bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal variability in resting heart rate associates with empathy decline in pre‐symptomatic and symptomatic familial frontotemporal degeneration
Authors: Rhodes Emma , Massimo Lauren , Dratch Laynie , Irwin David J , Boeve Brad F. , Heuer Hilary W. , Boxer Adam L. , Rosen Howard J. , Rankin Katherine P. , Sturm Virginia , McMillan Corey T ,   ARTFL‐LEFFTDS (ALLFTD)
Published: January 2025

Background

Autonomic dysfunction has been linked to empathy deficits in symptomatic frontotemporal degeneration (FTD), but less is known about pre‐symptomatic FTD mutation carriers (preFTD+). Our prior work found that increasing resting heart rate (RHR) over time predicts decline in emotional empathy in preFTD+. Here, we replicate previous findings in a large, multi‐site consortium sample and assess relationships between RHR and empathy loss across disease stages.

Method

RHR and Interpersonal Reactivity Index (IRI) were obtained serially for up to 7 years in 348 preFTD+, 202 symptomatic FTD mutation carriers (FTD+), and 311 non‐carrier family members (FTD‐) enrolled in ALLFTD. IRI Perspective Taking (IRI‐PT) and Empathic Concern (IRI‐EC) subscales measured cognitive and emotional empathy, respectively. Separate multiple linear regressions related mutation status and annualized change in RHR to annualized change in IRI subscales and assessed interactions between RHR change and phenoconversion status among mutation carriers. Logistic regression was used to assess the association between change in RHR and phenoconversion among mutation carriers, and Wilcoxon signed‐rank tests were used to examine differences in change in RHR between all study groups.

Result

In asymptomatic participants (preFTD+ and FTD‐), increase in RHR over time was associated with greater decline in IRI‐EC (ß = ‐0.07, p<.001) and IRI‐PT (ß = ‐0.03, p = .011), regardless of mutation status. Among mutation carriers (preFTD+ and FTD+), increase in RHR was associated with greater decline in IRI‐EC (ß = ‐0.04, p = .041), and this effect was stronger in FTD+ compared to PreFTD+ (ß = ‐0.07, p = .038), while an increase in RHR was associated with decline in IRI‐PT only in FTD+ (ß = ‐0.07, p = .046). Change in RHR did not predict phenoconversion in mutation carriers (PreFTD+ and FTD+), but PreFTD+ showed less change in RHR over time relative to FTD+.

Conclusion

Changes in empathy in asymptomatic preFTD+ and FTD‐ are linked to variability in RHR regardless of genetic status, likely reflecting a non‐specific impact of autonomic functioning on empathy and prosocial behavior. In contrast, increasing RHR predicts decline in cognitive and emotional empathy in FTD mutation carriers but primarily after phenoconversion, suggesting that autonomic contributions to empathy in familial FTD increase with disease progression and could be an early marker of manifest disease.
Irisin attenuates astrocyte activation and rescues memory in Alzheimer model mice
Authors: Heimfarth Luana , Ribeiro Felipe C , Fortuna Juliana , Ferreira Sergio T
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synapse and memory failure, and severe cognitive impairment. Physical exercise stimulates neuroprotective pathways, has pro‐cognitive actions, and has been reported to alleviate memory impairment in AD. Irisin, an exercise‐induced hormone, is secreted following proteolytic cleavage of fibronectin type‐III‐domain‐containing 5 (FNDC5). Irisin regulates peripheral metabolism, and has been found to protect synapses and rescue memory in mouse models of AD. The aim of the current study was to evaluate the possible role of irisin in astrocytes within the framework of AD pathophysiology.

Methods

We exposed primary cortical astrocyte cultures to irisin (25 nM), and the expression of neurotrophic factors and/or MAPK activity were determined by RT‐PCR or western blot, respectively. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of irisin.

Result

We demonstrate that irisin promotes the expression of brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived neurotrophic factor (GDNF) in astrocytes, and stimulates transient activation of extracellular signal‐regulated kinase 1/2 (ERK 1/2). We further show that irisin attenuates memory impairments in an AD mouse model, and modulates GDNF and insulin‐like growth factor‐1 (IGF1) signaling in vivo.

Conclusion

Our findings support the idea that physiological protection by irisin against synaptotoxic AβOs can be mediated by modulation of astrocyte‐derived factors.
Differential Protein Expression in Alzheimer’s Disease Prefrontal Cortex
Authors: Gholampour Maryam , Basu Malay , Swerdlow Russell H , Haeri Mohammad
Published: January 2025

Background

Understanding the proteomes of specific cell types within the brain is crucial for elucidating the mechanisms underlying Alzheimer’s disease (AD). However, the isolation and analysis of these diverse and low‐abundance cell populations remain significant challenges. This study aims to assess GeoMxTM Digital Spatial Profiler (DSP) by NanoString Technologies (NanoString, Seattle, USA) capable of spatially resolving protein expression profile of AD brains extracted from formalin‐fixed paraffin‐embedded (FFPE) specimens.

Method

We analyzed protein expression profile of prefrontal cortices in post‐mortem AD brains (n = 4) and age‐matched controls (n = 4) using DSP. Regions of interest (ROIs) were targeted at gray matter and the DSP panel recorded the spatial expression of 76 proteins alongside three cell specific markers (GFAP for astrocytes, Iba1 for microglia, NeuN for neurons, and nuclear stain for DNA/nuclei). Protein expression was normalized to spiked‐in ERCC RNA controls and background‐corrected using IgG controls. Group‐wise comparisons employed linear mixed models, and pairwise comparisons used t‐tests with Benjamini‐Hochberg (BH) adjustment.

Results

In each ROI, an average of 774 cells were counted, consisting of 61 GFAP, 74 microglia, and 370 neurons for each case. As expected, levels of amyloid‐β (Aβ) 1‐42, phospho‐tau (S396), and phospho‐tau (S214) were significantly elevated in AD, as confirmed by immunohistochemistry (IHC). Interestingly, Neprilysin (NEP), a key regulator of Aβ levels that catalyzes its proteolysis and prevents plaque formation, exhibited increased expression in all cell types (astrocytes, microglia, and neurons). Additionally, CD40, a crucial protein for Aβ‐induced microglial activation, showed higher levels in AD neurons, specifically.

Conclusion

While there are still some limitations, DSP technology demonstrates a potential for analyzing the brain proteome in post‐mortem tissues. Screening protein expression in larger cohorts using DSP could hold promise for identifying tissue‐based biomarkers.
Tau is required for pneumonia‐induced cerebrovascular dysfunction
Authors: Chaney Samantha D , McAdams Lauren H , Gwin Meredith S , Stevens Troy T , Lin Mike , Nelson Amy R.
Published: January 2025

Background

Many survivors of lung injury, including those with bacterial pneumonia and COVID‐19, suffer from incident dementia. Patients who have had pneumonia and other infections are at a higher risk for developing Alzheimer’s disease and related dementias (ADRD) (Chu et al., BBI, 2022, Sipila et al., Lancet Infec Dis, 2021, Girard et al., J Gen Intern Med, 2018). Previous experimental studies have shown that tau is required for pneumonia‐elicited deficits in long‐term potentiation (Balczon et al., FASEB J, 2021). Neurovascular unit dysfunction, including breakdown of the blood‐brain barrier (BBB) and gliosis, occurs early in the ADRD pathophysiological cascade. We have shown that bacterial pneumonia causes BBB breakdown, gliosis, and increased tau phosphorylation in the brain. Here, we investigated whether tau is required for pneumonia‐induced cerebrovascular dysfunction.

Method

C57BL/6J or tau knockout (KO) adult mice (1‐3 months old, both male and female) were intratracheally infected with P. aeruginosa (PA103, ExoU and ExoT competent, 105 CFU) for 24 hours. Next, we performed immunofluorescence staining for CD13 (pericytes), lectin (endothelial cells), IgG (BBB leakage), GFAP (reactive astrocytes), and Iba1 (microglia) on serially sectioned brain slices, and imaged and analyzed hippocampus and cortex.

Result

BBB leakage and reactive astrocytes and microglia were increased in the hippocampus and cortex 24 hours post‐infection with PA103 compared to saline in C57BL/6J mice. Pericyte coverage of capillaries was reduced in the hippocampus 24 hours post‐infection with PA103 compared to saline in C57BL/6J mice. There was no significant difference in BBB leakage, pericyte coverage or gliosis 24 hours post‐infection with PA103 compared to saline in tau KO mice.

Conclusion

Tau is required for bacterial pneumonia‐induced BBB breakdown and gliosis, revealing a novel immune role for this pathological hallmark of ADRD. Future studies should focus on 1) mechanism(s) by which pneumonia‐induced tau causes neurovascular unit dysfunction, 2) whether cytotoxic tau produced by the lungs during infection contributes to ADRD, 3) how the tau generated in pneumonia compares to ADRD tau variants and phosphorylation states, and 4) the applicability and benefit of therapeutics targeting tau, such as anti‐tau antibodies, on incident dementia associated with pneumonia and/or on cerebrovascular dysfunction in mild‐cognitive impairment and ADRD.
Neuropathological and cell type‐specific effects of Kv1.3 blockers in a pre‐clinical AD mouse model
Authors: Srivastava Upasna , Bowen Christine A , Kumar Prateek , Sampson Maureen , Xiao Hailian , Zeng Hollis , Sing Anson , Sojka Caitlin , Bhatia Tarun , Wulff Heike , Sloan Steven A , Rangaraju Srikant ,   Department of Neurology
Published: January 2025

Background

Kv1.3 channels are promising therapeutic targets to modulate neuroinflammatory responses in neurodegenerative disease including Alzheimer’s disease (AD). Although the ability of Kv1.3 blockers to reduce neuropathology in AD mouse models has been demonstrated, the cellular mechanisms remain unclear.

Method

5xFAD mice aged 6 months were treated with PAP‐1 (a small molecule Kv1.3 blocker, chow), ShK‐223 (peptide blocker, intra‐peritoneal twice‐weekly), control chow, or vehicle injections until 9 months age. We assessed neurobehavior, Aβ burden neuropathology and single‐nuclei transcriptomics (10x Chromium 3’). For Sn‐RNA‐seq, 137,375 cortical nuclei from n = 4 mice/group passed QC after alignment, data integration (Seurat) and batch effects removal (Harmony), followed by cell‐type annotation using a reference and its prediction score, pseudo‐bulk analysis was performed using cell‐type subsets based on the contrast PAP‐1 versus Control. DEGs were identified using (glmGamPoi) based on log2FC > < 0.25 and adjP <0.05, and magnitude of drug effect was compared across cell types. Utilized GSEA with ClusterProfiler and enrichGO to investigate Kv1.3 blockade effects on diverse cell populations.

Result

While both Kv1.3 blockers (PAP‐1 and ShK‐223) reduced Ab plaque burden in 5xFAD mice, lower Ab42 ELISA‐measured levels and improved fear conditioning behavior were only observed in the PAP‐1 group. snRNAseq revealed distinct cell type clusters, with consistent cell type proportions across all treatment groups. 5xFAD mice exhibited increased disease‐associated microglia compared to WT mice. In pseudo‐bulk analyses, PAP‐1 had the most significant impact on microglia compared to other cell types, evident from the proportion of DEGs in the sampled transcriptome. In microglia, PAP‐1 upregulated complement genes (C1qa, C1qb, C1qc), induced glial cell differentiation, transmembrane transport and voltage‐gated potassium channel. PAP‐1 treatment enhanced myelination (Plp1), oligodendrocyte differentiation and neuronal ensheathment in oligodendrocytes. These aligned with heightened activity of cognition and synapse‐related genes in astrocytes, glutamatergic and GABAergic neurons.

Conclusion

Our studies re‐affirm beneficial neuropathological effects of pharmacological Kv1.3 blockade in Ab models, and additionally reveal differential effects and mechanisms of membrane permeable and brain penetrant versus non‐permeant Kv1.3 blockers. PAP‐1 prominently affects microglia and oligodendrocytes, suggesting they may be potential targets of Kv1.3 blockade. Additionally, evidence indicates pro‐myelination and synaptic‐protective effects of Kv1.3 blockade.
Higher Cerebrovascular Reactivity Predicts Better Memory Function in Older Adults Without Dementia
Authors: Kapoor Arunima , Engstrom Allison C , Dutt Shubir , Gaubert Aimée , Alitin John Paul M , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Shao Xingfeng , Wang Danny JJ , Nation Daniel A.
Published: January 2025

Background

Optimal cerebral blood flow is crucial to maintaining cognitive function. Cerebrovascular reactivity (CVR) is a dynamic measure of cerebrovascular function which represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli. Prior studies have demonstrated an association between impaired CVR and cognitive function in cerebrovascular and neurodegenerative conditions, including cerebral amyloid angiopathy and Alzheimer disease. However, few studies have examined the association between cerebrovascular reactivity and cognitive function in older adults prior to the onset of cognitive decline.

Method

Independently living older adults (N = 111, mean age = 69.2 years; SD = 7.1; age range 55‐89 years; 29.7% male, mean education = 16.5 years; SD = 2.4) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and neuropsychological assessment. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypercapnia (vasodilation) induced by visually guided breathing exercises (15s breath holds) and indexed by capnography. We specifically examined verbal and visual memory, assessed using the RAVLT word list learning and memory, WMS‐R Logical Memory I and II, and WMS‐IV Visual Reproduction I and II.

Result

Adjusting for age, sex and education, multiple regression analyses revealed a significant positive association between CVR to hypercapnia and RAVLT word list delayed recall (B = .084, 95% CI (.001, .167), p = .048), Logical Memory II (B = .240, 95% CI (.012, .468), p = .039) and Visual Reproduction II (B = .280, 95% CI (.097, .464), p = .003).

Conclusion

In older adults without stroke or dementia, higher cerebrovascular reactivity is associated with better memory function. Cerebrovascular dysfunction is known to precede and contribute to the development of cognitive impairment. These findings suggest that cerebrovascular dysfunction influences cognitive performance even in preclinical stages. Future longitudinal may elucidate whether early cerebrovascular reactivity changes can predict long‐term development of dementia.
A multiethnic transcriptome for Alzheimer Disease identifies cross‐ancestry and ancestry‐specific expression profiles
Authors: Yang Zikun , Cieza Basilio , Reyes‐Dumeyer Dolly , Lee Annie J. , Dugger Brittany N , Jin Lee‐Way , Murray Melissa E. , Dickson Dennis W. , Pericak‐Vance Margaret A , Vance Jeffery M. , Foroud Tatiana M. , Teich Andrew F , Mayeux Richard , Tosto Giuseppe
Published: January 2025

Background

Alzheimer’s Disease (AD) presents complex molecular heterogeneity, influenced by a variety of factors including heterogeneous phenotypic, genetic, and neuropathologic presentations. Regulation of gene expression mechanisms is a primary interest of investigations aiming to uncover the underlying disease mechanisms and progression.

Method

We generated bulk RNA‐sequencing in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks, and conducted differential gene expression and enrichment analyses. We sought to identify cross‐ancestry and ancestry‐specific differentially expressed genes (DEG) and pathways across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We validated our findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Lastly, we validated top DEG using publically‐available human single‐nucleus RNA sequencing (snRNAseq) data.

Result

AD‐known genes VGF (LFC = ‐0.661, padj = 3.78) and ADAMTS2 (padj = 1.21) were consistently differentially expressed across statistical models, ethnic groups, and replicated in ROS/MAP (Figure 1). Genes from the heat shock protein (HSP) family, e.g. HSPB7 (padj = 3.78), were the top DEG, also replicated in ROS/MAP. Ethnic‐stratified analyses prioritized TNFSF14 and SPOCD1 as top DEG in Hispanic samples. Gene set enrichment analysis highlighted several significantly pathways, including “TYROBP causal network in microglia” (WP3945; padj = 1.68) and “Alzheimer Disease” (WP5124; padj = 4.24). snRNAseq validated several DEG, including VGF downregulated in neurons (padj = 1.1).

Conclusion

To our knowledge, this is the largest diverse transcriptome study for AD in post‐mortem tissue. We identified perturbated genes and pathways resulting in cross‐ethnic and ethnic‐specific findings, ultimately highlighting the importance of diversity in AD investigations.
Sex differences for clinical and pathological correlates of APOEe4 in people with Lewy body pathology
Authors: Bayram Ece , Litvan Irene
Published: January 2025

Background

In people with Lewy body (LB) pathology, Alzheimer’s (AD) co‐pathology staging has stronger association with cognition for females, and LB pathology staging has stronger association with behavioral and motor symptoms for males. As APOEe4 allele is a risk factor for LB and AD pathologies, in both females and males; we investigated whether APOEe4 association with clinical profile and pathology staging differs by sex in people with LB pathology.

Methods

Data were obtained from the National Alzheimer’s Coordinating Center Uniform Data Set (UDS), Neuropathology and Genetic Data Set for UDS visits conducted between September 2005 and August 2019. 294 females and 490 males with available APOEe4 count data from 33 Alzheimer’s Disease Research Centers, with brainstem, limbic or neocortical LB pathology were included, excluding those with other neuropathologic diagnoses. Interactions between sex and APOE ε4 count for pathology staging (LB, AD), clinical diagnosis (LB disease, AD), dementia likelihood and severity (CDR® Dementia Staging Instrument‐Sum of Boxes), behavioral symptom severity (Neuropsychiatric Inventory Questionnaire) at last visit were assessed with linear models controlling for age.

Results

40.5% of females, 40.8% of males had one APOEe4; 12.2% of females, 12.9% of males had two APOEe4 alleles (p = .95). Compared to males, females were older at last visit and died older. APOEe4 was not associated with LB pathology staging. Compared to males, APOEe4 was associated with higher level of AD pathology staging (B = 1.48 for females, B = 0.66 for males; p<.001); higher likelihood of AD clinical diagnosis (B = 1.30 for females, B = 0.49 for males; p<.001); lower likelihood of LB disease clinical diagnosis (B = ‐0.76 for females, B = ‐0.16, p<.001); higher likelihood for dementia (B = 1.76 for females, B = 1.21 for males; p<.001) and more severe dementia (B = 2.69 for females, B = 1.53 for males; p<.001) for females. Compared to females, APOEe4 was associated with more severe behavioral symptoms for males (B = 0.36 for females, B = 1.34 for males; p<.001).

Conclusions

In people with LB pathology, APOEe4 is associated with AD co‐pathology staging, clinical diagnosis, dementia likelihood, dementia and behavioral symptom severity. However, these associations can be different for females and males. Clinical and pathological associations of genetic factors can differ by sex in LB disease.
Integrated analysis approaches to decode functional consequences of molecular quantitative trait loci for complex traits
Authors: Nachun Daniel
Published: January 2025

Background

Genome‐wide association studies (GWAS) have identified thousands of genomic regions associated with complex diseases but understanding the underlying causal mechanisms remains a significant challenge. The FunGen‐xQTL project has addressed this by generating and harmonizing molecular quantitative trait loci (xQTL) across multiple layers of molecular traits in human brains, cerebrospinal fluid, and blood‐derived cells relevant to neurodegenerative disorders. Existing approaches for integrating xQTL data with GWAS have typically focused on individual molecular traits in individual QTL layers. There is a scarcity of systematic, rigorous computational methods that effectively utilize the diverse data from the FunGen‐xQTL project to understand the convergence of complex disease pathogenesis across various ‘omics levels.

Methods

FunGen‐xQTL has evaluated current best practices for xQTL integration with GWAS, creating standardized analysis protocols and bioinformatics workflows for a chosen set of methods. We have developed new computational tools for many tasks: Functional fine mapping for methylation, histone acetylation and chromatin accessibility QTLs (fSuSiE)

• Multi‐omic fine mapping for joint analysis of different ‘omics layers (mvSuSiE)

• Pairwise enrichment, colocalization, TWAS and Mendelian randomization (pecotmr)

• Multi‐omic colocalization with gradient boosting (colocBoost)

• Multi‐omic and multi‐trait TWAS and Mendelian randomization (mr.mash, CTWAS)

• Multi‐omic discovery of transQTL effects on gene networks (transCCA)

• Improved predictive models for identifying rare variants that impact function genomics (Watershed2)

• Improved quantification of splicing for splicing QTL mapping (leafcutter2).

Results

In both simulated and real data, we have found that our novel methods outperform existing methods for discovering associations between xQTL and GWAS when applied to different xQTL types. We have prepared precompiled packages for the conda family of package managers which are bundled together into containers for each workflow that can be deployed on cloud providers or local computing clusters. We have designed different schemes for xQTL integration, including disease‐centric, gene‐centric, and event‐centric analysis, to characterize the functional landscape of xQTLs around AD loci.

Conclusions

Our novel tools have improved our ability to identify shared genetic etiology between multiple related molecular traits, metabolic pathways, and Alzheimer’s disease (AD) that are highlighted by the other talks in this session.
Fine‐mapping of existing and novel functional quantitative trait locireveals local genetic influences of epigenetic and transcriptomic regulation in human brains
Authors: Marcora Edoardo , Sun Hao
Published: January 2025

Background

The FunGen‐xQTL project has significantly advanced genetics by developing and exploring novel quantitative trait loci (QTL) types in human brains, enriching our understanding of complex neurological disease etiology. We broadened the scope of epigenomic QTL analysis, integrating histone acetylation QTLs (haQTLs) and methylation QTLs (mQTLs) that affect multiple histone acetylation peaks or methylation CpG sites spatially. Additionally, we investigated a new category of splicing QTLs (sQTLs) implicated in nonsense‐mediated decay (NMD).

Method

Utilizing unique computational methods developed by FunGen‐xQTL for genome‐wide statistical fine‐mapping, we dissected intricate gene regulation networks at single‐base resolution, effectively accounting for linkage disequilibrium confounding.

Result

Our research has unveiled complex multi‐omic regulations via fine‐mapped epigenomic QTLs using our new method called fSuSiE. We identified specific genetic variants performing dual roles as both epigenomic and eQTLs across different genes, indicative of 3D multi‐gene interactions. For instance, cis‐variant rs62324750 for TMEM131L uniquely acts as a negative eQTL, negative haQTL, and positive mQTL. This complex interaction extends to nearby genes TRIM2 and MND1, where rs11728062 impacts gene expression as a negative haQTL and positive mQTL through epigenomic markers spanning gene bodies. Oligodendrocyte‐specific Hi‐C data further support these findings, suggesting novel regulatory mechanisms involving disruption of transcriptional repressor bindings. Moreover, neuronal Hi‐C and ChiP‐Seq data uncover a unique xQTL interaction pattern in APOL2, indicative of 3D protein‐chromatin structures in transcription regulation.

Employing LeafCutter2 methods from FunGen‐xQTL, we investigated the genetic basis of NMD by identifying premature termination codons from RNA‐seq data and fine‐map the corresponding sQTL for such unproductive splicing events. In the ROSMAP DLPFC dataset, we distinguished 45,999 unproductive from 130,664 productive splicing events for NMD. We observed a higher colocalization ratio of unproductive sQTLs with eQTLs, illuminating new insights into AD etiology. Notably, an unproductive sQTL in TSPAN14, colocalized with an AD GWAS signal, revealed significant gene expression and intron usage differences across genotypes, suggesting RNA expression of TSPAN14 may be mediated by genetically regulated NMD events.

Conclusion

Our work demonstrates the complex interplay of novel QTL types in gene regulation and offers significant insights for future research into the genetic mechanisms of complex diseases.
Cognitive and behavioral decline predicted by perimenopausal symptoms: A CAN‐PROTECT study
Authors: Crockford Jasper F. E. , Guan Dylan X. , Einstein Gillian , Smith Eric E. , Ismail Zahinoor
Published: January 2025

Background

Menopause has been associated with greater dementia risk. We investigated the relationship between the presence of specific symptoms experienced during menopause (i.e., perimenopausal symptoms) and later‐life emergence of cognitive and behavioral symptoms that are linked to elevated dementia risk.

Method

Participant data were from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) study. The sample for this analysis comprised 896 post‐menopausal participants, who recalled the presence or absence of 11 perimenopausal symptoms. Symptoms were categorized as vasomotor, weight changes, vaginal dryness, irregular periods, sleep problems, mood changes, brain fog, and other unnamed symptoms. Currently experienced subjective cognitive symptoms were measured with the Everyday Cognition (ECog‐II) scale. Emergent and persistent neuropsychiatric symptoms were measured with the Mild Behavioral Impairment Checklist (MBI‐C). Higher scores reflected greater severity on both measures. A negative binomial regression examined the association between perimenopausal symptoms and cognitive function. A zero‐inflated negative binomial regression examined the association between perimenopausal symptoms and MBI symptoms. All models adjusted for age of menopausal onset, menopausal hormone therapy (MHT), menopause type (i.e., spontaneous, or due to medical reasons), age, and years of education.

Result

Symptoms of brain fog, weight changes, and mood changes were associated with poorer current ECog‐II score (b = 74.8, 95%CI [47.2, 108.0], p<.001; b = 24.4, 95%CI [8.9, 42.2], p = .001; b = 36.2, 95%CI [17.3, 58.3], p<.001, respectively). Comparatively, use of estrogen and non‐estrogen‐based MHT during menopause was not significantly associated with current ECog‐II scores (b = ‐11.0,95%CI[‐25.3, 6.5], p = .2; b = 16.9, 95%CI[‐10.9, 56.1], p = .3, respectively). Weight and mood symptoms of perimenopause were significantly associated with poorer current MBI‐C score (b = 24.4,95%CI[2.4,51.1], p = .03; b = 68.4%,95%CI[36.3,108.1], p<.001, respectively). MBI‐C scores differed based on type of MHT used. Estrogen‐based MHT was associated with a statistically significant 26.9% lower MBI‐C score (95%CI[‐43.3, ‐5.7], p = .02), while score did not differ significantly with non‐estrogen‐based MHT (b = ‐19.1,95%CI[‐44.6, 18.1], p = .3).

Conclusion

The experience of brain fog, weight changes, and mood changes during perimenopause may predict greater risk for cognitive and behavioral changes later on. Use of estrogen‐based MHT may mitigate the relationship between perimenopause symptoms and MBI symptoms. However, longitudinal data are required to explore mechanisms.
Multi‐ancestry whole genome sequencing analysis of 36,361 individuals from the Alzheimer’s Disease Sequencing Project (ADSP)
Authors: Kunkle Brian W. , Farrell John J. , Akgun Bilcag , Wang Dongyu , Zhu Congcong , Hamilton‐Nelson Kara L. , Dietrich Sven‐Thorsten , Zhang Xiaoling , Rampersaud Andy , Yang Jiemin , Naj Adam C. , Martin Eden R. , DeStefano Anita L. , Choi Seung Hoan ,   the Alzheimer’s Disease Sequencing Project (ADSP)
Published: January 2025

Background

The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify genetic variation contributing to the development or protection of Alzheimer’s disease (AD) in diverse ancestral populations. The latest ADSP whole genome sequencing (WGS) data release includes over 36,000 individuals from 37 datasets (NIAGADS NG00067.v11 ADSP R4). Quality control (QC) of these data has been performed and association analyses are underway.

Method

We performed QC filtering based on metrics including GATK VQSR, genotype missingness rate (<20%), comtamination rate, singleton rate, heterozygous/homozygous ratio, ABHet ratio ([0.3, 0.7]), Ti/Tv ratio, and a differential allele frequency between PCR‐free and PCR‐amplification library protocol. After filtering, two genome‐wide association analytical pipelines are being implemented: 1) a population‐specific analysis using a Gaussian mixture model genetic clustering approach to identify genetic similarity clusters for defining populations, and 2) a pooled analysis of all populations accounting for population structure and empirical relationships using GENESIS KING, PC‐Air and PC‐Relate methods. Using SAIGE, planned analyses include single variant logistic mixed model analysis and set‐based association tests (Burden, SKAT, SKAT‐O) for coding and noncoding rare variant groups.

Result

After QC, we retained over 293 million single nucleotide variants (SNVs), 15 million small deletions, 6 million small insertions, and over 11,000 AD and related dementia (ADRD) cases, for downstream association analysis. With high‐quality non‐correlated variants (n = xx), we defined 8 genetically similar population clusters for population‐specific analyses comprising ∼800 Amish, ∼12,200 European, ∼5,400 African/African American, ∼5,700 Hispanic/Amerindian/African, ∼2,500 Hispanic/Amerindian, ∼1,200 Ashkenazi Jewish, ∼2,600 Indian, and ∼200 other individuals. In the principal component analysis, the Ashkenazi and Amish population revealed distinct clusters separate from the European reference population.

Conclusion

A major goal of the ADSP is to fully reveal the genetic architecture of AD/ADRD across diverse ancestral populations with the hope that new discoveries and the therapeutic or prevention strategies they enable will benefit all ancestral groups. Complementary pooled‐population and population‐specific analyses of the ADSP’s latest WGS data release are underway and new insights from these investigations are anticipated.
Heterogeneity of brain endothelial cell transcriptome in Alzheimer’s disease brain tissue
Authors: Yue Qian , Hoi Pui Man Maggie
Published: January 2025

Brain endothelial cell (BEC) dysfunction in Alzheimer’s disease (AD) have attracted much more attention in recent years. A series of multi‐omics study is carried out to indicate the specific endothelial state during AD progression. We have summarized the most recent AD multi‐omics study on AD BECs. This figure shows multiple characterization of transcriptomic information. BEC transcriptomic alteration shows region‐specific and subpopulation‐specific manner, in which different groups of differentially expressed genes (DEGs) are detected in each category, as well as related signaling pathways and biological processes. DEGs and related biological processes also shows changing trends as the disease progresses from no neuritic plaques (Braak0‐II) to severe neuritic plaques (BraakVI), which indicates that the pathologic process in AD is dynamic. Then we show the potential downstream and upstream factors related to BEC DEGs, including BEC receptors, transcription factors and AD GWAS loci. Finally, we show the DEGs as well as related biological processes in BECs near the Aβ plaques, or in cerebral amyloid angiopathy (CAA). An overlap between microglia risk GWAS and BMECs DEG is noticed and shown. In addition, BEC DEGs also indicate the activation of BEC receptors that may be related to several AD ligands produced by other brain cells like oligodendrocytes, astrocytes, pericytes, and neurons, showing the close relationship between BEC pathology and other cell pathology. Taken together, BEC transcriptomic information strongly indicated the close relationship between BEC DEGs and AD pathogenesis and is valuble for the exploration of therapeutic strategies for AD by targeting BEC dysfunction.
APOE Genotypes and Alzheimer’s Disease Risk in Older Ugandans
Authors: Lwere Kamada
Published: January 2025

Background

Apolipoprotein E (APOE) gene has three common alleles: ԑ2, ԑ3, and ԑ4, which influence Alzheimer’s disease (AD) risk. APOE ԑ4 allele increases AD risk, while APOE ԑ2 allele may protect against AD. This study aimed to examine the distribution and prevalence of APOE genotypes and their association with AD in older Ugandans.

Method

Forty‐three participants aged ≥ 65 years were recruited from two villages in Wakiso district, Uganda. Suspected AD cases were identified using the Montreal Cognitive Assessment (MoCA) tool. APOE genotypes were determined from blood samples using molecular biology techniques.

Preliminary results

The participants (n = 43) had a mean age of 79.0 ± 11.4 years, with a range from 62 to 120 years, and 86% were female. The distribution and prevalence of APOE genotypes varied across the sample, with ԑ3ԑ3 being the most common (53.5%), followed by ԑ2ԑ3 (23.3%), ԑ2ԑ2 (4.7%), and ԑ3ԑ4 (2.3%). The frequency of ԑ3ԑ3 genotype was consistent across different age groups, reflecting its dominance in the studied population. Females displayed a broader variety of APOE genotypes than males, including ԑ2ԑ3, ԑ2ԑ2, and ԑ3ԑ4. APOE ԑ4 allele was more prevalent among participants with higher MoCA scores, suggesting lower AD risk.

Conclusion

This study reveals the APOE genotyping patterns and their relation to AD risk in older Ugandans. The low frequency of APOE ԑ4 allele and its inverse association with AD risk are intriguing and warrant further investigation. Future studies should include larger and more representative samples, as well as other biomarkers and clinical measures of AD.
Alzheimer’s Disease Polygenic Risk in the LEADS Cohort
Authors: Nudelman Kelly N. , Pentchev Julian V. , Jackson Trever , Eloyan Ani , Dage Jeffrey L. , Foroud Tatiana M. , Hammers Dustin B. , Carrillo Maria C. , Dickerson Bradford C. , Rabinovici Gil D. , Apostolova Liana G. ,   the LEADS Consortium
Published: January 2025

Background

Currently, it is unclear to what extent late‐onset Alzheimer’s disease (AD) risk variants contribute to early‐onset AD (EOAD). One method to clarify the contribution of late‐onset AD genetic risk to EOAD is to investigate the association of AD polygenic risk scores (PRS) with EOAD. We hypothesize that in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), EOAD participants will have greater PRS than early‐onset amyloid‐negative cognitively‐impaired participants (EOnonAD) and controls, and investigate the association of AD PRS with age of disease onset (AoO) and cognitive performance.

Methods

GWAS data was generated for LEADS participants, including those with EOAD, EOnonAD, and controls, with the Illumina Global Screening Array. A PRS was calculated using the 31 SNPs and weights published previously by Desikan et al. (2017) for LEADS participants with imputed GWAS data (N = 369). Logistic regression models including age, sex, PRS, and genetic ancestry principal components were tested to identify predictors of EOAD (N = 210) vs. EOnonAD (N = 69) and controls (N = 89). ANCOVA models were used to assess group differences in PRS scores. Kaplan‐Meier regression was used to assess differences in EOAD AoO for tertile‐binned PRS groups. Within EOAD, pre‐calculated cognitive domain scores for speed and attention, working memory, episodic memory, language, and visuospatial performance were assessed for correlation with PRS.

Results

The AD PRS was a predictor of EOAD (p = 0.014), with the model explaining 10.5% of variance (X2 = 40.971, p<0.001). EOAD participants had higher PRS scores (mean = 0.0012, standard deviation (SD) = 0.015) compared to EOnonAD and controls (mean = ‐0.0018, SD = 0.015) (F = 6.602, p = 0.011). Survival analysis indicated no significant differences in EOAD AoO between PRS groups (X2 = 3.396, p = 0.183). In the EOAD group, PRS was associated with cognitive scores for speed and attention (r = 0.204, p = 0.007), language (r = 0.230, p = 0.002), and visuospatial performance (r = 0.166, p = 0.037).

Conclusions

In the LEADS cohort, AD PRS is a predictor for EOAD, and is associated with cognitive performance, but does not predict EOAD AoO. This suggests that while late onset AD‐associated genetic variants contribute to disease risk and processes, they do not account for a large portion of disease risk, and do not explain differences in disease AoO in the LEADS cohort.
Molecular Mechanism of Substrate Recognition and Cleavage by Human γ‐Secretase
Authors: Guo Xuefei
Published: January 2025

Background

Successive cleavages of amyloid precursor protein C‐terminal 99 residues (APP‐C99) by human γ‐secretase result in amyloid‐β peptides (Aβs) of varying lengths, the main constituents of amyloid plaques in Alzheimer’s disease patients. Most cleavages have a step size of three residues, as exemplified by sequential generation of Aβ49, Aβ46, Aβ43, and Aβ40.

Method

To elucidate the mechanism of substrate cleavage, we determined atomic structures of human γ‐secretase bound individually to APP‐C99, Aβ49, Aβ46, and Aβ43.

Result

Remarkably, in all cases, the substrate has the same structural features: a transmembrane α‐helix that binds PS1, a three‐residue linker, and a β‐strand that forms a hybrid β‐sheet with two β‐strands of PS1. Proteolytic cleavage occurs at the peptide bond just preceding the substrate β‐strand.

Conclusion

Therefore, each cleavage is followed by unwinding of the substrate α‐helix by one turn, translocation of the α‐helix towards the C‐terminus, and formation of a new β‐strand. This mechanism is consistent with existing biochemical data and may also explain the cleavages of other substrates by human γ‐secretase.
Association between Cortical Thickness and Mild Behavioral Impairment in a Southeast Asian Population ‐ Biomarkers and Cognition Study, Singapore BIOCIS
Authors: Leow Yi Jin , Vipin Ashwati , Tanoto Pricilia , Azam Mohammed Adnan , Sandhu Gurveen Kaur , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran
Published: January 2025

Background

Mild Behavioral Impairment (MBI) is the onset of sustained neuropsychiatric symptoms that are considered as a possible precursor to neurodegenerative conditions, especially dementia. The concept of MBI recognizes that behavioral changes may be an early sign of brain changes due to neurodegeneration. Very recent research has shown behavioral changes in MBI might be linked to changes in brain structure, including cortical thickness. Cortical thickness is associated with various neurodegenerative diseases, including Alzheimer’s disease and other forms of dementia. We examined the association between cortical thickness and neuropsychiatric symptoms(NPS) in a multi‐ethnic Southeast Asian population.

Method

657 participants were recruited from the community living in Singapore. 399 were cognitively unimpaired (CU), 253 with mild cognitive impairment (MCI), and overall, the mean age = 59.86 years, mean education = 14.52 years with 40.2% males.

Participants completed the Mild Behavioural Impairment‐Checklist (MBI‐C), a self‐reported questionnaire. Mild Behavioural Impairment(MBI) classification was based on established clinical cut‐offs of 8.5.

Participants underwent magnetic resonance imaging (MRI) scan on a 3T Siemens Prisma Fit (Siemens, Erlangen, Germany). Structural MRI was acquired using T1‐weighted MPRAGE sequence. Structural images were preprocessed using FreeSurfer (https://surfer.nmr.mgh.harvard.edu/, software version 7.2). For each participant’s T1 images, automated segmentation and cortical parcellation was carried out using the FreeSurfer “recon‐all” processing stream, which included motion correction, removal of nonbrain tissue, automated Talairach transformation, intensity correction, volumetric segmentation, and cortical surface reconstruction and parcellation.

Result

In the left hemisphere, the cortical thickness of the cuneus, entorhinal, parstriangularis, precuneus, rostral anterior cingulate, was significantly associated with the likelihood of being classified as MBI. The right – entorhinal, inferior parietal, pars orbitalis, supramarginal and frontal pole cortical thickness was significantly associated with the likelihood of being classified as MBI.

Conclusion

The results highlight the importance of MBI as potential early indicators of cognitive impairment and suggest that these impairments are associated with changes in cortical thickness and increased risk of cognitive decline. The complex interplay between behavioral and cognitive symptoms in aging and neurodegenerative diseases needs to be defined.
Deciphering a Single‐cell atlas and loss‐of‐function analysis revealing ABCA7’s transcriptome insights in Alzheimer’s disease
Authors: De Deyn Lara , Duchateau Lena , Watzeels Tijs , Vicente Cristina , Van Dongen Jasper , Bijnens Baukje , De Pooter Tim , De Rijk Peter , Strazisar Mojca , Vandenberghe Wim , Thal Dietmar Rudolf , Mancuso Renzo , Rademakers Rosa , Küçükali Fahri , Sleegers Kristel
Published: January 2025

Background

ABCA7, an important risk gene for AD, encodes a transporter implicated in lipid transport and phagocytosis, and its disruptions have been linked to AD pathogenesis. However, the impact of these mutations on AD risk is complex due to their interaction with a multifaceted transcriptional architecture and cell type‐specificexpression patterns. This study aims to analyze the intricate patterns of ABCA7 expression across diverse cell types, considering various ABCA7 genotypes in relation to AD patients and non‐carrier controls, while also exploring the effects of ABCA7 mutations on transcriptome‐wide gene expression.

Method

To address this complexity, we performed droplet‐based single‐nuclei RNA sequencing on BA10 brain samples (ABCA7 mutation carriers [n = 9], non‐carrier AD patients [n = 6], and non‐carrier control [n = 8]) using 10x Chromium library preparation followed by sequencing on a NovaSeq6000 platform. Cell type annotation was performed using scSorter. Differential gene expression was analyzed using limma‐voom, and pathway analyses were performed using fgsea in R across cell types and studied groups.

Result

We obtained over 400,000 nuclei across 23 samples. Excitatory neurons had the highest proportion of cells expressing ABCA7. However, the highest average expression of ABCA7 was noted in microglia. We detected numerous differentially expressed genes between carrier and non‐carrier AD patients (pval_FDR_adj < 0.05 & abs(logFC) >1). Pathway analysis revealed a notable decrease in the expression of translation‐related genes in microglia, including those associated with nonsense‐mediated mRNA decay, in individuals carrying the mutation.

Conclusion

In conclusion, our study unveils distinctive patterns of ABCA7 expression and enriched pathways across major brain cell types, suggesting different roles of ABCA7 in different cell types.
Pathologically confirmed advanced stage of limbic predominant age related TDP‐43 encephalopathy (LATE): A case report
Authors: Jung Young Hee H , Lee Jin Hwan H , Park Sung‐Hye
Published: January 2025

Background

We herein introduce a case that was pathologically confirmed as an advanced stage of LATE.

Method

(case presentation) An 81‐year‐old woman visited a memory clinic complaining of memory impairment in the past few years. She had no psychiatric history and a history of significant hyperlipidemia and hypertension. On MMSE she scored 20 with CDR of 1 (SOB 6). T In the first‐year post‐onset, brain MRI indicated diffuse brain atrophy with hippocampal atrophy MTA‐Gr2). At the fifth year, the patient was unable to perform all ADL and frequently exhibited severe BPSD. Contrary to the worsening of clinical symptoms, brain CT revealed only slight increase in hippocampal atrophy (MTA‐Gr3), with no significant difference from the MRI findings 5 years ago. The patient died at the age of 88.

Result

The brain autopsy revealed global brain atrophy with 923g in brain weight. Final pathological diagnosis was Alzheimer’s disease (AD), limbic‐predominant age‐related TDP43 encephalopathy (LATE), and cerebrovascular disease. In detail, under the NIA‐AA ADNP grading, the level is intermediate, with scores of A3, B3, and C2 adding up to 8. The Thal phase is rated 3 out of a possible 5. The Braak stage, which indicates the progression of Alzheimer’s tau pathology, is at stages V to VI out of VI. The CERAD score was 2 out of 3. No evidence of cerebral amyloid angiopathy (CAA) was found (score of 0). The stage of LATE was 6 by Joseph staging system, thus, TDP43‐positive intraneuronal inclusions and neurites were found in the amygdala, entorhinal and temporal lobes, hippocampal cornu ammonis and dentate, basal ganglia, and tectum of the midbrain and olivary nucleus of the medulla oblongata. However, there was no hippocampal sclerosis.

Conclusion

In this report, the subject was initially diagnosed with Alzheimer’s dementia while alive; however, a post‐mortem autopsy revealed the primary condition to be an advanced stage of LATE, specifically at Joseph stage 6, coexisting with Alzheimer’s disease and cerebrovascular pathology. This case underscores the importance of understanding the pathological characteristics of TDP‐43 protein abnormalities and their related clinical manifestations.