Inventory Total score represents a meaningful within‐patient change in this population. Hazard ratios (HRs) for non‐response and Kaplan–Meier curves for the cumulative proportions achieving CMR (a 20‐point score reduction) and sustained clinically meaningful response (SCMR; a 20‐point score reduction that was maintained to trial end) were calculated over (A) 12 weeks (data from the randomized trial for brexpiprazole versus placebo) and (B) 24 weeks (data from the randomized + extension trials for ‘prior brexpiprazole’ [i.e., received brexpiprazole in both trials] versus ‘prior placebo’ [i.e., received placebo in the randomized trial and brexpiprazole in the extension trial]).

Result

Over 12 weeks, the percentages of patients achieving CMR were 61.8% for brexpiprazole (n = 225) versus 44.8% for placebo (n = 116); HR = 0.64; p = 0.006. Corresponding percentages of patients achieving SCMR were 49.3% for brexpiprazole versus 32.8% for placebo; HR = 0.58; p = 0.004. Over 24 weeks, the percentages of patients achieving CMR were 81.8% for prior brexpiprazole (n = 159) versus 72.6% for prior placebo (n = 95); HR = 0.63; p = 0.011. Corresponding percentages of patients achieving SCMR were 75.5% for prior brexpiprazole versus 68.4% for prior placebo; HR = 0.59; p = 0.010 (Figure).

Conclusion

Among patients with agitation associated with dementia due to Alzheimer’s disease, a high percentage of patients on brexpiprazole 2 or 3 mg/day achieved sustained clinically meaningful response.
Efficacy of brexpiprazole on agitation in patients with dementia due to Alzheimer’s disease exhibiting behaviors most bothersome to caregivers: post hoc pooled analysis of two randomized controlled trials
Authors: Brubaker Malaak , Wang David , Chumki Sanjeda R , Such Pedro , Zhang Zhen , Palma Anton M
Published: January 2025

Background

Agitation associated with dementia due to Alzheimer’s disease encompasses a wide range of behaviors, including excessive motor activity, verbal aggression, and physical aggression. In a survey of unpaid caregivers living with an individual with Alzheimer’s disease, the “most bothersome” agitation behaviors (which may influence the decision to transfer the patient to long‐term care) were: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention or help, trying to get to a different place, inappropriate dress or disrobing, pacing/aimless wandering, grabbing onto people, and throwing things. This post hoc analysis aimed to determine the efficacy of brexpiprazole on agitation in patients frequently exhibiting these bothersome behaviors.

Method

Data were included from two 12‐week, randomized, double‐blind, placebo‐controlled, parallel‐arm trials of fixed‐dose brexpiprazole in patients with agitation associated with dementia due to Alzheimer’s disease (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Efficacy was assessed using the Cohen‐Mansfield Agitation Inventory (CMAI), which comprises 29 agitation items scored from 1 (never occurs) to 7 (occurs a few times an hour). Least squares mean changes in CMAI Total score from baseline to Week 12 were determined in ten subsamples, each comprising patients for whom a specific “most bothersome” behavior occurred at least once per week (CMAI item score ≥3) at baseline. Data for brexpiprazole 2 or 3 mg/day (FDA‐approved dose) and for placebo were pooled.

Result

The pooled sample comprised 610 patients (brexpiprazole, n = 363; placebo, n = 247). At baseline, the ten “most bothersome” agitation behaviors occurred at least weekly in subsamples ranging from 134 patients (spitting) to 513 patients (pacing/aimless wandering). At Week 12, in the ten subsamples, between‐group least squares mean differences in CMAI Total score change favored brexpiprazole (all p<0.05 versus placebo) (Figure). In 8/10 subsamples, greater improvement for brexpiprazole versus placebo was observed from (at least) Week 8 onwards.

Conclusion

Agitation behaviors that are most bothersome to caregivers of patients with dementia due to Alzheimer’s disease (including excessive motor activity, verbal aggression, and physical aggression) were generally well represented in the brexpiprazole trials. In patients frequently exhibiting these bothersome behaviors, fixed‐dose brexpiprazole 2 or 3 mg/day was associated with larger improvements than placebo.
Metacognition as a tool to differentiate cognitively unimpaired from impaired subjects: judgments of learning in prospective memory task
Authors: Mendes Augusto J. , Ribaldi Federica , Chicherio Christian , Bastien Mathilde , Cappa Stefano F , Kliegel Matthias , Frisoni Giovanni B.
Published: January 2025

Background

Metacognition may give useful insight in early stages of Alzheimer’s disease (AD) continuum. Recent studies suggest differences in the ability of judging their own cognitive performance along clinical stages. For instance, subjects with mild cognitive impairment (MCI) overestimate, whereas people with subjective cognitive decline (SCD) tend to underestimate their cognitive performance. One cognitive function compromised in prodromal AD is prospective memory (PM), which refers to the ability to remember something that has to be done. However, the metacognitive abilities in PM tasks are still not clear when comparing individuals with varying degrees of cognitive impairment.

Method

Our study included 94 subjects from the Geneva Memory Center which are cognitively unimpaired (CU; n = 53), SCD (n = 26), and MCI (n = 15). All subjects performed a PM task with judgements of learning (JOL) to evaluate their metacognition. For that, participants were instructed to memorize a list of pairs of words and to press a specific key if the first word of the pair appeared in a posterior lexical decision task. A one‐way ANOVA tested the differences in PM performance and corresponding JOLs among the three clinical groups. Lastly, the association of PM metacognition with subjective complaints and anxiety levels was tested using Pearson correlations.

Result

The PM ability was significantly different among clinical groups (F = 10.5, p<0.001). Post‐hoc analysis revealed that MCI showed significantly lower PM in comparison with CU (p<0.001) and SCD (p = 0.003). Moreover, the JOL of PM also differed among the three groups (F = 4.5, p = 0.02), namely the MCI group showed lower JOLs in comparison with CU (p = 0.04). Likewise, correlations suggested a significant association between PM‐JOLs and subjective complaints (self‐other; R = 0.33, p = 0.006), whereas the association with anxiety was not statistically significant (p>0.05).

Conclusion

Our study suggested differences in the PM and its JOL between MCI and CU/SCD. However, our study was not able to differentiate between the CU and SCD groups at the PM and the corresponding JOL, even though their difference was significantly correlated with subjective functioning.
Harnessing chromatin loops to identify susceptibility genes in different populations for Alzheimer’s disease: rs3851179 links to PICALM not EED
Authors: Wang Liyong , Xu Wanying , Rajabli Farid , Celis Katrina , Lu Leina , Gearing Marla , Bennett David A. , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Schuck Theresa , Scott William K. , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. , Young Juan I , Jin Fulai , Vance Jeffery M.
Published: January 2025

Background

Annotation of target genes of non‐coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry‐specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi‐C analysis in frontal cortex of African American (AA) and Non‐Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer‐promoter (EP) interactions. In our initial analyses, we applied HiC to uncover the regulatory architecture of rs3851179 linked to the embryonic ectoderm development gene (EED) in the ADSP gene verification list.

Method

Hi‐C libraries were derived from four AA and four NHW donors matched for age, sex, and APOE genotype. The AA samples had 68∼88% African (AF) genome while NHW samples had >95% European (EU) genome. DeepLoop was used to generate robust maps of chromatin loops. Hi‐C data from each population were pooled to generate reference chromatin loop maps for the AF and EU genomes.

Result

rs3851179 (OR = 0.9, P = 3.0 × 10−48) resides between EED and PICALM, about 80 Kb away from both with each gene transcribed in opposite directions. Although PICALM is designated as a causal gene, EED is designated a susceptibility gene by ADSP based on the transcription direction and distance from rs3851179. Hi‐C data from both AF and EU genome in frontal cortex revealed that rs3851179 co‐localizes with a loop anchor, connecting H3K27ac peaks (enhancer) overlapping rs3851179 to the proximal promoter of PICALM, suggesting that PICALM but not EED is the target gene, corroborated by the GTEX e‐QTL data.

Conclusion

This initial application of Hi‐C data demonstrates the utility of chromatin regulatory maps in nominating target genes of GWAS hits in non‐coding loci. The generation and eventual application of Hi‐C maps in African and Amerindian genomes (which are part of the AA or American Hispanic genomic admixture) will be key dissecting ancestry‐specific genetic loci and, thereby, broadening diversity in AD research.
Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer’s Disease in the Alzheimer’s Disease Sequencing Project: study design and methodology
Authors: Kumar Ajneesh , Ray Nicholas R. , Zaman Andrew F , Manoochehri Masood , Stein Colin , Mena Pedro R. , Sweet Robert , Hohman Timothy J. , Cuccaro Michael L. , Beecham Gary W , Huey Edward D. , Reitz Christiane
Published: January 2025

Background

Neuropsychiatric Symptoms (NPS) including aggression, psychosis, anxiety, apathy and depression are highly prevalent in Alzheimer’s Disease patients and are associated with accelerated decline and a detrimental impact on suffering and quality of life of both patients and caregivers. There are no effective pharmaceutical interventions targeting these symptoms, making a better understanding of the etiologic mechanisms underlying NPS in AD critical to develop improved treatments.

Method

To facilitate identification of genetic loci and mechanistic pathways underlying NPS in AD, we have initiated an effort (NIH: U01AG079850) to collate and harmonize all available NPS data in over 70 cohorts (>80,000 samples) of diverse ancestries with whole‐genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP), and analyze these data to identify genetic loci and mechanistic pathways associated with NPS in AD.

Result

A publicly available genomics resource for NPS in AD with extensive harmonized NPS phenotype data. Primary core analyses will (1) identify novel genetic risk factors associated with neuropsychiatric symptoms in AD, (2) characterize the shared genetic architecture of neuropsychiatric symptoms in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of neuropsychiatric symptoms in AD.

Conclusion

Expansion of the ADSP to harmonized and refined NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations.
Spatially defined transcriptomic changes across the hippocampus of J20 mice
Authors: Sander Millie , Lunnon Katie , Ballard Clive G , Brown Jonathan T
Published: January 2025

Background

The J20 mouse is an established model of amyloid pathology, exhibiting neuropathological and behavioural symptoms reflective of human Alzheimer’s disease (AD). Previous work, conducted by Castanho et al (2020), revealed transcriptomic change in the hippocampus of J20 mice to be associated with the accumulation of amyloid pathology. Here, we investigated the spatial distribution of such transcriptomic changes using novel spatial transcriptomic technology.

Method

10µm fresh‐frozen brain slices were collected from the brains of J20 mice and WT controls. Slices were mounted on 10x genomics visium slides and processed according to the manufacturer recommendations. A total of 47 spatial clusters were identified, 6 of which corresponded to the hippocampus. Differential expression analysis was conducted on the hippocampus and sub‐regions of interest (CA1 & CA3 pyramidal cell layers, and dentate gyrus granule cell layer). High dimensional weighted gene co‐expression network analysis (hdWGCNA) was conducted to identify spatially‐resolves networks of co‐expressed genes.

Result

Various differentially expressed genes (DEGs) were identified across the hippocampus of J20 mice compared with WT controls. Many of said DEGs were found to be cluster‐specific, indicating transcriptomic change to be specific to hippocampal sub‐regions. hdWGCNA modules were also highly region‐specific. Many of said genes/hdWGCNA modules, and the associated biological pathways, were associated with AD pathology and behaviour.

Conclusion

Overall, these results demonstrate region‐specific transcriptional changes in the hippocampus of J20 mice compared with WT controls. DEGs and networks of co‐expressed genes were found to be associated with disease‐associated pathways, giving insight into region‐specific pathological changes with disease.
“Polygenic Genetic Risk Factors in Alzheimer’s Disease: A Case‐Control Study in Peruvian Population”
Authors: Zegarra‐Valdivia Jonathan Adrian , Arana‐Nombera Harold Alessandro , Perez‐Fernandez Leandro Aron , Casimiro‐Arana Milagros del Rocio , Alamo‐Medina Reyna Elizabeth , Gallegos‐Manayay Viviana Nayelli , Oliva‐Piscoya María del Rosario , Vásquez‐Zuñe Nobuko , Abanto‐Saldaña Eduardo Sebastián , Ordinola Maria Celinda Cruz , Manrique Carmen Paredes , Renteria Miguel E. , Castro‐Suarez Sheila ,   Neuroscience and Mental Health Group
Published: January 2025

Background

Alzheimer’s Disease (AD) is the most prevalent form of dementia globally. While some familial cases are observed, sporadic AD cases are more common and reflect a high level of complexity, with individual risk determined by the interaction of polygenic and environmental factors.

Objective

To characterize polygenic genetic risk factors in individuals with cognitive impairment and Alzheimer’s Disease across four regions of Peru.

Method

This will be a prospective observational case‐control study. We will identify the neurocognitive profile of participants and collect saliva samples for subsequent genetic profiling. Participants will be divided into three main groups: those with cognitive impairment, those diagnosed with AD, and control subjects over 50 years old without dementia.

Results

We expect to validate the effect of risk variants previously identified in the European population within the Peruvian population. Additionally, the aim is to identify new genetic risk factors specific to the Peruvian population. Collectively, the findings from this study could lay the groundwork for implementing a polygenic risk score model, which would estimate an individual’s genetic risk of developing Alzheimer’s Disease.

Conclusion

This study aims to significantly contribute to the understanding of Alzheimer’s Disease’s genetic underpinnings in the Peruvian population. By exploring both known and novel genetic risk factors, we hope to enhance early detection strategies and personalized risk assessments for AD, ultimately guiding more targeted interventions and preventative measures.
Identification of tau UFMylation in vitro and in vivo
Authors: Yan Tingxiang , Madden Benjamin J. , Murray Melissa E. , Dickson Dennis W. , Springer Wolfdieter , Fiesel Fabienne C
Published: January 2025

Background

UFMylation is an understudied ubiquitin‐like post‐translational modification (PTM). Like ubiquitin, UFM1 is conjugated to substrates via a catalytic cascade involving a UFM1‐specific E1 (UBA5), E2 (UFC1), and an E3 ligase complex (UFL1, DDRGK1 and CDK5RAP3). UFMylation is reversible, and this is mediated by UFSP2. UFMylation plays essential roles in several biological processes including the DNA damage response, endoplasmic reticulum homeostasis, unfolded protein response, autophagic functions, and immune response. Importantly, UFMylation is also crucial for healthy brain development. Alzheimer’s disease (AD), a complex neurodegenerative disorder, is characterized by the accumulation of pathologic tau and beta‐amyloid proteins and has been associated with abnormalities in the aforementioned processes. Intriguingly, the potential link between AD and UFMylation has not been investigated yet. Considering that pathological tau plays a critical role in AD, and tau also plays an important role for the DNA damage response in neurons under physiological conditions, we speculated that tau itself could be modified with UFM1.

Method

We performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2 and other UFMylation pathway components in RIPA‐soluble and insoluble fraction in human post‐mortem frontal cortex. To test whether tau can be modified by UFM1, we performed co‐immunoprecipitation (Co‐IP), Proximity Ligation Assays (PLA) and liquid chromatography‐tandem mass spectrometry (LC‐MS/MS).

Result

We found a significant reduction of soluble UFSP2, but an increase of soluble total UFM1 in AD compared to controls. We found that tau interacts with UFL1 and DDRGK1. In addition, using immunoprecipitation of denaturing lysates we found that tau can indeed be covalently modified by UFM1 when overexpressed. We detected strong signal of HA‐UFM1‐tau in neurons but not in negative controls using PLA. Furthermore, we immunoprecipitated denatured UFM1 from human autopsy brain, and detected two specific UFM1‐tau bands with tau antibodies. Together, this data strongly indicates that tau is UFMylated under endogenous conditions. Using LC‐MS/MS, we identified 17 UFMylation sites in tau proteins.

Conclusion

UFMylation is dysregulated in AD; tau protein can be modified by UFM1 both in vitro and in vivo, which enables a more comprehensive understanding of tau PTMs.
CSF sTREM2 is associated with neuroprotective microglial states early in Alzheimer’s disease and deleterious effects later in the disease trajectory
Authors: Crook Harry , Wahdan Malak , Tuil Marie Emilie , Livingston Nicholas R , Raza Sanara , Nowell Joseph , Edison Paul
Published: January 2025

Background

Neuroinflammation is a key component of Alzheimer’s Disease (AD) pathology. Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial to microglial involvement in AD, mediating trem2‐dependent activation and Disease‐Associated Microglia (DAM) polarization. However, GWAS revealed that loss‐of‐function mutations of its encoding gene are an important risk factor for AD. There is mounting evidence supporting a biphasic microglial response in AD trajectory, and such contrasting effects would support this.

We evaluated the influence of cerebrospinal fluid soluble TREM2 (CSF sTREM2) on AD pathology in healthy, Mild Cognitive Impairment (MCI), and AD patients.

Method

Patients were grouped by diagnosis and each group segmented according to amyloid and tau, into amyloid‐positive (Aβ+) and negative (Aβ‐), and tau‐positive (tau+) and negative (tau‐). We used a combination of CSF biomarkers and positron emission tomography (PET) scans to assess neuropathological substrates of AD: CSF p‐tau181 for tau pathology, CSF Amyloid‐β 42 (Aβ42) and 18F‐florbetapir (18F‐AV45) PET scans for amyloid deposition, and magnetic resonance imaging (MRI) scans for neurodegeneration.

Result

We observed higher sTREM2 levels in Aβ+/tau+ AD compared with Aβ+/tau‐ AD and Aβ‐/tau‐ MCI patients. Likewise, Aβ+/tau+ MCI patients showed higher sTREM2 than Aβ‐/tau‐MCI patients. Furthermore, sTREM2 levels were negatively associated with cortical volume in MCI and AD, and with MMSE scores in AD.

sTREM2 was positively associated with CSF p‐tau181 in all groups except Aβ+ controls. However, a positive association with CSF Aβ42 was only observed in the Aβ‐ control and the Aβ+ and Aβ‐ MCI groups. Similarly, sTREM2 was positively correlated with amyloid load (18F‐AV45 uptake) in controls and MCI patients yet negatively correlated in the AD group.

Conclusion

The MCI and AD stages of the disease showed contrasting associations between sTREM2 and neuroimaging markers for AD pathology. These suggest diverging effects of the microglial response along AD trajectory, with a neuroprotective phase in early AD and a neurotoxic one later on. This could indicate that microglia polarize first towards an anti‐inflammatory phenotype before switching to a pro‐inflammatory one as neuropathology progresses.
Exploring the Relationship Between Adipose Tissue and Alzheimer’s Disease Pathogenesis
Authors: Bettinetti‐Luque Miriam , Trujillo‐Estrada Laura , Andreo‐Lopez Juana , Campos‐Moreno Cynthia , Fatuarte‐Juli Ivan , Morales‐Cabello Mario , Da Cunha Celia , Sanchez‐Mejias Elisabeth , LaFerla Frank M , Gutierrez Antonia , Baglietto‐Vargas David
Published: January 2025

Background

Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of visceral adipose tissue. Here, we hypothesize that the visceral adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders.

Method

We used histological stains, immunohistochemistry and biochemical means to determine changes in the visceral adipose tissue from WT and db/db mice. Moreover, similar techniques were used in 3xTg‐AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology.

Result

Our study shows that recipient 3xTg‐AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg‐AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL‐1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg‐AD mice from db/db fat pads compared to 3xTg‐AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity.

Conclusion

Overall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and obesity/diabetes type II through visceral adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.

This study was supported by Minister of Science and Innovation grant PID2019‐108911RA‐100 (D.B.V.), Alzheimer’s Association grant AARG‐22‐9282/9, Beatriz Galindo program BAGAL18/00052 (D.B.V.), University of Malaga grant PPIT.UMA.B1‐2021_32(LTE) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co‐financed by FEDER funds from European Union.
A systematic review with meta‐analysis of the GABAergic system in transgenic rodent models of amyloidosis and tauopathy
Authors: Mensch André Nunes , Carello‐Collar Giovanna , Ramos Vanessa G. , Bellaver Bruna , Ferreira Pamela C.L. , Rosa‐Neto Pedro , Pascoal Tharick A. , de Bastiani Marco Antônio , Zimmer Eduardo R.
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid‐β (Aβ) plaques and tau tangles in the brain, and neurotransmission dysfunctions. Indeed, our group recently demonstrated that the γ‐aminobutyric acid (GABA)ergic system is vulnerable to AD pathology in humans. However, whether this vulnerability is also present in AD rodent models is still unknown. Thus, we aimed to examine the GABAergic system in rodent models of amyloidosis and tauopathy.

Method

We systematically reviewed the literature following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABA transporters (GAT), and GABAA and GABAB receptors in the brain of 3xTg‐AD, 5xFAD, APP/PSEN1, McGill‐R‐Thy1‐APP, Tg2576, TauPS2APP, TgCRND8, APP SweDI, and hAPP‐J20 AD rodent models. Then, we performed a random‐effects meta‐analysis of standardized mean differences (SMD) using the metafor and metaviz packages in R (FDR‐adjusted p‐value < 0.05).

Result

The search identified 3,631 articles and 27 met the inclusion criteria (Table 1 and Figure 1A). The systematic review showed decreased levels of GAD65/67 in the hippocampus, dentate gyrus, and hilus of TauPS2APP, hippocampus of TgCRND8, hippocampus and cortex of APP SweDI, and suprachiasmatic nucleus of Tg2576 mouse models. However, no differences in the cortex and cerebellum of APP/PSEN1 and hippocampus of hAPP‐J20 mice were found (Figure 1B). APP/PSEN1 had decreased vGAT in the hippocampus and increased in cortex (Figure 1B). GABAA receptors (Figure 1B) were decreased in APP/PSEN1 mice, while GABAB receptors (Figure 1B) remained unchanged. Due to insufficient number of studies, we meta‐analyzed only GABA. There were no differences in GABA levels in the cortex of APP/PSEN1 and Tg2576 mouse models (Figures 2A and 2B, p = 0.226 and 0.968, respectively), and in the hippocampal GABA levels in 5xFAD mice (Figure 2C, p = 0.924).

Conclusion

Here, we show decreased levels of GABAergic synthesis enzymes and GABAA receptors, and alterations in GABA transporters in AD rodent models. By contrast, there were no changes in GABA levels and GABAB receptors. Our results suggest that the AD rodent models recapitulate the GABAergic system vulnerability seen in human AD.
HSV1 infection elicits distinct immune responses in microglia and macrophages
Authors: Singal Chitra Mohinder Singh , Bradshaw Elizabeth M , Elyaman Wassim
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common form of dementia. The neurotropic virus herpes simplex virus 1 (HSV1) has been linked to the pathogenesis of AD. While ∼65% of the US population is infected with HSV1, in the majority of cases the virus is dormant and infected individuals are asymptomatic. HSV1 infects immune cells such as macrophages and microglia, essential components of the innate immune response that are involved in neuroinflammation and neurodegeneration in AD.

Method

Monocytes were isolated from PBMCs of healthy donors and differentiated into macrophages and monocyte‐derived microglia‐like cells (MDMi) in the presence of stimulatory cytokines for 6 days and 10 days respectively. The differentiated cells were infected with HSV1 and the cytokine profiles were measured by the LegendPlex assay. Additionally, fluorescently‐labeled Abeta1‐42 uptake was analyzed after 24 hours of infection.

Result

There was a significant increase in several inflammatory cytokines including IL‐4, IL‐6, TNFα, and IP‐10 in macrophages, whereas there was no significant change in MDMi after 4 or 24 hours of infection. Interestingly, Abeta1‐42 uptake in HSV1‐infected macrophages was decreased compared to their controls, whereas in HSV1‐infected MDMi, there was an enhancement of Abeta1‐42 uptake.

Conclusion

Macrophages exhibit an enhanced inflammatory response in contrast to microglia upon HSV1 infection and an opposite reaction in Abeta1‐42 uptake. Our findings indicate distinct responses of these two cell types to HSV1 infection, providing novel insight into our understanding of their unique tissue‐specific roles.
Investigating the Role of Mitochondrial DNA in Alzheimer’s Disease Biomarker Expression
Authors: Kemna Riley E , Weidling Ian , Kueck Paul J , Johnson Chelsea N , John Casey S. , Swerdlow Russell H , Wilkins Heather M , Morris Jill K
Published: January 2025

Background

Impaired metabolic function and mitochondrial metabolism increase risk of Alzheimer’s Disease (AD) development, which is the leading form of dementia and one of the main causes of death in older adults. Altered mitochondrial function can reduce efficiency of cellular maintenance processes like mitophagy and proteostasis, leading to protein aggregation and cytotoxicity. Mitochondria differ from other organelles, as they have their own unique genetic component (mtDNA), which encodes proteins essential for mitochondrial translation and oxidative metabolism. Differences in mtDNA between individuals affect mitochondrial function and can increase risk of certain diseases; it is not well studied how mtDNA impacts AD pathology.

Method

SH‐SY5Y cytoplasmic hybrid (cybrid) cell lines were generated using mtDNA from clinical research volunteers (n = 18 cognitively healthy (CH) older adults (mean age 73.8), n = 7 MCI (mean age 78.1), n = 10 AD (mean age 75.3)) enrolled in the Relationship of Energetics and Cognitive Trajectory study. Groups did not differ by sex. Cells were analyzed for protein expression by western blot, metabolic flux by Agilent Seahorse XF Analyzer, and protein secretion by ELISA. Plasma pTau217 (AlzPATH) and Aβ42 (N4PE) were assessed by Simoa HD‐X (Quanterix) to compare blood biomarker values with cellular outcomes.

Result

Cybrids from individuals with MCI and AD had elevated intracellular pTau217 (p = 0.033, p = 0.006 respectively). Cybrids from CH individuals secreted significantly more Aβ42 than those from individuals with AD (p = 0.002). Cybrid pTau217 and plasma pTau217 from the same subjects correlated significantly (p<0.001). Cybrids showed altered mitochondrial function by diagnostic group in all ETC complexes (p<0.05), and altered ETC complex expression in all proteins except Complex II, which is not encoded by mtDNA. Mitochondrial transcription factor A (TFAM) was significantly reduced in cybrids from AD individuals (p = 0.010) compared to those from CH subjects.

Conclusion

Cytoplasmic hybrid cell lines generated with mtDNA from individuals with and without AD express diagnostic differences in novel AD biomarkers. This suggests that mitochondrial function, specifically that which is influenced by mtDNA, plays an imperative role in AD pathology. Ongoing research in the cybrid cell model will help elucidate how altered cellular and bioenergetic function contribute to AD etiology.
Gut microbiome phytoestrogen production and its protective role in Alzheimer’s disease
Authors: Loew Ethan B , McCormick Beth , Haran John P
Published: January 2025

Background

In Alzheimer’s disease (AD), changes in intestinal microbiota and systemic inflammation are concomitant with neuroinflammation and cognitive decline. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation and immunosenescence seen in AD. Our research has demonstrated a decreased taxonomic diversity and an increased abundance of pathobionts in the gut of AD patients (Haran, mBio 2019), which is sufficient to promote amyloid and tau deposition in a mouse model (Chen, Gut 2023). It is unclear, however, if effects from the AD microbiome on the central nervous system can be mitigated. Here, we propose a protective mechanism where bacterial metabolites influence cognition via estrogen signaling.

Method

We have performed gut microbiome profiling on a cohort of 178 nursing home residents and used in vitro models to quantify the effects of AD‐associated bacteria and bacterial products on inflammation.

Result

We have identified a commensal bacterium, Adlercreutzia equolifaciens, to be depleted in our cohort of older adults with AD and further depleted in adults with progressive versus stable AD. A. equolifaciens metabolizes dietary isoflavones to produce (s)‐equol, a bacterial metabolite which binds to estrogen receptors. We treated cells expressing estrogen receptor beta, which is predominately expressed along the intestinal epithelium, with (s)‐equol and demonstrated (s)‐equol induces transcription of host genomic estrogen response genes (Vehicle normalized luciferase = 0.007, estradiol = 1.04, (s)‐equol = 1.23, p<0.0001). We have further demonstrated that treatment of intestinal epithelial cells with 17β‐estradiol induced the transcription of regulators of the innate immune response in an ERβ dependent manner (Vehicle RQ = 0.88, estradiol = 1.84, p<0.05). Finally, we have discovered that colonization with A. equolifaciens in the gut of older adults is associated with lower rates of colonization by the intestinal pathobiont Escherichia (Estimation of regression β‐coefficient = ‐1.422, p<0.05).

Conclusion

Adlercreutzia equolifaciens and similar phytoestrogen‐metabolizing bacteria may protect the intestinal epithelium against bacterial invasion and subsequent systemic inflammation, thereby preventing cognitive decline. Our continuing work aims to further establish the connection between AD related neurocognitive decline, the microbiome, and immune system. A. equolifaciens is therefore a strong candidate as a microbiome‐based therapeutic acting along the gut‐brain axis in AD.
Association between known Alzheimer’s disease risk genetic variants and hippocampal atrophy along the Alzheimer’s disease continuum in a Korean cohort
Authors: Ahn Hyejin , Byun Min Soo , Yi Dahyun , Jung Gijung , Huang Yen‐Ning , Risacher Shannon L. , Griswold Anthony J. , Pericak‐Vance Margaret A , Kim Yu Kyeong , Lee Yun‐Sang , Sohn Chul‐Ho , Kang Koung Mi , Lee Jun‐Young , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young
Published: January 2025

Background

Large‐scale genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) from European ancestry identified many genetic variants associated with clinical diagnosis of AD dementia. However, it remains unclear whether these AD‐related variants are associated with AD biomarkers, particularly hippocampal atrophy, a well‐known neurodegeneration biomarker of AD in a Korean population. In this study, we investigated the association between known AD risk single nucleotide polymorphisms (SNPs) and hippocampal atrophy along the AD continuum in older Korean adults.

Method

A total of 487 participants (258 cognitively normal olde adults [CN], 144 mild cognitive impairment [MCI], 85 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) were included for analysis. All participants underwent 11C‐PiB‐PET/MRI. Hippocampal volume adjusted for intracranial volume (HVa) was obtained from 3D T1‐weighted MRI scans using FreeSurfer and used as a neurodegeneration marker of AD. Global beta‐amyloid (Aβ) deposition was calculated from PiB uptake in the global cortical region‐of‐interest using SPM12. From the genetic evidence gathered by the AD Sequencing Project (ADSP), which consists of 76 SNPs associated with AD, we selected 38 SNPs with a minor allele frequency (MAF) greater than 1% from the genotyping data imputed using the TOPMed imputation server in the KBASE cohort.

Result

Among 38 known AD‐related SNPs, three SNPs (rs6966331 in EPDR1, rs2242595 in MYO15A, and rs17125924 in FERMT2) were associated with HVa in an initial exploratory analysis (p<0.05). In a subsequent confirmatory analysis, the associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with HVa remained significant after controlling for age, sex, and APOE4 carrier status, as well as global Aβ deposition (p<0.001 and p = 0.009 for rs6966331 and rs2242595, respectively) (Table 1).

Conclusion

Our study identified associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with hippocampal volume in Korean older adults, and these associations were independent of cerebral Aβ deposition and APOE4 carrier status. These findings suggest that these AD‐related loci may contribute to the development of AD dementia via Aβ‐independent neurodegeneration.
CSF immune cell phenotypes and their related pathway activation differ by Alzheimers disease stage compared to normal controls
Authors: Bebek Gurkan , Zhao Ziyin , Hwang Mi‐Hyun , Bergmann Cornelia , Pillai Jagan A.
Published: January 2025

Background

There is significant interest in understanding the nature of the inflammatory response and its role in Alzheimers disease (AD) pathophysiology. Immune cell phenotypes and their key pathway activation by AD stage is unclear. We therefore evaluated immune cell phenotypes in the cerebrospinal fluid (CSF) and their transcriptional profile comparing AD‐dementia, Mild Cognitive Impairment (MCI)‐AD and normal cognition controls using transcriptomics.

Method

We characterized the gene expression profiles of immune cells in the CSF using both bulk RNA sequencing (RNAseq) and complementary single cell transcriptomics (scRNAseq). First, in a cross‐sectional cohort study, including 6 individuals with MCI‐AD meeting NIA/AA 2011 criteria and 9 amyloid negative controls with normal cognition, (mean age 68.75 years (SD 5.2), 58.8% Female), we identified significant pathways using gene set enrichment analysis (GSEA). Next, using scRNAseq analysis on2 AD‐dementia, 2 MCI‐AD and 2 normal controls we further elucidated the gene expression level changes in distinct immune cells. After clustering into immune cell types, we assessed their activation by GSEA and Gene set variation analysis (GSVA).

Result

RNAseq analysis identified 47 genes that were differentially expressed between MCI‐AD and normal control samples (adj‐p‐val<0.05). GSEA identified downregulation of antigen processing, interferon signaling pathways, and neutrophil degranulation (adj‐p‐val<0.05). Next, scRNAseq, analysis defined immune cells within each sample and identified altered pathways that were in each cell type. We observed that CD4+CD8+ T cells were highly represented in AD‐dementia (17%) and MCI‐AD(14%) but not in normal controls(11%) (p<0.00001). The immune cell types that differed by disease stage between AD‐dementia and MCI‐AD were monocytes; increasing disease severity was associated with a transition from more classical monocytes to intermediate and nonclassical monocytes. The key pathways associated with monocytes were IL6 JAK STAT3 signaling, particularly STAT3, which is involved in monocyte‐to‐macrophage differentiation and the transition of classic monocytes to other subsets. Additionally, the pathways include interferon gamma (IFNg) response and TNF signaling via NF‐kB, which play important roles in activating macrophages and monocytes and promoting differentiation.

Conclusion

Our data show enrichment in the proportion of CD4+CD8+ T cells and pathways related to monocyte differentiation that differ across AD stage.