bluuebunny/crossref_metadata_2025 huggingface dataset:
SUVN‐L3307032, A Positive Allosteric Modulator (PAM) at Muscarinic M4 Receptor for the Treatment of Neuropsychiatric Symptoms
Authors: Shinde Anil , Guduru Naga Sai Soma Chandra Sekhar , Das Ankit , Bitra Keerthi Sai , Bobbili Hima Bindu , Mukkollu Kavya Sree , Allu Chaitanya Sree , Vanga Shivani , Shyam Radhey , Kallepalli Rajesh , Abraham Renny , Nirogi Ramakrishna
Published: January 2025

Background

Centrally acting muscarinic acetylcholine receptor antagonists like atropine and scopolamine can induce psychosis‐like symptoms. Xanomeline, a muscarinic M1/M4 preferring agonist attenuated the effects of amphetamine (animal model for schizophrenia) in the wild‐type mice, however, such effects were absent in muscarinic M4 knockout mice. In addition, xanomeline was also found to be effective in attenuating neuropsychiatric symptoms. Thus, muscarinic M4 agents can modulate brain circuitry that is dysregulated in disease states.

Method

The effects of SUVN‐L3307032 on the allosteric site of the M4 receptor were evaluated using the cell‐based reporter gene assay. The pharmacokinetic properties of SUVN‐L3307032 were studied both in rodent and non‐rodent species. SUVN‐L3307032 was assessed for its effects on amphetamine‐induced hyperlocomotion in rats at doses of 3, 10, 30, and 60 mg/kg. Preliminary toxicity studies were conducted in rats and dogs to evaluate the safety of SUVN‐L3307032.

Result

SUVN‐L3307032 was found to be a positive allosteric modulator of muscarinic M4 (M4‐PAM) receptor. SUVN‐L3307032 showed good oral bioavailability in rats and dogs. It also has excellent brain penetration with an adequate free fraction in the brain. SUVN‐L3307032 showed dose‐dependent receptor occupancy at tested doses of 3, 10, 30, and 60 mg/kg. At the tested doses, SUVN‐L3307032 dose‐dependently attenuated amphetamine‐induced hyperlocomotion. The observation from the amphetamine‐induced hyperlocomotion assay correlated well with the occupancy at the allosteric site of muscarinic M4 receptors.

Preliminary toxicity studies did not show any concerns for further development.

SUVN‐L3307032 is being further characterized in animal models for neuropsychiatric symptoms.

Conclusion

SUVN‐L3307032 could be a promising agent for the management of neuropsychiatric symptoms.
Cerebral Amyloid Angiopathy like pathology accompanied by intense gliosis in T2D‐induced APPxhQC mice
Authors: Babalola Joshua , Neddens Joerg , Leitinger Gerd , Hutter‐Paier Birgit , Hoefler Gerald
Published: January 2025

Background

Cerebral Amyloid Angiopathy (CAA), characterized by the presence of amyloid β (Aβ) deposits in cerebral blood vessels has been associated with cognitive impairment and Alzheimer’s disease (AD). Vascular risk factors, such as type 2 diabetes (T2D), are known to affect vascular pathology and CAA‐like depositions. Furthermore, Aβ deposition in blood vessels accompanied my inflammation especially gliosis, has been reported in the transgenic AD mouse models 5xFAD and APPSL that express human Aβ. In this study, we therefore investigated the prevalence of CAA‐like pathology in T2D‐induced APPxhQC transgenic mice.

Method

Male transgenic APPxhQC mice, expressing human APP751 with the Swedish and the London mutation and human glutaminyl cyclase (hQC) enzyme, were used. Mice were either fed with high fat (HFD) or control diet and daily treated with streptozocin for 3 days. Brain concentrations of soluble and insoluble Aβ 1‐38, 1‐40 and 1‐42 peptides were determined using an immunosorbent assay. Aβ deposits and gliosis were detected by immunofluorescent labelling.

Results

Exceptionally strong but hollow Aβ deposits in the thalamus that go in medio‐lateral direction were found surrounding deposit free areas. These hollow Aβ deposits were accompanied by intense microglia and astrocytic activation upon HFD‐streptozocin treatment. The location and course of these hollow deposits indicated that they surrounded blood vessels. Additionally, plaque‐associated insoluble Aβ40 deposits in T2D‐induced APPxhQC mice were significantly higher compared to the control group.

Conclusion

Presence of Aβ deposits surrounding blood vessels accompanied by intense gliosis seems common in APPxhQC mice and might indicate a CAA‐like pathology specific to this AD model.
Instruments used to assess language in low‐educated individuals with mild cognitive impairment: a systematic review
Authors: Alves Emily Viega , Beber Bárbara Costa , Castilhos Raphael Machado
Published: January 2025

Background

Mild Cognitive Impairment (MCI) is a cognitive decline that is greater than expected for an individual’s age and level of education, but which does not interfere with functionality. It may be divided into amnestic (when it predominantly affects memory) and non‐amnestic (other cognitive domains). One of the cognitive functions that may be affected by MCI is language. As this is a function closely linked to education, it is essential to understand how it is assessed in people with low levels of schooling in different populations, such as those with cognitive impairment. Therefore, this study aimed to perform a systematic review of measures of language in low‐educated individuals with MCI.

Method

This is a systematic review of the literature. The search was performed in four databases: PubMed, Embase, LILACS, and Scielo, using MeSH descriptors related to MCI with low education and in which there was a description of tests used. We included papers that assessed language domain in individuals with MCI. The PRISMA guideline was adopted to better conduct the review.

Results

The search strategy initially resulted in 2978 articles. After excluding duplicates and applying the eligibility criteria, 23 papers were selected for full‐text reading and 8 were included for analysis. The tools used for language assessment were not standardized, ranging from isolated tasks to subtests of larger instruments and complete batteries. The most common instrument was the Boston Diagnostic Aphasia Examination (25%), which was applied completely in one study and partially in another. The most commonly tested language skills were verbal fluency assessed in 75% of the works and naming, present in 50% of the studies. Skills such as reading and writing were little explored, possibly because educational issues impact on the possibility of reliably assessing these abilities.

Conclusion

There is no consensus and no specific instruments for assessing language in low‐educated individuals with MCI. In addition, few language skills are tested in this population, which means there is a need to create better‐validated tests designed for this public.
Genomic Frontiers in Alzheimer’s Research: A Primer on the Alzheimer’s Disease Sequencing Project (ADSP) and its AI/ML Opportunities
Authors: Wang Li‐San , Leung Yuk Yee , Lee Wan‐Ping , Kuzma Amanda B , Valladares Otto , Bush William S. , Martin Eden R. , Naj Adam C. , Hohman Timothy J. , Schellenberg Gerard D. ,   Alzheimer’s Disease Sequencing Project
Published: January 2025

Background

In this introductory talk, we embark on a journey of through the genomic frontiers of Alzheimer’s research via the revolutionary Alzheimer’s Disease Sequencing Project (ADSP).

Method

ADSP integrates together various components that collectively unravel the intricate genetic landscape of Alzheimer’s disease with the ultimate goal of advancing precision medicine for the millions affected globally by this devastating disease. With a goal of sequencing and analyzing up to 150,000 complete genomes and associated clinical and functional data in the next five years, ADSP has amassed an unprecedented wealth of genomic data from diverse populations, providing a comprehensive and holistic understanding of the genetic underpinnings of Alzheimer’s disease.

Result

This presentation serves as a primer, exploring various components of the ADSP and discuss the unprecedented opportunities it presents for Alzheimer’s disease and AI/ML researchers: (1) Diversity Initiative: The ADSP places a paramount emphasis on diversity, ensuring the inclusion of a wide range of populations in its genomic dataset. (2) Phenotype Harmonization: Harmonizing phenotypic data across diverse cohorts is a critical aspect of the ADSP, facilitating meaningful comparisons and analyses. (3) Functional Genomics: Moving beyond genetic variations, the ADSP incorporates functional genomics to discern the biological mechanisms at play. (4) AI/ML Opportunities: the focus of this session, we will start by illuminating the wide range of opportunities the ADSP offers to AI/ML researchers. From predictive modeling to identifying novel biomarkers and therapeutic targets, we will explore the vast landscape of possibilities for data‐driven discoveries that can shape the future of Alzheimer’s research and precision medicine.

Conclusion

As we uncover the potential of AI/ML within the ADSP, we will emphasize the need for collaborative initiatives between AI/ML researchers and the broader Alzheimer’s research community. The synergy between these fields holds the key to unlocking breakthroughs that can translate genomic insights into tangible clinical advancements.
Examining pathology of Alzheimer’s disease via clusterin and Aβ interaction
Authors: Kim Danyeong , Shim Kyu Hwan , Gong Yunseo , Yang Hyewon , Kang Min Ju , An Seong Soo
Published: January 2025

Background

Clusterin, a multifunctional glycoprotein, is implicated in Alzheimer’s disease (AD) pathogenesis due to its roles in Aβ aggregation and clearance. Hence, understanding the specific interactions between Clusterin and Aβ would be a crucial for unraveling AD mechanisms and exploring therapeutic avenues. Previous study reported that clusterin bound with Aβ directly. This study investigated the specific fractions of clusterin interacting with Aβ in AD. Our focus extended to analyzing patient samples, offering clinical relevance. This comprehensive approach aimed to deepen insights into AD pathology for potential therapeutic and diagnostic applications.

Method

Clusterin was synthesized into 4 fragments (CLU #1, 2, 3, 4) and identified in Aβ fibrilization and oligomerization inhibition effects through thioflavin T (ThT) and Multiple detection system (MDS) assay. The fragments were conducted for Aβ inhibition effects through ThT and MDS assay. SH‐SY5Y cells were measured for Aβ protections of clusterin fragments. ELISA was assessed for clusterin and co‐interaction of clusterin‐Aβ in AD plasma samples.

Result

Our results proved that clusterin inhibited Aβ fibrilization. Especially, clusterin #2 significantly decreased both Aβ fibrilization and oligomerization. The clusterin #3 also showed Aβ oligomerization inhibition effect, but less than the #2. The #2 and #3 increased cell viability after treatment of Aβ protofibrils. By extension to inhibit clusterin and Aβ from clinical samples, clusterin levels slightly decreased in AD plasma samples in comparison to healthy control. Next, co‐interactions of clusterin‐Aβ were decreased in AD samples.

Conclusion

This study highlighted the inhibition effect of Aβ by clusterin through its close interactions. Especially, specific fragments (#2) of clusterin strongly decreased Aβ oligomerization, and recovered cell viability after Aβ protofibril treatment. This suggested that clusterin supported the direct interaction with Aβ, furthermore involving its removal. In clinical aspects, the decreased levels of clusterin in AD plasma were observed, along with reduced clusterin‐Aβ co‐interactions, which indicated the potential impairments in Aβ clearance mechanisms, contributing to AD pathology progression. The findings contributed to our understanding of the complex interplays between Clusterin and Aβ in AD, offering insights for therapeutic and diagnostic development.
Perseverations and switching during a semantic verbal fluency task
Authors: Dubey Neha , Basu Jayanti , Ghosh Amitabha
Published: January 2025

Background

It is believed that delayed perseveration on a semantic verbal fluency (SVF) test may occur due to impaired working memory (WM). However, the relation between perseveration and switching, and the self‐generated interference one has to overcome when switching back to a previously visited subcategory has not been explored. In this study we wanted to see: 1) if perseverative errors in SVF test require switching and subsequent switch back to a previously explored subcategory; (2) if this trend would parallel cognitive decline.

Method

We studied three groups, amnestic mild cognitive impairment (aMCI) (n = 30), Alzheimer’s disease (AD) (n = 30) and healthy controls (HC) (n = 60) based on their performance on an SVF task along with tests of executive function. Our primary analysis, focussed on the association of switching and switch back with the first perseverative error.

Result

Perseveration was significantly associated with switch back for individuals with cognitive decline and healthy controls (χ2 = 24.88, p = .000359). Fewer switches and switchbacks were needed to trigger a perseveration as we moved along the continuum of cognitively healthy to cognitively impaired (HC>aMCI>AD). Finally, across all groups, perseverations were a result of more switchbacks (Wald chi‐square = 8.909, p = .003) rather than other factors.

Conclusion

These findings suggest that it is switching and eventual switch back to a previous subcategory, and not the distance from the index word alone, that trigger perseverative errors in SVF tasks.
Anosognosia in Alzheimer's disease: the interplay between resting state Default Mode Network and Salience Network
Authors: Tondelli Manuela , Ballotta Daniela , Carbone Chiara , Maramotti Riccardo , Chiari Annalisa , Zamboni Giovanna
Published: January 2025

Background

Recent evidence suggests that unawareness in Alzheimer’s disease (AD) continuum can be explained by a failure of the connections between brain regions involved in accessing and monitoring self and other information. It has been demonstrated that AD patients with anosognosia have reduced network connectivity in the default mode network (DMN); in addition, stronger connectivity of bilateral anterior cingulate cortex (ACC) was showed to be associated with anosognosia in prodromal AD suggesting a possible role of this region in mechanisms of “adaptation” to anosognosia early in the disease. Therefore, we hypothesized that anosognosia in AD could be associated with an imbalance between the activity of the DMN and the salience network (SN) detectable using resting state functional magnetic resonance imaging (fMRI).

Methods

Sixty patients with MCI and AD dementia underwent fMRI and neuropsychological assessment including the Anosognosia Questionnaire Dementia (AQ‐D), a measure of anosognosia based on a discrepancy score between the patient’s and carer’s judgments. Independent component analysis was applied and: i) correlation analyses between the AQ‐D score and functional connectivity in SN and DMN, and ii) comparison analyses of functional connectivity in DMN and SN between aware or unaware patients were performed.

Results

AQ‐D scores negatively correlated with intrinsic functional connectivity within the DMN in the retrosplenial cortex and precuneus, irrespective of cognitive impairment stage and age. We also found that unaware patients had higher connectivity within the SN in the anterior cingulate cortex compared to aware patients.

Conclusion

in patients with MCI and AD dementia, higher degrees of anosognosia are associated with lower functional connectivity within the DMN in the retrosplenial cortex and higher functional connectivity within the SN in the anterior cingulate cortex. This suggests that DMN and salience network might interplay in anosognosia expression in the AD continuum.
Differentiating Sporadic behavioural variant Frontotemporal Dementia from late‐onset Primary Psychiatric Disorders: the DIPPA‐FTD study
Authors: de Boer Sterre C. M. , Fenoglio Chiara , Fumagalli Giorgio G , Riedl Lina , Matis Sophie , Chatterton Zac , Rue Ishana , Landin‐Romero Ramon , van der Lee Sven J , Sommer Patrick , Grimmer Timo , Diehl‐Schmid Janine , Teunissen Charlotte , Galimberti Daniela , Halliday Glenda M , Ducharme Simon , Piguet Olivier , Pijnenburg Yolande A.L.
Published: January 2025

Background

Sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features and lack of reliable biomarkers. The multi‐centre study DIPPA‐FTD aims to develop diagnostic‐ and prognostic‐algorithms that can distinguish sporadic bvFTD from late‐onset PPD. The aim of the retrospective DIPPA‐FTD study was to identify the strongest clinical discriminators.

Method

DIPPA‐FTD has compiled a retrospective database with 508 sporadic bvFTD and 152 late‐onset PPD cases from five cohorts, making it the largest sporadic FTD cohort to date. Logistic regression models and ROC curve analysis were applied to determine discriminative value per clinical marker in separate subsets; (i) neuropsychological features, (ii) visual brain atrophy rating scales and (iii) serum NfL+GFAP. A global (backward stepwise) logistic regression was also conducted in the most optimal subset that had all markers per modality available. All models were adjusted for age, sex and education when indicated.

Result

For marker (i) (bvFTD n = 217, PPD n = 75) higher scores of letter fluency (OR:1.47, p<0.001), global cognitive screening (OR:1.72, p = 0.01) and lower attention scores (OR:0.77, p = 0.05) were significantly associated with increased likelihood of PPD and reached an AUC of 0.77. Marker (ii) visual atrophy rating composite score (bvFTD n = 211, PPD n = 112) reached diagnostic accuracy of 79% and fronto‐insula was the most useful discriminator (AUC 0.80). Analysis of marker (iii) NfL+GFAP (bvFTD n = 275, PPD n = 82) showed that NfL and GFAP levels were significantly higher in bvFTD. Combination of NfL+GFAP yielded highest AUC value (0.88). The combined dataset with all markers variables available (bvFTD n = 120, PPD n = 40) reached an AUC of 0.89. Higher NfL (OR:1.09, p<0.01), more atrophy in fronto‐insula (OR:2.38, p = 0.02) and enlarged mean ventricular space (OR:3.84, p = 0.05) were significant predictors for sporadic bvFTD.

Conclusion

Global cognition, letter fluency and attention scores, fronto‐insula brain atrophy and NfL+GFAP have a significant role in discriminating sporadic bvFTD from PPD. Combination of markers can increase diagnostic accuracy in clinical setting. Promising markers identified in this retrospective study will be validated in the prospective DIPPA‐FTD study and integrated in a data‐driven approach to develop diagnostic and prognostic tools, enabling early‐stage diagnosis sporadic bvFTD which is required for trial enrolment.
Interrelationships of social determinants with cognition, vascular health, and physical functioning
Authors: Amofa‐Ho Priscilla A
Published: January 2025

Background

The primary aim of the current analysis was to evaluate the cumulative effect of different social determinants of health (SDoH) factors on vascular burden, cognition, and physical functioning.

Method

We conducted a secondary data analysis of the MIDUS 2 cross‐sectional study. Participants were ages 55 and above. Measures derived from the Framingham Stroke Risk Profile, Brief Test of Adult Cognition by Telephone, and MOS‐36 were used to represent vascular burden, cognition, and intermediate activities of daily living, respectively. SDoH variables included education, income, health insurance, stress, and support from family and friends. Associations were evaluated using composite‐based structural equation model (c‐SEM) embedded in an overall.

Result

Among cognitively normal adults (N = 568; mean age = 64.6), higher education, less stress, and higher income significantly contributed to the SDoH composite. Better standing in SDoH was associated with better physical functioning (beta = ‐0.21, p<0.001) and higher cognition (beta = 0.54, p<0.001). Significant direct effects of SDoH on vascular burden (beta = ‐0.12, p<0.05) and cognition (beta = 0.51, p<0.001), and of vascular burden on cognition (beta = ‐0.28, p<0.001) were found. Mediation analysis indicated that the unique effects of SDoH on cognition remained significant after controlling for vascular burden (beta = 0.04, p<0.05). After accounting for vascular burden and cognition, SDoH did not have a significant unique effect on physical functioning.

Conclusion

Our results support the disablement process that suggests that factors outside of the disease model (like SDoH factors) impact both the underlying diseases that lead to physical and functional limitation, all of which are associated with dementia/cognitive decline.
Dynamic disease‐associated gene regulatory transitions unmask genetic risk associated neurodegenerative cell states
Authors: Han Xia , Rexach Jessica E
Published: January 2025

Background

Abnormal tau protein accumulation selectively affects distinct brain regions and specific neuron and glia populations in tau‐related dementias like Alzheimer’s disease (AD), frontotemporal dementia (FTD, Pick’s disease type), and Progressive supranuclear palsy (PSP). The regulatory mechanisms governing cell‐type vulnerability remain unclear.

Method

In a cross‐disorder single‐nucleus analysis, we examined 663,896 nuclei, assessing chromatin accessibility in three brain regions (motor cortex, visual cortex and insular cortex) across PSP, AD, and FTD in 40 individuals. Integrating genetic data with single‐nucleus RNA sequencing, we identified cell‐type‐specific cis‐regulatory elements (CREs) influencing disease‐associated transcriptional changes. Connecting GWAS signals to cell types enabled precise mapping of risk‐associated genetic elements to disorder‐specific gene regulatory events, accounting for dynamic gene regulation in the diseased brain.

Result

Disorder enriched CRE modules were primarily activated in PSP astrocytes and FTD microglia. PSP exhibited increased astrocyte involvement, identified by distinct changes in astrocytes (ast.C1). In contrast, FTD featured microglia with suppressed GRN expression (mg.C4). Differentially accessible gene regulatory elements in mg.C4 uniquely and significantly contributed to FTD risk heritability across microglia. Disease dynamic chromatin accessibility peaks and gene enhancer elements, especially in astrocytes, accounted for more AD and PSP heritability, while FTD heritability predominantly involved microglial upregulated peaks.

Conclusion

This study enhances our understanding of disease heritability, reinforcing the multicellular model of neurodegeneration. Glial cell types interacting with disease‐specific elements form disorder‐specific networks, deepening knowledge of genomic and cellular mechanisms in tau‐associated neurodegeneration.
Vascular Burden, dementia biomarkers and Neuropsychiatric Symptoms in Dementia
Authors: Chen Cheng‐Sheng , Lin Hsiu‐Fen
Published: January 2025

Background

Neuropsychiatric symptoms (NPSs) significantly impact outcomes for individuals with dementia, with multiple factors contributing, including neurobiology. This study aims to enhance our understanding of the neurobiology of NPSs by examining the links between vascular burdens, dementia biomarkers, and NPSs.

Method

Patients with dementia receiving outpatient services were included. The Neuropsychiatric Inventory (NPI) assessed NPSs. Vascular burdens were evaluated through clinical vascular diseases and white matter hyperintensities (WMH) severity using the Fazekas score in brain MRI. Additionally, ApoE genotypes and visual ratings of medial temporal atrophy (MTA) in brain MRI were used as dementia biomarkers.

Result

Forty‐five dementia patients participated, with the majority having Alzheimer’s disease (80%), followed by vascular dementia (8.9%), dementia with Lewy bodies (8.9%), and frontotemporal dementia (2.2%). The results indicated associations between depression symptoms and vascular diseases (p = 0.03), as well as anxiety symptoms (p = 0.03) and the depression/apathy cluster (p = 0.03) with MRI Fazekas scores. Regarding dementia markers, agitation/aggression was associated with ApoE ε4 (p = 0.02).

Conclusion

The findings suggest specific associations between vascular burden and ApoE ε4 with certain NPSs, linking vascular burden to depression and anxiety, and agitation to ApoE ε4.
Validation of the measures for activities of daily living in older adult with cognitive disorders: the Korean version of the University of California San Diego Performance‐based Skills Assessment
Authors: Yim Seon Jin , Kim Kayoung , Joo Chaelin , Han Joo Hyun
Published: January 2025

Background

The study aimed to evaluate the validity of the Korean version of the University of California San Diego Performance‐based Skills Assessment, Validation of Intermediate Measures (K‐UPSA‐2‐VIM) in patients with dementia (D), Mild cognitive impairment (MCI), cognitive normal control group (CN), and explore the usefulness of the instrument as a measure of ADL in older adults with cognitive disorder.

Method

Study participants were 25 patients with D, 43 patients with MCI, 111 controls with CN group, respectively. For cognitive assessment, Mini Mental State Examination (K‐MMSE‐2), Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery (CERAD‐K‐NP), Clinical Dementia Rating (CDR) were used. For functional assessment, Barthel‐Activities of Daily Living (B‐ADL), Instrumental Activities of Daily Living (K‐IADL), Dementia Screening questionnaire (K‐DSQ), K‐UPSA‐2‐VIM were used. Multivariate Analysis of Covariance (MANCOVA) was conducted to assess whether statistically significant differences existed in the scores of K‐UPSA‐2‐VIM and functional assessment measures among the different cognitive subgroups. Receiver Operating Characteristic (ROC) curve analyses were conducted to determine the optimal cut‐off scores for K‐UPSA‐2‐VIM that exhibit maximum sensitivity and specificity in discriminating between CN and MCI groups, MCI and D groups, in respectively.

Result

Statistically significant differences were observed in all subdomains and total score of the K‐UPSA‐2‐VIM among three cognitive groups. All subdomains and the total score of K‐UPSA‐2‐VIM demonstrated a significant correlation with all subdomains of CERAD‐K‐NP. K‐UPSA‐2‐VIM demonstrated 75.7% of sensitivity and 65.1% of specificity, with an area under the curve (AUC) of 0.731 (95% CI:0.641‐0.821, p < 0.001) in discriminating between CN and MCI groups. In discriminating between MCI and D groups, 76.7% of sensitivity and 64.0% of specificity, with an AUC of 0.706 (95% CI:0.580‐0.833, p = 0.005) were demonstrated.

Conclusion

Our study results suggest that the K‐UPSA‐2‐VIM has diagnostic validity in Korean patients with dementia and mild cognitive impairment. The K‐UPSA‐2‐VIM is useful for assessing patients, including elderly individuals living alone without caregivers.
Large‐scale exome sequencing identifies novel genes for socioeconomic status, education, and cognition
Authors: Wu XinRui , Yu Jin‐Tai
Published: January 2025

Background

Cognition and its two critical proxies, socioeconomic status (SES) and educational attainment (EA), contribute substantially to human health and are heritable. Elucidating the genetic characteristics of SES/EA/Cognition not only helps to understand the innate individual differences in cognition, but also aids in unraveling the biological mechanisms of complex cognitive‐related disorders such as Alzheimer’s disease (AD). Here, we explored the rare and common protein‐coding variants impacting the comprehensive cognition phenotypic spectrum by leveraging large‐scale exomes.

Method

Using 350,770 exomes from the UK Biobank, we performed gene‐based collapsing analysis and single‐variant analysis for rare and common variants, respectively. Identified genes were biological annotated at multiple levels of gene sets, tissue types and cell types. The identified genetic associations with SES/EA/Cognition were further extended to brain structure, blood chemical markers, and neuropsychiatric phenotypes. Lastly, Mendelian randomization (MR) analysis and druggability evaluations were performed to reveal potential therapeutic targets.

Result

We identified 79 SES/EA/Cognition‐associated genes (64 novel) after Bonferroni correction, 29 from gene‐based collapsing tests for rare variants (P < 2.19 × 10‐8) and 50 from single‐variant association analysis for common variants (P < 1.08 × 10‐7). The intersection of rare variants with genome‐wide association studies signals prioritized ADGRB2 and KDM5B, and the effect of rare KDM5B variants was independent of nearby common variants. Pathway enrichment analysis revealed the involvement of synapse and hepatic metabolism. Multiple human brain tissue types as well as cell clusters of excitatory neuron and microgila were enriched. Rare variants in five genes (C2CD2L, IGF1R, AKNRD12, GIGYF1, KDM5B) and 35 common variants showed pleiotropy with broader biological phenotypes, including hippocampus volume and neurodegenerative diseases. MR analysis revealed the causal relationships between the expression levels of 23 genes in brain with SES/EA/Cognition (7 mapped to drug targets).

Conclusion

This study utilizes large‐scale exome sequencing to provide a more comprehensive genetic framework underlying SES/EA/Cognition, offering informative associated genes and biological insights. The identified 79 genes across full allele frequency spectrum, 64 of which exhibited novel associations, would provide an abundant resource for further in‐depth molecular mechanistic studies and drug development for cognition.
Spatial transcriptomics reveals neuroimmune mechanisms of Aβ clearance in immunized Alzheimer’s disease patients
Authors: van Olst Lynn , Simonton Brooke , Edwards Alex J , Forsyth Anne V , Jamshidi Pouya , Li Mengwei , Shepard Nate , Krainc Talia , Argue Benney , Zhang Ziyang , Xu Hang , Norman Jeanette , Castellani Rudolph J , Watson Thomas J , Chen Jinmiao , Nicoll James AR , Boche Delphine , Gate David
Published: January 2025

Background

Recent advances in Alzheimer’s disease (AD) therapeutics involve immunization against amyloid‐β (Aβ). Post‐mortem brain analysis from the first active Aβ immunotherapy trial indicated clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain unknown.

Method

Here, we utilized a novel spatial proteogenomics approach to study brain tissues from 13 AD patients immunized with Aβ. We compared these actively immunized patient brains to tissues from non‐immunized AD patients and non‐neurologic disease controls. Additionally, we used spatial proteogenomics and single‐cell RNA sequencing technologies to investigate the effects of lecanemab, a passive anti‐Aβ drug.

Result

We reveal the transcriptomic neuroimmune response in the Aβ plaque microenvironment following anti‐Aβ immunization. This response is characterized by an increase in genes associated with the TREM2‐APOE axis in microglia of the immunized AD cortex.

Conclusion

Altogether, our data uncover immediate and lasting neuroimmune responses in the AD brain induced by active and passive Aβ vaccination.
Association between telomere length and idiopathic normal pressure hydrocephalus: a Mendelian randomization study
Authors: Yang Feng , Cai Hanlin , Ren Meng Yi , Huang Keru , Gao Hui , Qin Linyuan , Wang Ruihan , Chen Ping Yong , Zhou Liangxue , Chen Qin
Published: January 2025

Background

Idiopathic normal pressure hydrocephalus (iNPH) is highly prevalent among elderly individuals, and there is a strong correlation between telomere length and biological aging. However, there is limited evidence to elucidate the relationship between telomere length and iNPH. This study aimed to investigate the associations between telomere length and iNPH using the Mendelian randomization (MR) method.

Method

The genetic variants of telomere length were obtained from 472,174 UK Biobank individuals. Summary level data of iNPH were acquired from 218,365 individuals of the FinnGen consortium. Five MR estimation methods, including inverse‐variance weighting (IVW), MR‐Egger regression, weighted median, weighted mode and simple mode, were used for causal inference. Comprehensive sensitivity analyses were conducted to test the robustness of our results. In addition, multivariable MR was further implemented to identify potential mechanisms in the causal pathway from telomere length to iNPH.

Result

Genetically determined longer telomere length was significantly associated with decreased risk of iNPH (OR = 0.44, 95% CI 0.24‐0.80; P = 0.008). No evident heterogeneity (Cochran Q = 138.11, P = 0.386) and pleiotropy (MR Egger intercept = 0.01, P = 0.514) were observed in the sensitivity analysis. In addition, multivariable MR indicated that the observed association was attenuated after adjustment for several vascular risk factors, including essential hypertension (IVW OR = 0.55, 95% CI 0.30‐1.03; P = 0.061), type 2 diabetes (IVW OR = 0.71, 95% CI 0.09‐5.39; P = 0.740) and coronary artery disease (IVW OR = 0.58, 95% CI 0.31‐1.07; P = 0.082).

Conclusion

Our MR study revealed a strong negative correlation of telomere length with iNPH. The causal relationship might be driven by several vascular risk factors.
Neurological, cognitive and psychiatric features of Primary Progressive Aphasia: a naturalistic study of a large cohort over 10 years
Authors: Tastevin Maud , Lavoie Monica , Laforce Robert
Published: January 2025

Background

Patients with Primary Progressive Aphasias (PPAs) almost systematically inquire about the longitudinal evolution of their disease in clinics but very little research exists on the issue.

Method

We studied 82 PPA patients from the Research Chair on PPA – Fondation de la Famille Lemaire Cohort over a 10‐year span (42 logopenic, 21 non‐fluent/agrammatic and 19 semantic PPAs) and collected data from 5 domains (language, cognition, motor, psychiatric, functional) at 5 time points from onset to death. Logistical regression analyses and repeated measures ANOVAs were conducted to delineate the longitudinal profile of each variant PPA.

Result

All patients presented anomia and executive impairments over time. Language deficits tended to be more significant for lvPPA, particularly after 3 years of evolution and this group showed broader cognitive impairments. Psychiatric symptoms were more frequent in svPPA and nfvPPA, particularly after 5 years of evolution. Motor features predominantly affected patients with nfvPPA after 2 years of evolution. Overall functional abilities remained preserved the longest in svPPA (up to 5 years).

Conclusion

To our knowledge, this naturalistic study on all major PPA symptoms over a 10‐year span from onset to death is the largest to date. Data from this study can help clinicians better inform and prepare their patients for future challenges as well as design more focused interventions.
Associations between 10‐year depressive symptom trajectories, cognitive function, and self‐management capacity skills among older primary care patients
Authors: Vogeley Abigail , Cecil Patrick , Opsasnick Lauren , Curtis Laura M , Yoshino‐Benavente Julia , Bonham Morgan , Russell Andrea , O'Conor Rachel , Wolf Michael S , Lovett Rebecca
Published: January 2025

Background

Chronic depression impacts the ability to successfully manage one’s health, yet mechanisms underlying this relationship are not fully understood. Cognitive dysfunction, or impairment, may result from persistent depression. We aimed to determine whether chronic depressive symptoms, leading to poor cognition, impacted self‐management capacity among older adults with chronic conditions.

Method

Data from 369 older adults from Chicago, IL and participating in a longitudinal cohort study on aging was used for this analysis. The Patient‐Reported Outcomes Measurement Information System (PROMIS) Depression 8‐item survey was administered across 4 time points over 10 years; raw scores were transformed into T‐scores. Group‐based trajectory modeling was used to identify latent depressive symptom trajectory groups. The Comprehensive Health Activities Scale (CHAS) was used to measure chronic disease self‐management skills, including comprehension and recall of print, spoken, and multimedia information. A factor score representing fluid cognitive function was derived from 11 measures across 4 cognitive domains (processing speed, working memory, inductive reasoning, long‐term memory). Demographic‐adjusted multinomial linear regressions were used to assess associations between depressive symptom trajectory groups and self‐management skills, first without and then including fluid cognitive function.

Result

Mean participant age was 71 years (SD 5.3); most participants were female (71%) and non‐Hispanic white (54%). 86% had 2+ chronic medical conditions (mean 3.3 (SD 1.8)). Three distinct depressive symptom trajectories emerged: participants displayed either consistently minimal (42%), normative (46%), or persistently elevated (12%) symptoms. In multivariable analyses, participants in the persistently elevated group had poorer self‐management performance (β = ‐6.4; 95% CI: ‐11.1, ‐1.7; p = 0.007). Adjusting for cognitive function attenuated this association to a level of non‐significance, while a strong association emerged between cognition and self‐management skills (β = 16.1; 95% CI: 14.4, 17.8; p<0.001).

Conclusion

Persistent depression may reduce self‐care capacity, likely due to poorer cognitive function. Improved understanding of how depression may alter cognitive function or lead to its progressive decline, and ultimately impact self‐care capacity, may inform future health system interventions to support the management of comorbid conditions.
Linguistically‐appropriate tools to assess cognition in Mandarin speakers
Authors: Hu William T. , Chen Michelle H. , Li Mei‐Ling , Su Guibin J , Lin Feng Vankee
Published: January 2025

Background

Assessment of cognition in older Chinese Americans currently relies on content‐translated instruments with limited considerations for logographic (vs. alphabetic) nature of Chinese, cultural experience (pre‐ and post‐immigration), speech rate, and multilingualism. This results in confusion between fluency tasks, systematic error in digit span, disparate familiarity with stimuli according to country of origin (e.g., Taiwan vs. China), and low overall ecological validity. Here we developed and tested new instruments on memory (logical memory & word list learning), executive function (culturally‐appropriate Trail Making Test B), and language (fluency based on character, phoneme/pinyin, and homonym) to account for these factors.

Method

Bilingual (Mandarin and English, n = 50) and Mandarin‐only (n = 50) speakers were recruited in the NYC/New Jersey (Rutgers) and SF Bay (Stanford) areas. Bilingual adults completed both English and Mandarin cognitive testing for correlation, while monolingual speakers completed only Mandarin testing for reliability. Instruments in simplified and traditional Chinese were available for all, and each participant additionally underwent Clinical Dementia Rating, language proficiency(Mandarin, English), and brain MRI analysis.

Result

Participants had a median age of 66 yr (range 56‐84), and monolingual participants had been in the US for less than bilingual participants (33 vs. 42 yr, p = 0.004). New Mandarin tests had very high reliability (median Cronbach’s alpha of 0.935 range 0.807‐0.969). Among bilingual participants, performance in English and Mandarin for language‐independent tests (Trail Making Test A, written Symbol Digit Substitution Test) and some language‐dependent (e.g., animal fluency, Trail Making Test B) tests had acceptable to high reliability (standardized Cronbach’s alpha 0.638‐0.838). Total learning and delayed recall of corpus‐adjusted (based on word use frequency in American English and Beijing Chinese) also had high reliability (0.681 and 0.774) between languages, while character‐guided and animal fluency in Mandarin (0.560, p = 0.004) had similar correlation as English‐based letter‐guided and animal fluency (0.600, p = 0.005). Logical memory in English was associated with English proficiency and learning of a list of English words, but not logical memory in Mandarin.

Conclusion

Most novel Mandarin cognitive assessments showed high inter‐language reliability in bilingual older adults, and their diagnostic validity is being prospectively tested.
Whole‐brain Cellome‐Wide Association Study (CWAS) Unveils Ultra‐Early Neurodegeneration Phenomena in a 3D Spatial Cell Atlas
Authors: Mitani Tomoki T , Yamaura Kosei , Matsumoto Katsuhiko , Yamada Rikuhiro , Susaki Etsuo A , Ueda Hiroki R
Published: January 2025

Background

In aging societies, neurodegenerative diseases, such as Alzheimer’s disease, are receiving attention. These diseases are primary targets for preemptive medicine, emphasizing the importance of early detection and preventive treatment before the onset of severe, treatment‐resistant damages. However, there is a lack of comprehensive investigation of lesions and molecular targets in the entire organ, whereas spatial identification of early‐stage lesions is potentially overlooked at the single‐cell level.

Method

Here, we propose a novel approach, CWAS (whole body/organ cellome‐wide association studies), which integrates and analyzes spatio‐temporal cellular information across the entire mouse organ into a comprehensive organ cell atlas using tissue‐clearing imaging technologies [1,2].

Result

In our initial application to neurodegenerative models, we have been able to identify previously unreported neural degenerations at specific times and locations at the single‐cell level. In addition, our time‐series analysis in a mouse model of Alzheimer’s disease revealed the possible simultaneous onset of amyloid deposition and neurodegeneration, challenging the traditional amyloid hypothesis. Furthermore, we were able to identify unique multicellular inflammation networks surrounding neurodegenerative lesions in several disease models.

Conclusion

Our findings establish the concept of “spatial cellomics” realized through spatially precise organ mapping and integrated multiomics analysis at the single‐cell level. This approach shifts pathology, providing deeper insight into disease mechanisms and preventive strategies.

References

[1] Murakami TC, et al. Nat Neurosci. 2018;21(4):625‐637.

[2] Matsumoto K*, Mitani TT*, Horiguchi SA, et al*. (*equal contribution) Nat Protoc. 2019;14(12):3506‐3537.
Functional Capacity in Activities of Daily Living in the Alzheimer’s Disease Continuum
Authors: Henriquez Fernando , Dominguez Carmen , Grandi Fabrissio , Campo Cecilia Gonzalez , Contreras Patricio Riquelme , Lillo Patricia , Martínez‐Pernía David , Thumala Daniela , Henriquez Rodrigo , Aboitiz Francisco , Chonchol Andrea Slachevsky
Published: January 2025

Background

The most common and prevalent dementia worldwide is Alzheimer’s disease (AD). AD is a continuum composed of Subjective Cognitive Impairment (SCD), Mild Cognitive Impairment (MCI), and Alzheimer’s Disease dementia (ADD) stage. One of the main clinical variables in patients with dementia is performance in functional capacity since its alterations are associated with poor prognosis and disease progression. Functional capacity is measured through activities of daily living (ADL), which are divided into three domains: i) Basic (BADL), ii) Instrumental (IADL), and iii) Advanced (AADL). The study aimed to characterize the performance of the different stages of the AD continuum in the ADL domains and their association with cognitive abilities.

Method

A cross‐sectional study of subjects at different stages of the AD continuum was conducted: Healthy Controls (CTR) (n = 17), SCD (n = 77), MCI (n = 30), and ADD (n = 23), who were matched for age, sex, and education. ADLs were estimated using The Technology‐Activities of Daily Living Questionnaire (T‐ADLQ), which assesses the three domains and a total score. T‐ADLQ performance was compared across groups and correlated with cognitive ability instruments (ACE‐III and IFS).

Result

The results showed that patients with ADD performed worse on the BADL, IADL, and total ADLs compared to the other three groups. There were no significant differences between the CTR, SCD, and MCI on the BADL, IADL, and total ADLs. However, the AADL, in addition to differentiating the ADD patients from the other three groups, also showed differences between CTR and MCI subjects and between SCD and MCI subjects (Table 1 and Figure 1). The correlation study showed that AADL correlated significantly with global cognitive and executive function assessment (Figure 2).

Conclusion

AADL shows progressive functional impairment at different stages of the AD continuum, which is further associated with global cognitive and executive function performances. As one progresses to a more advanced stage of the disease continuum, the performance of ADLs, especially AADLs, worsens, which could indicate a marker of disease progression, allowing for better patient follow‐up.
Can Butyrate offer a novel approach to mitigate the pathology of AD?
Authors: Fernando Warnakulasuriya Mary Ann Dipika Binosha , Martins Ian J , Senerath Uththara , Bharadwaj Prashant , Martins Ralph N
Published: January 2025

Background

Our research group is currently exploring the potential of Butyric acid (NaB), a Short Chain Fatty Acid (SCFA), as a novel therapeutic agent for Alzheimer’s disease (AD).

Methods

In our investigation using the 5xFAD mouse model of AD, we observed that NaB had significant effects on Aβ levels, as well as on associative learning and cognitive functioning. Notably, we recorded a 40% reduction in brain Aβ and a 25% increase in fear response during both cued and contextual testing. Our studies employing M17 cell models demonstrated that butyrate provides a degree of protection against Aβ‐induced toxicity. Additionally, nanoindentation studies confirmed that butyrate induces changes in cell physiology. Building on these findings, we explored the impact of butyrate on astrocytes and microglial cells concerning amyloid beta toxicity.

Results

Current studies with stem cells have exhibited promising outcomes, indicating that butyrate significantly alleviates amyloid beta.

Conclusions

This investigation represents the initial confirmation of butyrate as an amyloid beta inhibitor across various Alzheimer’s disease (AD) models. The subsequent steps involve determining the levels of butyrate at different stages of AD by analyzing fecal samples and conducting tests to assess its therapeutic efficacy.
Serial order and complexity of Category Fluency words in an Italian cohort of MCI individuals
Authors: De Marco Matteo , Da Ronch Chiara , Venneri Annalena , Gallucci Maurizio
Published: January 2025

Background

The Category Fluency Test (CFT) is the most widely‐used test of semantic memory (SM). A number of studies indicate that the serial order (SO) in which words are generated during the CFT can be informative of the underlying level of SM integrity. In this study, SO and item‐level complexity of CFT words were investigated for the first time in a cohort of Italian individuals with mild cognitive impairment (MCI).

Method

The CFT (category: animals) was administered to 60 MCI individuals recruited as part of the TREviso DEMentia (TREDEM) registry and to 54 matched healthy controls. Each CFT word was scored according to its graphemic length its typicality within the cohort and, as per Italian normative values, also according to its frequency of use and age of acquisition. Rank‐based correlations were calculated for each individual between SO and each item‐level feature and z‐converted for data analysis. One‐way ANOVAs were then run to compare these correlational indices between the two groups, controlling for age, education and sex.

Result

A significant between‐group difference emerged from the analysis of the SO‐word length correlational index (p < 0.004). Both groups tended to generate increasingly longer words during CFT performance, but in the MCI group this increase was significantly steeper.

Conclusion

While word length does not embed any semantic information, these findings indicate that the graphemic length‐based organisation of lexical‐semantic material during recall is altered in native Italian‐speaking MCI individuals.