bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactome Analysis of Tau‐seed Isolated from AD Brains Suggests New Mechanism for Tau Aggregation and Spreading
Authors: Martinez Pablo , You Yanwen , Patel Henika , Jury Nur , Min Yuhao , Redding Javier , Huang Xiaoqing , Dutta Sayan , Mosley Amber L. , Rochet Jean‐Christophe , Zhang Jie , Ertekin‐Taner Nilüfer , Troncoso Juan C , Reeves Cristian A Lasagna
Published: January 2025

Background

Tau aggregates, a hallmark of Alzheimer’s disease (AD) and other tauopathies, spread throughout the brain, contributing to neurodegeneration. How this propagation occurs remains elusive. Previous research suggests that tau‐seed interactors play a crucial role. Based on this, the study aimed to identify novel tau‐seed interactors in AD brains and validate their impact in vivo.

Method

AD and control brain extracts were separated in fractions by Size Exclusion Chromatography. Fractions with the highest tau seeding activity, measured using a tai‐biosensor cell line, were analyzed by mass spectrometry to identify interacting proteins. Bioinformatic tools dissected enriched pathways, identifying interactors that were validated in a Drosophila tauopathy model by genetically interfering with their homologs and assessing tau accumulation and eye degeneration.

Results

Tau seeding activity was concentrated in high molecular weight fractions containing only a small portion of total tau in the AD brains. Compared to controls, AD brains revealed a distinct interactome for tau‐seeds, enriched in proteins associated with synaptic and mitochondrial pathways. Notably, Drosophila screening confirmed that several novel interactors significantly reduced tau accumulation and eye degeneration, suggesting their potential therapeutic relevance.

Conclusion

This study sheds light on tau propagation mechanisms in AD by identifying novel tau‐seed interactors. These interactors, particularly those involved in synaptic and mitochondrial pathways, offer promising targets for therapeutic interventions aimed at decreasing tau spread and potentially preventing neurodegeneration in tauopathies. The findings add to the growing evidence that targeting tau‐seed interactors, like previously identified BSN, could represent a novel strategy for treating these debilitating conditions.
Amyloid Precursor Protein alters Mitochondrial function and Mitophagy
Authors: Strope Taylor A. , Hauger Brittany M , Wilkins Heather M , Schroeder Kealan
Published: January 2025

Background

Amyloid Precursor Protein (APP) processing to Aβ is well understood but the function of APP is largely unknown. APP is expressed ubiquitously and localizes to mitochondria. The consequences of mitochondrial APP localization are not known. We leveraged models of altered APP mitochondrial localization to understand the relationship between APP and mitochondrial function.

Method

We have generated several isogenic iPSC lines using Crispr/Cas9 including WT APP (no gene targeting), 3M APP homozygous and hemizygous (which harbors mutations at amino acids +41, +44, and +52 (His to Asp)), APP knockdown (missing one allele), APP knockout (missing both alleles), and APP duplication. These iPSC lines were differentiated into both neurons and astrocytes. Mitochondrial localization of APP was quantified using Western blot analysis. Aβ was measured via ELISA. Mitochondrial respiratory function was analyzed using Seahorse Technology or Vmax spectrophotometric assays. Mitophagy was examined by qPCR against mitochondrial DNA content and an adenovirus expressing EGFP‐COX8. Mitochondrial biogenesis and turnover were measured using an adenoviral MitoTimer vector.

Result

3M APP and knockdown/knockout APP models had reduced mitochondrial APP localization while APP duplication had increased mitochondrial APP localization. Models with reduced APP localization to mitochondria had reduced Aβ production, while APP duplication had increased Aβ production. Reduced mitophagy levels and altered mitochondrial biogenesis were observed in models with reduced mitochondrial APP localization. APP duplication increased mitophagy and altered mitochondrial biogenesis. Both reduced and increased mitochondrial APP localization reduced mitochondrial respiratory function.

Conclusion

APP localization to mitochondria alters mitochondrial function, mitochondrial mass, and mitophagy. Further studies are in progress to elucidate the effects of mitochondrial localization of APP on bioenergetics.
Inhibition of thrombin signaling after traumatic brain injury improves neurobehavioral dysfunction in 5xFAD mice
Authors: Iannucci Jaclyn , Arismendi Victoria , Bandopadhyay Shreya , Grammas Paula , Shapiro Lee A.
Published: January 2025

Background

Traumatic brain injury (TBI) is a serious societal concern and is considered a major risk factor for the development of Alzheimer’s disease (AD) and related dementias. Identifying shared pathological mediators that contribute to the progression of AD following TBI may allow therapeutic targeting to reduce the likelihood of developing AD following TBI. Cerebrovascular dysfunction is present in both AD and TBI, and thrombin has been implicated as a mediator of cerebrovascular dysfunction and inflammation. Elevated thrombin levels and thrombin signaling following TBI have been associated with cognitive impairment. Thrombin has similarly been implicated as a pathological mediator in AD. Many of thrombin’s detrimental cellular effects have been linked to thrombin activation of protease activated receptors (PARs), including PAR‐1, which are expressed on a number of cell types in the brain and periphery, including endothelial cells, astrocytes, microglia, and neurons. Therefore, inhibiting thrombin activation of PAR‐1 may be a treatment strategy for AD pathogenesis after TBI. We hypothesize that targeting PAR‐1 activation will mitigate the TBI‐induced increase in AD pathogenesis.

Methods

8‐week‐old male 5xFAD mice received either our lateral fluid percussion injury (FPI) model of TBI or sham surgery. This was followed 3 hours later by inhibition of PAR‐1 activation via treatment with a selective PAR‐1 inhibitor (SCH‐79797; 25µg/kg, i.p.) or vehicle control (DMSO). Behavioral measures included digigait assessment of acute motor deficits, depression‐associated behaviors, including social interaction and burrowing, and cognitive behaviors. Mice were subsequently sacrificed and tissue was collected for analysis of AD‐associated pathology as well as cerebrovascular dysfunction.

Results

FPI causes chronic cerebrovascular alterations in 5xFAD mice. FPI was also found to induce deficits in depression‐associated behaviors in 5xFAD mice, most notably social interaction. FPI also induced hippocampal‐associated cognitive impairment in both the Y‐maze and Barnes maze. The impaired affective and cognitive behaviors were improved by SCH‐79797 treatment.

Conclusions

These findings indicate that there is chronic cerebrovascular dysfunction in 5xFAD mice that can be exacerbated by FPI and highlight the potential for targeting thrombin and related signaling processes for mitigating these effects after injury.
Enhanced microglial dynamics in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease
Authors: Jury Nur , Redding Javier , You Yanwen , Martinez Pablo , Karahan Hande , Juarez Enrique Chimal , Johnson Travis S , Zhang Jie , Kim Jungsu , Troncoso Juan C , Reeves Cristian A Lasagna
Published: January 2025

Background

Asymptomatic Alzheimer’s disease (AsymAD) refers to individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology, including beta‐amyloid (Aβ) deposits, neuritic plaques and neurofibrillary tangles upon autopsy. Unlike AD cases, AsymAD exhibits low neuroinflammation and fewer soluble pathological tau species at synaptic levels. However, the link between these observations and the ability to counteract AD pathology is not fully understood. Evidence from AD mice models suggests that the plaque microenvironment significantly influences Aβ plaque‐associated tau pathogenesis. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline.

Method

We conducted a detailed histological and biochemical analysis using postmortem brain samples from age‐matched controls (N = 13), AD (N = 19), and AsymAD subjects (N = 17). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the gene expression within the Aβ‐plaque microenvironment in AsymAD versus AD cases. To further explore the mechanisms insights of our findings we used human microglial cells.

Result

Our findings showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation with increased surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD versus AD brains, and tau seeding activity was comparable to that in healthy brains. To further characterize the plaque niche, we used spatial transcriptomics, finding an increase in components of the actin‐based motility pathways within the microglia surrounding amyloid plaques in AsymAD brains. Ongoing mechanistic experiments in vitro aim to elucidate the role of this pathway in microglial response to Aβ.

Conclusion

Our findings indicate that the amyloid‐plaque microenvironment in AsymAD brains is characterized by microglia with highly efficient actin‐based cell motility mechanisms and decreased tau seeding versus that observed in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.
Usability and Compliance of Online Cognitive Assessments in the British 1946 Birth Cohort
Authors: Giunchiglia Valentina , Cai Ziyuan , Giovane Martina Del , Street Rebecca E , Lu Kirsty , Wong Andrew , Popham Maria , Murray‐Smith Heidi , Richards Marcus , Crutch Sebastian J. , Schott Jonathan M. , Hampshire Adam
Published: January 2025

Background

Cognitive assessments are essential for detecting and monitoring cognitive changes in neurological populations. Compared to standard pen‐and‐paper tests, online cognitive tasks offer a more accessible, scalable, repeatable and cost‐effective approach to assessment. Cognitron is an online cognitive assessment platform with previously demonstrated validity and reliability (1). This study aims to derive meaningful insights into the application of online and computerized assessments in older age cohorts by examine the usability of Cognitron tasks with the MRC National Survey of Health and Development (NSHD; the 1946 British birth cohort).

Method

1753 members of the NSHD cohort (all aged 77) were invited to complete a battery comprising 13 Cognitron tasks, spanning multiple cognitive domains, on their home devices. Each task generated measures of accuracy and reaction time. We examined data quality, completion rates, and levels of engagement and compliance. Qualitative data from email (N = 200) and telephone (N = 78) queries were analysed to determine insights into participant experiences.

Result

990 members (56.47%) consented to participate in the study, of whom 813 attempted the battery (46.34%). 739/813 (90.89%) completed all cognitive tests (average completion time = 40 minutes). 8 tasks (61.53%) were completed by all participants. 4 tasks had <2% of participants incompletely engaging. One task (Choice Reaction Time) had 9% of data with signs of non‐compliance and was dropped from further analysis (Figure 1). The most common signs of non‐compliance were repetitive clicking in the same screen location, switching of browser page, accuracy scores below minimum expected (e.g. failing the simplest trials) and non‐engagement with >90% of trials (Table 1). The qualitative analysis of the reasons participants contacted the study by email or telephone identified five key themes: (1) technical issues (N = 137), (2) general queries (N = 88), (3) reasons for withdrawing (N = 72), (4) providing feedback (N = 43) and (5) subjective reports (N = 28) (Figure 2).

Conclusion

Cognitron assessment was characterised by high completion, engagement and compliance rates in the NSHD cohort, suggesting that online cognitive assessments have potential to monitor cognitive changes in older age cohorts, including those at risk of developing dementia.

Reference

(1) Del Giovane, Martina, et al. (2023) EClinicalMedicine 59 https://doi.org/10.1016/j.eclinm.2023.101980
Mapping the neuroimmune landscape of Alzheimer’s disease in African Americans
Authors: Ifediora Nkechime E. , Nimmagadda Nivedita , Lee Emily , Canoll Peter D. , Schneider Julie A. , Bennett David A. , Menon Vilas , Barnes Lisa L. , Olah Marta
Published: January 2025

Background

African Americans (AA) are disproportionally burdened by Alzheimer’s disease (AD), but there is a scarcity of research focusing on understanding the neuroimmune component of AD pathogenesis in this population. It is generally accepted that microglia would be an ideal therapeutic target for AD and that genetic, lifestyle, societal and environmental factors and stressors have the potential to shape microglia phenotypes and their contribution to neurodegenerative processes. The overarching goal of the current study is to establish the population structure of microglia in older AAs and to investigate the relationship of the different microglia subsets with histopathological hallmarks of brain aging and AD in AAs.

Method

We utilized our established pipeline to isolate live microglia (and other immune cells) from human brain and investigate them at the single cell level using a multi‐omic approach employing transcriptomic, epigenetic and proteomic profiling. This approach, that has recently yielded the first map of microglia population structure in the aged human brain of NHW donors, has been supplemented with in situ investigation of microglia phenotypes and their association with AD pathology in archival tissue specimens.

Result

We isolated and profiled live microglia from the dorsolateral prefrontal cortex and the anterior watershed deep white matter of 10 AA donors from the Minority Aging Research Study (MARS). Both of these brain regions have been previously associated with cognitive decline. Using single cell RNA‐sequencing, unsupervised hierarchical clustering of the data revealed nine distinct microglia phenotypes: two homeostatic subsets and seven differentiated subsets, similarly to what we previously described in NHW donors. Intriguingly, we detected a different population structure of microglia in AA donors when compared to NHWs. To establish an in depth understanding of these findings we investigated the chromatin accessibility and proteomic profile of the different subsets as well as their relationship to histopathological traits of brain aging in AA donors.

Conclusion

While microglia in the cortex and white matter of older AA donors acquire the same functional phenotypes as microglia in the brains of NHW donors, they display a distinct population structure. Our findings underline the importance of studying the neuroimmune compartment of AD specifically in AAs.
Mitochondrial Dysfunction in Down Syndrome associated Alzheimer’s Disease
Authors: Smith Keith P , Strope Taylor A. , Hauger Brittany M , Lysaker Colton R , Shaddy‐Gouvion Cynthia , Haeri Mohammad , Head Elizabeth , Swerdlow Russell H , Wilkins Heather M
Published: January 2025

Background

Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer’s disease (AD). However, the role of these pathologies in Down Syndrome associated Alzheimer’s Disease (DSAD) is unknown. Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), from which Aβ is generated, is found in mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. How these interactions contribute to DSAD pathology and progression are unknown. Here we interrogated the association of full‐length APP with mitochondria, mitochondrial function, and AD pathological hallmarks.

Method

ND (n = 10, without DS) and DS associated Alzheimer’s Disease (DSAD, n = 10) postmortem brain tissue was obtained from the University of California Irvine. A human iPSC line was purchased from WiCell with Trisomy 21 and a isogenic control line which underwent Crispr/Cas9 genome editing to remove the extra chromosome 21 copy. iPSC models were differentiated into neurons, astrocytes, and cerebral organoids using StemCell Technologies reagents and protocols. We examined mitochondrial function using a Seahorse XF analyzer. We measured full‐length APP protein levels in whole cell extracts and mitochondrial fractions via Western Blotting. We measured Aβ levels with ELISA kits from ThermoFisher.

Result

DSAD postmortem brain tissue had reduced mitochondrial function regardless of sex. Full‐length APP levels were significantly higher in mitochondrial fractions in DSAD brain tissue. Full‐length APP levels in mitochondrial fractions correlated with mitochondrial function. Higher mitochondrial APP (full‐length) levels associated with lower mitochondrial function. iPSC derived models showed similar phenotypes to postmortem brain tissues, including increased mitochondrial APP levels, and decreased mitochondrial function.

Conclusion

We describe a relationship between mitochondrial APP accumulation, and mitochondrial function. These data support a centralized role for mitochondrial function in APP physiology and APP may play a role in modulating mitochondrial function. Further, DSAD postmortem tissue and iPSC models show significant mitochondrial dysfunction.
Cognitive, behavioral, and quality of life outcomes in cognitively unimpaired older persons with or without sleep complaints
Authors: Guan Dylan X. , Beaudin Andrew , Smith Eric E. , Ismail Zahinoor
Published: January 2025

Background

Changes in sleep are common in older persons and have been linked to higher dementia risk. The link between sleep complaints and early risk markers of Alzheimer’s disease (AD), namely subjective changes in cognition and mild behavioral impairment (MBI), have not been fully explored. This study investigated associations between sleep complaints with cognitive and behavioral AD risk markers and quality of life (QoL) among cognitively unimpaired older persons. We hypothesized that older persons reporting sleep changes would also report more severe cognitive and behavioral changes, and poorer QoL.

Method

Participants (n = 1395) were from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) study. Sleep complaints were self‐reported presence or absence of sleep disruption (symptoms of insomnia or sleep‐related movement disorders), daytime sleepiness, sleep‐disordered breathing, or prolonged sleep duration. Outcomes included the Everyday Cognition (ECog‐II) scale, Mild Behavioral Impairment Checklist (MBI‐C), and Quality of Life and Function (QFS‐5) scale. Age, sex, years of education, marital status, and ethnocultural origin were balanced across exposure groups using inverse probability of treatment weighting. Negative binomial and bootstrapped linear regressions were used, as appropriate, to model sleep complaint (exposure) associations with ECog‐II and MBI‐C total scores, and QFS‐5 mean scores (outcomes).

Result

Participant characteristics are summarized in Table 1. Table 2 shows that all sleep complaints were associated with poorer everyday cognition, more severe MBI symptoms, and poorer QoL. However, excessive daytime sleepiness was generally the most strongly associated with the three outcomes with them having 1.50 (95%CI [1.40, 1.60]) and 2.29 (95%CI [2.10, 2.50]) times higher ECog‐II and MBI‐C score compared to participants without daytime sleepiness, and a 0.71 SD (95%CI [0.59, 0.82]) lower QFS‐5 mean score.

Conclusion

Sleep complaints, even among cognitively unimpaired older persons, are linked to cognitive and behavioral risk markers of AD, as well as poorer QoL. These findings provide further evidence that sleep complaints represent modifiable risk factors or may reflect a prodrome for AD, and may contribute to overall disease burden.
Hippocampal transcriptomic similarities and differences among mouse models of amyloidosis
Authors: Paes Rodrigo Sebben , Carello‐Collar Giovanna , Limberger Christian , De Bastiani Marco , Baldasso Gabriela Mantovani , Zimmer Eduardo R.
Published: January 2025

Background

Animal models of amyloidosis have been instrumental in Alzheimer’s disease (AD) research since they can resemble pathophysiological features of human AD. Nevertheless, each model is generated through different genetic engineering strategies, resulting in distinct phenotypes. In this context, whether AD core molecular programs are conserved among mouse models remains to be addressed. Herein, we aimed to explore similarities and differences among the transcriptomic of three mouse models of amyloidosis.

Method

We obtained hippocampal transcriptomics data from the Gene Expression Omnibus (GEO) repository of two transgenic mouse models (APP/PS1 and 3xTg‐AD mice), and the AMP‐AD Knowledge Portal of one knock‐in mouse model (hAß‐KI mice). The GEOquery package was used to download data from GEO and data from the AMP‐AD Knowledge Portal were downloaded with synapser and synapserutils packages. Next, we performed gene expression analysis to obtain the differentially expressed genes (DEGs, FDR‐adjusted p‐value < 0.05). We also determined the intersection of DEGs among models. Then, we performed functional enrichment analysis (FEA) to obtain Gene ontology (GO) terms of Biological Processes (GOBP) using the enrichGO function of clusterProfiler package (v3.16.1).

Result

We found 5055, 1073, and 162 DEGs in the APP/PS1, 3xTg‐AD, and hAß‐KI mice, respectively (Fig. 1A). APP/PS1 and 3xTg mouse models presented more overlapping DEGs (433 DEGs shared, Fig. 1A). Interestingly, only four genes were consistently differentially expressed across all mouse models (VGF, CORT, EDEM1, and C4B). The FEA revealed multiple enriched GOBP terms in each model [1609 in APP/PS1, 1685 in 3xTg‐AD, and 25 in the hAß‐KI, adj. p‐value <0.1, and 16 GOBP terms overlapping across the three AD mouse models (Fig. 1B).

Conclusion

In this study, we demonstrate that APP/PS1 and 3xTg‐AD exhibit greater transcriptomic similarities between each other than with hAß‐KI. Only four DEGs were consistently identified in all models. However, despite this, the three models show common alterations in 16 biological processes. These findings collectively indicate that, at the biological processes level, transgenic mouse models carrying autosomal dominant Alzheimer’s disease traits and a knock‐in (KI) mouse model share common pathophysiological features, being suited for translational studies.
Measuring The Speed and Accuracy of Semantic Retrieval with the Semantic Stroop Task
Authors: Kahly Omar , Hall Kathleen , Baldo Juliana , Schendel Krista , Herron Timothy J , Geraci Kristin , Blank Michael , Jaramillo Isabella , Williams Garrett , Miranda Miranda , Chok Jas M. , Lwi Sandy J. , Curran Brian , Santavicca Isabella , Thomas Lexie , Spinelli Maria G , Johnson David K , Woods David L.
Published: January 2025

Background

Semantic memory assessments are sensitive indicators of cognitive decline in pre‐clinical Alzheimer’s Disease (AD), with slowed reaction time and diminished accuracy serving as markers for amyloid accumulation. We introduce the Semantic Stroop Test—a brief (4.3 minute), automated semantic retrieval and executive function task included in the California Cognitive Assessment Battery (CCAB).

Method

The Semantic Stroop Test was administered to 572 healthy adults (50% female, Age = 65.6 years, ±10.6). Participants were tested in their homes using tablet computers. Two sessions were administered on consecutive days, with tests remotely monitored (Figure 1).

Participants were instructed to produce an antonym in response to words in red font and a synonym in response to words in blue font. Sixteen words were presented in random order (Figure 1). Then the same 16 words were presented again in opposite colors. Verbal reaction time (RT) and response accuracy were quantified for each word.

Result

The Semantic Stroop Test showed excellent test‐retest reliability (r = 0.71 accuracy, r = 0.82 RT) and switch failure detection (r = 0.47) in tracking errors. A multiple regression model revealed significant effects of Age and Vocabulary (p<0001) on Accuracy and accounted for 41% of the variance. RT analysis also showed significant effects of both Age and Vocabulary (p<.0001) as well as Education (p<.05), with the model accounting for 30.1% of the variance. Faster RT was associated with higher Accuracy (r = ‐.51) (Figure 2). Furthermore, subjects with consistent sequential responses (e.g., synonym‐synonym) were more accurate than response‐switch trials. Subjects were also more accurate in response to antonym‐based cues than synonyms with 88% vs 79% correct.

Conclusion

The Semantic Stroop Test demonstrates excellent psychometric properties. It reliably captures age‐related cognitive effects through accuracy and speed measures of semantic retrieval while remaining sensitive to executive function processes such as cue‐based switching.
African ancestry component could change APOE4 effect size for AD of a diverse population
Authors: Bicalho Maria Aparecida Camargos , VIANA BERNARDO DE MATTOS , Cintra Marco Túlio , Hansen Erika de Oliveira , Burgos Ivonne Carolina Bolaños , Engelmann Gabriela Tomé Oliveira , de Miranda Debora Marques , Romano‐Silva Marco Aurélio , Parveen Kayenat , Dalmasso Maria Carolina , de Marco Luiz Armando Cunha , Ramirez Alfredo
Published: January 2025

Background

Worldwide, the actual number of 55 million people diagnosed with dementia is estimated to increase to 139 million people affected by dementia in 2050. 61% of these individuals resided in low and middle‐income countries (LMIC). Genetic risk factors account for up to 80% of the attributable risk of Alzheimer’s disease (AD), the leading cause of dementia. Thus, one can argue that most of the pathophysiological pathways in AD are driven by genetic determinants. Despite the increasing number of dementia cases in LMIC, poor generalizability of genetic studies across populations arises from the abundance of studies focused on European descent and the lack of studies in globally diverse populations.

Method

We developed a case control study, including older adults selected from Cog‐aging Research Group of the UFMG, Brazil, divided in two groups: control and AD (AD and AD plus vascular dementia). They were submitted to the same neuropsychological and geriatric protocols. Diagnosis of AD dementia were based on Mckhann criteria. DNA samples were subjected to genome‐wide‐genotyping using the Infinium Global Screening Array (Illumina). Quality controls were performed using PLINK and R. After QC, remaining samples were analyzed for population stratification. TOPMed imputation server was used to perform imputation. Principal components (PC) analysis considered phenotype, sex, and age.

Result

The final sample was composed by 573 samples, 181 controls and 309 cases, 389 female and 184 males. Our sample was composed predominantly by Caucasian and African genetic ancestries (Figure 1). From 23 top hit variants, only APOE4 allele reached significant values (Figure 2), with an effect size lower than that observed in other populations (p = 1.06E‐08; B = 1.42). Haplotype analysis of the APOE region revealed that two other variants (chr19:44906745:G:A and chr19:44918903:C:G), which have shown lower MAF in African than in Caucasian population, could change the APOE4 effect in our population (Figure 3).

Conclusion

Our sample is composed by a heterogeneous genetic ancestry, different from the other Latin America populations. APOE4 allele presented a lower effect size to AD than some other populations. This result could be related to two other variants, associated with the African component, influencing the effect of APOE4 allele.
Selective Vulnerability to Tau Pathology in Serotonergic Dorsal Raphe Nucleus Neurons
Authors: Cooper Benjamin J , Hunter Mikayla L , Pierson Samantha R , Marcinkiewcz Catherine A , Hefti Marco M , Fiock Kimberly L
Published: January 2025

Background

The dorsal raphe nucleus (DRN) is the primary source of serotonergic projections to supratentorial structures. We and others have shown that it is selectively vulnerable to tau pathology in both human and mouse models of early AD. Although well characterized in mice, the neurochemical anatomy of the human DRN, and in particular the role of Vesicular glutamate transporter‐3 (VGLUT3)‐expressing neocortical projection neurons in tau pathology, remains unclear.

Method

Post‐mortem human brain tissue was obtained from previously consented cases stored in the Iowa Neuropathology Resource Laboratory. Next of kin provided consent for research use of tissue. Sections were processed, embedded in paraffin, and sectioned in the usual fashion. Tyrosine hydroxylase (TH), tryptophan hydroxylase 2 (TPH2), and phosphorylated tau (AT8) were visualized by immunofluorescence, while VGLUT3 transcripts were identified by RNA in situ bybridization. Imaging was done using a Cytation5 platform with downstream analysis using MATLAB and R.

Result

We found that, similar to mice, the human dorsal raphe has both VGLUT3‐positive and –negative serotonergic neurons. Unlike mice however, in the human DRN, these are not anatomically separate, and the proportion of TPH2 neurons that are VGLUT3 appears to be higher than in mice. In patients with DRN tau aggregates, these appear to selectively affect TPH2+/VGLUT3+ neurons.

Conclusion

Serotonergic neurons in the dorsal raphe express high levels of VGLUT3, with an anatomic distribution differing from that seen in mice, and these neurons appear to be selectively vulnerable to tau pathology.
Epigenetics and Alzheimer’s Disease: A Literature Review
Authors: da Silva Bibiana Ruppenthal
Published: January 2025

Background

In recent years, researchers have linked epigenetic factors to numerous diseases, one of them being Alzheimer’s Disease (AD). Those factors may lead to the disease but also serve as a path for new treatments and prevention methods.

Method

A wide selection of articles in the PubMed platform that focused on epigenetics, Alzheimer’s Disease, and correlating aspects among them were reviewed.

Result

Previous studies have shown that the main epigenetic factors associated with AD are diet and nutrition, exercise, and stress. An anti‐inflammatory diet rich in copper and zinc results in a decrease in the development of AD since the dysregulation of the nutrients leads to the modification of the amyloid metabolism known to participate in the pathogenesis of AD. At the same time, neurodegeneration may be reduced by up to 45% with the practice of physical exercise, showing that the molecules created by the stimulation could allow discoveries on physiological pathways and non‐drug therapy for prevention. Studies have also found that catecholamine and corticosteroid systems in late‐onset AD can be caused by early life stress. Moreover, epigenetic changes are prone to happen during the prenatal stage and childhood, which indicates the importance of the aspects mentioned in the entire life and not only during the adult years. The absence of the factors mentioned previously could lead to epigenetic mechanisms that modify chromatin and gene expression. These mechanisms are histone acetylation, microRNA, DNA methylation, and histone methylation. The most important ones for AD are the last two that are responsible for silencing gene expression, especially gene APOE, crucial for the amyloid β downstream effect on the aggregation of phosphorylated tau in the brain, and when histone H3 is methylated, it affects synaptic transmissions, shaft bursts, and nerve development, and the trimethylation of histone H3 lysine K4 is associated with the expression of genes related to memory and the protein Zif268 that helps to maintain long‐term potentiation in the recognition memory, respectively.

Conclusion

Overall, epigenetics is a significant area of study to understand the cause of AD and to discover new methods for prevention, diagnosis, treatment, and hopefully one day cure.
Histofluorescence analysis of Pittsburgh Compound B labeled pathology in Down syndrome putamen and frontal cortex
Authors: Rouanet Jeremy P. , Ngo Kim Chan , Shamas Tamara M , Phelan Brenna , Fung Ashley L. , Phelan Michael J. , Pascual Jesse R. , Ngo Phong , Andrews Elizabeth J. , Wright Sierra , Lai Florence , Kofler Julia , Ikonomovic Milos D , Head Elizabeth ,   Alzheimer Biomarkers Consortium ‐ Down Syndrome (ABC‐DS)
Published: January 2025

Background

Brain deposits of amyloid‐β (Aβ), one of the hallmark pathologies of Alzheimer disease (AD), are consistently present in people with Down syndrome (DS) after the age of 30 years. Positron emission tomography (PET) radioligands like [3H]Pittsburgh Compound‐B (PiB) allow for visualizing Aβ accumulation in living people. In DS, the earliest and strongest PiB‐PET retention is in the striatum, differing from late‐onset AD. The neuropathological substrates of early PiB retention in DS striatum are unknown. The goal of this postmortem study is to compare histofluorescent labeling with cyano‐PiB, a fluorescent derivative of PiB, in the striatum and frontal cortex of people with DS.

Method

Cyano‐PiB histofluorescence load (% area) was evaluated on postmortem tissue from putamen and frontal cortex (n = 43; age 42‐70 years, 24F/19M) using whole slide imaging and digital quantification. Cyano‐PiB histofluorescence was combined with Aβ immunofluorescence on a subset (n = 3) of cases.

Result

After the age of 42 years, cyano‐PiB loads did not increase as a function of age at death in frontal cortex (layers II‐IV; p = 0.64) and putamen (p = 0.76). Cyano‐PiB loads were not greater in putamen compared to frontal cortex. Putamen and frontal cortex cyano‐PiB loads directly correlated (r = 0.52). Cyano‐PiB labeled plaques were immunolabelled with Aβ‐targeting antibodies 6E10, 12F4, and 4G8, in both putamen and frontal cortex, with less overlap observed in deep frontal cortical layers.

Conclusion

Striatal cyano‐PiB load in putamen was not greater than in the frontal cortex layers II‐IV in people with DS above the age of 42 years. The partial overlap of cyano‐PiB labeled amyloid plaques with Aβ immunoreactive plaques suggests that only a subset of Aβ plaques were detected with cyano‐PiB. Further characterization of cyano‐PiB loads in deep layers of the frontal cortex as well as in DS cases at younger ages is warranted.
Validation Of the Tau Heterogeneity Evaluation in Alzheimer’s Disease (THETA) Score Using Longitudinal and Histopathology Data
Authors: Gebre Robel K , Moscoso Alexis , Raghavan Sheelakumari , Wiste Heather J. , Heeman Fiona , Costoya‐Sánchez Alejandro , Schwarz Christopher G. , Spychalla Anthony J. , Lowe Val J. , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Schöll Michael , Murray Melissa E. , Jack Clifford R. , Vemuri Prashanthi
Published: January 2025

Background

We recently developed a novel tau‐PET summary measure THETA, capturing regional heterogeneity and identifying tau status, using ground truth visual assessments from a large single‐center cross‐sectional dataset and validated on independent cohorts [1, 2]. In this study, we aimed to evaluate the performance of THETA on longitudinal and histopathology data.

Method

We included longitudinal tau‐PET ([18F]flortaucipir) data from 696 Mayo Clinic Study of Aging (MCSA) and ADRC participants, with histopathology in n = 90. Fig. 1 shows the model that uses regional standard uptake value ratios (SUVR) and a target of binary class of tau positivity for prediction of THETA. This model was applied to predict tau status on each followup scan. Slopes of the meta‐ROIs’ tau SUVRs and THETA were evaluated by diagnostic group and as a function of baseline amyloid SUVR in discordant CU participants (where meta‐ROI and visual assessments did not match at baseline) and in incident‐THETA+ CU participants (whose THETA moved from below to above 1 over serial tau‐PET scans). We evaluated tau measurements as a function of Braak stages for neurofibrillary tangles.

Result

Longitudinal plots of meta‐ROIs for diagnostic groups were very similar, but the expanded range of THETA based on visual positivity prediction clearly identified tau positive or tau‐negative scans. In discordant‐CU (n = 97) and incident‐THETA+ CU participants (n = 14 all amyloid positive at follow‐up but only 65% at baseline), the relationship between baseline amyloid and rate of tau increase was stronger for THETA than temporal meta‐ROI (Fig. 2). Separation between baseline and follow‐up was greater for THETA (t‐statistics = 90) compared to temporal meta‐ROI (t‐statistics = 20) (p<0.01) in the incident‐THETA+ CU participants. THETA showed a slightly stronger association with Braak stage than meta‐ROIs (rho = 0.87 vs. ≤0.83, p<0.05), with better separation of clinical diagnoses (Fig. 3).

Conclusion

THETA remained clearly negative or positive in MCI and AD, providing consistent information on underlying etiology of impairment at both baseline and follow‐up. Although binary in its construction, THETA both provided separation of values based on tau status and its change correlated with baseline amyloid burden especially in discordant‐CU where tau deposition is not in typical meta‐ROIs. Further work is needed to confirm if THETA captures early tau changes.
Blood‐Based Biomarkers to Aid in Alzheimer’s Disease Prediction or Diagnosis: Analysis in a Multi‐Ethnic Cohort Study
Authors: Bahl Aanya , Honig Lawrence S. , Kang Min Suk , Sanchez Danurys , Reyes‐Dumeyer Dolly , Manly Jennifer J. , Lantigua Rafael A. , Dage Jeffrey L. , Brickman Adam M. , Vardarajan Badri N. , Mayeux Richard , Gu Yian
Published: January 2025

Background

Blood‐based biomarkers may aid in the diagnosis of Alzheimer’s Disease (AD), but their contribution may be confounded by the presence of multiple chronic conditions and have not been well‐tested in community populations. In the current study, we aimed to determine whether blood‐based biomarkers can aid in refining a multi‐ethnic, urban clinically diagnosed AD community‐based cohort.

Method

We included 546 individuals in the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study in this cross‐sectional study. Six biomarkers, including phosphorylated‐tau‐181 (P‐tau181), total (T‐tau), amyloid‐beta 40 and 42 (Aβ40, Aβ42), Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain (NfL) were measured using Quanterix SIMOA HD‐X platforms. The association between the biomarkers and AD or cognitive impairment was tested using logistic regression, adjusted for age, sex, ethnic group, and years of education. Individuals were subsequently characterized as ‘biomarker positive’ or ‘biomarker negative’ based on combined GFAP and P‐tau181/Aβ42 cut scores.

Result

The mean age of individuals was 79.3 years (6.56) and 379 (69.4%) were women, 133 (24.48%), were Non‐Hispanic Black, 153 (28.0%) Non‐Hispanic White, and 248 (45.4%) were Hispanic. A clinical diagnosis of AD was made in 129 (25.49%) individuals. Low Aβ42 (OR = 0.18, [95% CI: 0.04 ‐ 0.92]), low Aβ42/Aβ40 (OR = 0.49, [95% CI: 0.228 ‐ 0.872), and high P‐tau181/Ab42 (OR = 5.494, [95% CI: 1.523 – 20.416]) were associated with a clinical diagnosis of AD suggesting a role as predictive biomarkers. However, the best combination, GFAP and P‐tau181/Aβ42 cut scores, yielded a sensitivity of 41% and specificity of 70.5% for clinically diagnosed AD. The concordance was 54.5% and the discordance was present in both directions. Low education, cardiovascular and other comorbidities might contribute to the discrepancy between biomarker positivity and clinical diagnosis.

Conclusion

While GFAP and P‐tau181/Aβ42 levels are associated with AD pathology and can aid in the diagnosis of AD, the presence of multiple chronic conditions may lead to either false positives or negatives. Large multi‐ethnic community cohort studies are needed to further examine the utility of these biomarkers in aiding in the clinical diagnosis of AD.
Integrative approach to profile resilience and risk factors in Alzheimer’s disease
Authors: Is Ozkan , Bergman Jeremiah , Wang Xue , Tutor‐New Frederick Q , Is Ozkan , Quicksall Zachary , Atik Merve , Reddy Joseph S. , Duvuuri Venkata N.S. , Min Yuhao , Gao Junli , Sotelo Katie D , Nguyen Thuy , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilüfer
Published: January 2025

Background

A complex, multicellular disease with genetic and immunological elements, Alzheimer’s disease (AD) affects millions worldwide. There has been previous research linking AD to the missense variants ABI3‐rs616338‐T and PLCG2‐rs72824905‐G, and the altered expression of these genes has been shown to disrupt microglial function. In our understanding of AD risk and resilience, limited research has been conducted on how these variants affect microglial subtypes and states in AD.

Methods

We previously identified DOCK8 protein as a target for fluorescent activated nuclei sorting (FANS) to enrich microglia nuclei from frozen human brains. Using this enrichment strategy, we generated microglia enriched snRNAseq data from temporal cortex tissue of 30 donors harboring ABI3 or PLCG2 missense mutations, or neither mutation. We introduced PLCG2 variant in either homozygote, and heterozygote forms into an AD patient derived iPSC through CRISPR/Cas9 approach, differentiated these cells into microglia cells (IMGLs) following established protocols, and generated scRNAseq data after treatment with Amyloidβ. We applied standard alignment and quality control pipelines to the snRNAseq and scRNAseq datasets in parallel. Established markers of microglia states and subtypes were utilized to annotate the clusters; analyzed for their hub gene expression using comparisons between cluster differential profiling to determine signature pathways. Differential gene expression was assessed using pseudo bulk and MAST approaches.

Results

We obtained single nuclei transcriptome profiles of 54,000 frozen human brain nuclei, of which 35,000 are microglia, through snRNAseq, and single cell profiles of 63,000 iMGLs through scRNAseq, using our standard alignment and quality control procedures. Our differential gene expression analysis identified novel genes and pathways which were identified as part of resilience or AD risk networks in microglia subtypes and states. These alterations were validated using orthogonal experimental methods and further explored for their conservation using in vivo external datasets. Pseudotime inference will be completed to probe microglia marker gene expression dynamics, treatment conditions, along with continuous cell‐state changes.

Conclusion

Our study uncovers microglia subtype specific resilience and risk factors provided by AD related genetic variants using snRNAseq from frozen human brain and scRNAseq from IPSC derived microglia cells. These findings nominate novel targets and pathways with therapeutic potential.
Identifying the Severity of Dementia Based on Cognitive Performance and Index of Independence in Basic Activities of Daily Living
Authors: Huynh Duong , Ghomi Reza Hosseini , Huang Bin , Patterson Mary
Published: January 2025

Background

Alzheimer’s disease and related dementias (ADRD) are characterized by impairments in an individual’s cognitive and functional abilities. Computerized cognitive tests have been shown to be effective in detecting mild cognitive impairment and ADRD but whether they can stage the ADRD disease remains to be studied.

Method

Retrospective analysis was performed on a BrainCheck dataset containing 1,749 ADRD patients with different cognitive and functional assessments completed for cognitive care planning, including the Dementia Severity Rating Scale (DSRS), the Katz Index of Independence in Activities of Daily Living (ADL), and the BrainCheck cognitive assessment battery (BC‐Assess). The patients were staged according to their DSRS total score (DSRS‐TS): 971 mild‐stage (DSRS‐TS: 10‐18), 664 moderate‐stage (19‐26), and 114 severe‐stage (37‐54) patients. Pearson correlation was calculated to assess the strength of associations between BC‐Assess overall score (BC‐OS), ADL total score (ADL‐TS), and DSRS‐TS. A three‐way Multivariate‐Analysis‐of‐Variance (MANOVA) was used to examine how the ADL‐TS and the BC‐OS combined differ across stages after controlling for age group and gender. Multinomial logistic regression was used to evaluate the possibility of using patients’ ADL‐TS and/or BC‐OS to predict their condition.

Result

Correlations between scores are moderate. A stronger correlation was found between the DSRS‐TS and the ADL‐TS (r = ‐0.58) than that between the DSRS‐TS and the BC‐OS (r = ‐0.54) and between the ADL‐TS and the BC‐OS (r = 0.38). The ADL‐TS and BC‐OS vary significantly across ADRD stages. ROC analysis of the logistic regression shows that, although either ADL‐TS or BC‐OS can effectively predict ADRD stage, highest accuracy is when both scores are included in the model (ROC‐AUC: mild = 0.94; moderate = 0.77; severe = 0.9; micro‐average = 0.93). Except a low sensitivity in identifying the moderate group, a sensitivity/specificity of at least 76% was observed for all models and stages.

Conclusion

Our results suggest a progressive decline in both cognitive and functional abilities as patients move through the stages of ADRD. Among ADRD patients, performance in a cognitive assessment (BC‐Assess) or in basic activities of daily living (ADL) is informative of severity diagnosis. However, combining both measures generates highest accuracy.
Analysis of genetic variants TREM2 and plasma gingipain K and R level in patients with Alzheimer’s disease
Authors: Hurla Mikolaj , Banaszek Natalia , Florczak‐Wyspianska Jolanta , Michalczyszyn Olivia , Owecki Wojciech , Kozubski Wojciech , Dorszewska Jolanta
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by an acquired, progressive impairment of cognitive functions. The pathogenesis of this disease remains unknown. It is explained based on the following theories: amyloid cascade, inflammation, vascular, and infection hypothesis. Recently hypothesized that Porphyromonas gingivalis may be a unifying factor linking the different hypotheses related to AD pathogenesis. P. gingivalis produces cysteine proteinases called gingipain K and gingipain R, which are virulence factors. P. gingivalis plays a significant role in periodontitis. Periodontitis is provoked by bacterial lipopolysaccharide, which then leads to an immune response. The TREM2 gene is involved in the immune response. P. gingivalis may be responsible for reducing the expression of the TREM2 gene and TREM2 protein. TREM2 protein deficiency may impair Aß degradation, which may significantly increase the risk of AD. It has been showed a tendency for earlier onset of symptoms and faster progression of AD in people who were carriers of the potentially pathogenic TREM2 (rs143332484) CT variant of this gene. The study aimed to analyze plasma gingipain K and R concentration and TREM2 (rs143332484) genetic variants in AD patients, control subjects related to AD cases (CR), and control subjects without a family history of AD (CU).

Method

The studies were conducted on 74 subjects (AD and controls). The TREM2 genotype was determined by HRM and sequencing. The gingipain K and R concentrations were determined by the ELISA method.

Results

The highest concentration of gingipain K (p = 0.0820) and R (p = 0.0740) was found in AD compared to CR, and CU. The TREM2 CT genotype was most common in AD patients. Patients with this genotype had the highest concentration of gingipain K. However, AD patients with the TREM2 CC genotype showed statistically significantly higher concentrations of gingipain R (p<0.05) compared to CR and CU.

Conclusion

It seems that both gingipains K and R may be involved in the pathogenesis of AD.