bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomics analyses of CSF and Plasma for discovery of early vascular pathologies in neurodegenerative disease
Authors: Elahi Fanny M
Published: December 2023

Background

Cerebral small vessel disease (cSVD) is a major cause of brain degeneration and dementia for which we have no therapies. My lab applies new molecular omics technology to human biospecimen for an initial unbiased approach to discovery of clinically‐relevant dysregulated molecular pathways in humans living with disease. To this end, we have focused our efforts on an autosomal dominant form of disease–CADASIL (Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts and Leukoencephalopathy) caused by mutations in NOTCH3 . Given its autosomal dominant nature, CADASIL provides a unique opportunity to build an all‐in‐human modeling pipeline for therapeutic discovery.

Method

We have performed proteomics analyses in plasma samples (CADASIL n = 58, controls n = 60) as an unbiased starting point for discovery of dysregulated molecular pathways and are building patient iPSC derived multi‐cellular in vitro models (iCADASIL) to identify molecular drivers of pathological cell‐cell communications within the neuro‐glio‐vascular unit. Both bulk proteomics as well as spatial transcriptomics (GeoMx, Nanostring) from donated brain samples are used to extract disease‐associated molecular signatures from human tissue for (1) testing the validity of iCADASIL models, and for (2) comparison with blood proteomics and identification of promising plasma biomarkers for non‐invasive staging of neurovascular pathology in living humans for the purposes of future clinical trial design.

Result

Our initial results indicate that dysregulations in angiogenesis, changes to extracellular matrix and immune dysfunction, including neutrophilic activation, may be features of early disease stages with relevance to mild brain phenotypes such as slowed processing speed and executive dysfunction. In vitro angiogenesis assays and immune cell extravasation assays are underway in our iCADASIL models.

Conclusion

The unbiased proteomics performed on CADASIL ‐ control plasma confirmed known molecular dysregulations as well as identified new avenues of investigation that we are pursuing via iCADASIL models. The combination of omics methods applied to multiple biospecimen, including in vivo plasma and ex vivo brain tissue provides a powerful approach for discovery of therapeutically targetable pathways with relevance to disease‐associated phenotypes.
Using single cell transcriptomic data to elucidate cell‐type protein signatures of disease
Authors: Miedema Suzanne S.M.
Published: December 2023

Background

Key to developing treatment strategies for neurodegenerative disease is identifying cell type‐specific pathways that drive disease initiation and progression. Advancements in single cell/nuclei transcriptomics (sc/snRNAseq) have elucidated how RNA expression differs between cell types in disease. In addition, these efforts have yielded detailed transcriptomic profiles belonging to specific cell subtypes. For the proteomic field, deep single cell measurements have been practically unreachable. What can we learn from sc/snRNAseq resources about cell type‐specific proteomic profiles? Can we use them as reference for elucidating involvement cell types in disease at the protein level?

Method

We discuss two studies performed in our lab. First, we use sc/snRNAseq resources [References 1,2,4] to infer which cell types are involved in the proteomic changes in FTD [5]. Secondly, we compare the proteomic profiles of granulovacuolar degeneration‐positive and tangle‐positive neurons from AD with transcriptomic resources [3].

Result

We demonstrate that applying sc/snRNAseq resources can elucidate involvement of major brain cell types in neurodegenerative disease processes at the protein level. Doing this for highly specified cell types is not advisable, due to the correlation gap between RNA and protein expression levels.

Conclusion

We aim to reveal cell type‐specific disease mechanisms in neurodegenerative disease to pave the way for cell‐targeted treatments. Future endeavours will enlarge our insights in the single cell proteomics field.

References:

[1] Darmanis S, Sloan SA, Zhang Y, et al (2015) A survey of human brain transcriptome diversity at the single cell level. PNAS 112:7285‐7290.

[2] Hodge RD, Bakken TE, Miller JA, et al (2019) Conserved cell types with divergent features in human versus mouse cortex. Nature 573:61‐68.

[3] Hondius, D. C., Koopmans, F., Leistner, C., et al. (2021). The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease. Acta Neuropathologica, 141(3), 341‐358.

[4] Lake BB, Chen S, Sos BC, et al (2018) Integrative single‐cell analysis of transcriptional and epigenetic states in the human adult brain. Nat Biotechnol 36:70‐80.

[5] Miedema, S.S.M., Mol, M.O., Koopmans, F.T.W. et al. Distinct cell type‐specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia. Acta Neuropathol Comm 10, 100 (2022).
Predicting clinical decline over 36 months with a memory‐based digital biomarker
Authors: Bruno Davide , Zinkunegi Ainara Jauregi , Bock Jason R
Published: December 2023

Background

Word‐list recall tests are routinely employed in clinical practice for dementia screening. Process scoring and latent modeling of these tests, where underlying neurocognitive mechanisms are exploited, have shown potential to enhance test accuracy without requiring test redesign. We examined Embic’s digital biomarker M, a measure of recall derived from multinomial processing trees and hierarchical Bayesian computational methods, as a predictor of conversion to mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and of increase in Clinical Dementia Rating (CDR) score.

Methods

Secondary data analyses were carried out from ADNI data. M was computed from Rey’s AVLT data, and compared to standard AVLT clinical metrics (total and delayed recall). We conducted logistic regression analyses with diagnosis at 36 months (normal vs. MCI + AD) as outcome; all 169 participants were classified as normal at baseline, and 13 of these progressed to a clinical diagnosis (see Table 1). We controlled for baseline age, gender and years of education; and ran separate analyses with other metrics to avoid multicollinearity. We then repeated the same analytical framework with CDR scores (stable at 0 vs. increased to 0.5 or 1) at 36 months as outcome: stable participants were 141, and 24 increased (see Table 2). Covariates and predictors were the same as in the previous analysis.

Results

M predicted conversion to MCI or AD after three years (FDR‐corrected p value = 0.048), while neither AVLT total nor delayed recall did. Performance metrics showed that M generated 92% accuracy, or probability of yielding a correct classification, and 100% specificity, or no false positives (Figure 1). Analogously, M, but not standard AVLT metrics, also predicted a CDR increase after three years (FDR‐corrected p value = 0.003), with high accuracy (84%), specificity (96%), and precision (80%), or positive predictive value (Figure 2). Sensitivity analyses with ordinal regression broadly confirmed these findings.

Conclusions

These results indicate Embic’s digital biomarker M outperforms some of AVLT’s traditional metrics in identifying individuals who will progress to MCI and AD after three years, from a healthy baseline.
Rare copy number variation in the GR@ACE/DEGESCO dementia dataset of spanish population
Authors: de Rojas Itziar , García‐Ribas Guillermo , Sanchez‐Juan Pascual , Perez‐Tur Jordi , Pastor Pau , Bullido María J. , Álvarez‐Martínez Victoria , Real Luis Miguel , Mir Pablo , Piñol‐Ripoll Gerard , García‐Alberca Jose María , Medina Miguel , Sáez María Eugenia , Carracedo Angel , Tárraga Lluís , Boada Mercè , Van Der Lee Sven J , Ruiz Agustin ,   GR@ACE/DEGESCO
Published: December 2023

Background

Recent studies have found that duplications or deletions of DNA fragments, known as copy number variants (CNVs), may play a role in missing heritability for complex human diseases.

Method

In that sense, we conducted a scan for CNVs in the GR@ACE/DEGESCO dementia dataset of Spanish population1 (n = 20,080 individuals using Axiom 815K Spanish biobank array (Thermo Fisher)). We ran CNV calling algorithms from PennCNV software to obtain high‐confidence calls for CNVs. After extensive quality control (QC) for individuals (sex discrepancies, excess of heterozygosity, high missingness, familiar relations and population outliers were excluded), CNVs (>50kb and nSNPs>10 were included), removing spurious CNVs in telomeric/centromeric regions, gene QC (ANOVA comparisons between DNA origin source evaluated in controls), 8,275 controls and 7,818 dementia cases were selected for following analysis.

Result

Global burden analyses revealed highly significant differences between dementia cases and controls (dem/ctrl) in CNV rate of deletions (p = 2.69E‐04, meanctrl‐dem = 1.53‐1.38) but not in duplications (p = 0.535, meanctrl‐dem = 1.63‐1.61). However, only the number of genes affected by CNVs was significantly different in deletions (p = 0.042, meanctrl‐dem = 3.62‐3.10; duplications p = 0.448, meanctrl‐dem = 5.93‐5.68). We also observed a nominal deletion‐gene‐affected association by genes related to nervous system development pathway or intellectual disability such as VPS13B2 (nine cases affected), PKP3 (Freqctrl‐dem 0.17‐0.25%) and FBRSL13 (Freqctrl‐dem 0.15‐0.26%). The current study did not detect significant differences in CNVs that affect known Alzheimer’s disease (AD) loci identified by recent genome‐wide association studies4 (deletions Fisher test p = 0.0875, duplications Fisher Test p = 0.5853). Nevertheless, we found three important AD genes with CNVs potentially associated to dementia. Specifically, we detected MAPT protective deletions (Freqctrl‐dem 0.16‐0.01%), ABCA7 risk deletions (Freqctrl‐dem 0.05‐0.14%) and APP CNVs detected in five dementia cases (0.064%). Because the technology used in our study has limitations in detecting small CNVs, future studies must carefully assess the presence of smaller CNVs and their relationship with dementia.

Conclusion

We have detected potential CNVs in the Spanish population for Alzheimer’s disease, however, because the technology used in our study has limitations in detecting small CNVs, future studies must carefully assess the presence of smaller CNVs and their relationship with dementia.
APOEε4 facilitates the accumulation and connectivity‐mediated spreading of tau pathology at lower amyloid levels
Authors: Steward Anna , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Wanger Fabian , Dehsarvi Amir , Svaldi Diana , Higgins Ixavier A. , Brendel Matthias , Shcherbinin Sergey , Ewers Michael , Franzmeier Nicolai
Published: December 2023

Background

Targeting amyloid (Aß) may show highest clinical efficacy when preventing downstream tau spreading and subsequent neurodegeneration. Thus, it’s critical to establish Aß‐PET thresholds at which tau spreading is triggered, which may depend on ApoE4, i.e. a key genetic risk factor for Aß, tau and cognitive decline. Yet, ApoE4’s impact on Aß‐related tau spreading is unclear, which may bias intervention studies. Thus, we assessed whether ApoE4‐carriage facilitates Aß‐associated tau spreading and determined thresholds at which Aß‐related tau trajectories diverge between ApoE4‐carriers vs. non‐carriers. Lastly, we ran simulated trials using tau‐PET endpoints to test whether including ApoE4‐carriers increases the sensitivity to detect treatment effects at lower Aß‐levels.

Method

We included non‐demented ADNI subjects (n = 237), and a replication sample (18F‐AV‐1451‐A05 trial, n = 130). We combined ApoE4‐status, amyloid‐PET and longitudinal flortaucipir tau‐PET alongside resting‐state fMRI‐connectivity templates from n = 42 Aß‐ controls to assess connectivity‐based tau spreading (subject‐specific tau epicentre connectivity ranked regions i.e. Q1‐Q4) together with tau accumulation in Braak‐stage specific regions. We used i) mediation models to test whether ApoE4 effects on Braak‐stage specific tau accumulation were mediated by centiloid and ii) linear models to determine the centiloid by ApoE4 interaction on tau accumulation in Q1‐Q4 and Braak‐stage regions and iii) determined confidence interval‐based cut‐points of ApoE4‐related divergence in tau trajectories. Lastly, we estimated ApoE4‐stratified sample sizes to detect simulated treatments effects on tau accumulation across increasing centiloid windows.

Result

Using bootstrapped mediation we found that centiloid mediated faster ApoE4‐related tau‐PET increase in early Braak‐stage regions (ADNI/A05, BraakIII: B = 0.19/0.33, p<0.001/<0.001), and that ApoE4 facilitates Aß‐related tau spreading (ApoE4*centiloid interaction on tau‐PET increase) in early Braak‐stage and connectivity‐based ROIs. We identified centiloid cut‐points (∼10‐15) where Aß‐related tau accumulation rates diverged between ApoE4 carriers vs. non‐carriers through Braak and connectivity stages (Fig.1), which replicated across samples. Lastly, focusing on ApoE4‐carriers exclusively in simulated clinical trials increased the sensitivity for detecting treatment effects on tau accumulation at lower centiloid levels (Fig.2).

Conclusion

ApoE4 is related to earlier Aß‐related tau accumulation, which may drive faster ApoE4‐related disease progression. Our results are relevant for clinical trial design, illustrating that ApoE4‐carriers may require earlier anti‐Aß intervention to attenuate downstream tau spreading.
Association of resilience with successful ageing and the mediating role of community participation
Authors: Park Sangmi , Kim Jung‐Ran , Lee Chang Dae
Published: December 2023

Background

Higher level of resilience plays a positive role in successful ageing. Participation was reported as a factor related to resilience and successful ageing. As resilience is developed based on interaction between personal characteristics and environment over time, enhancing resilience level of individuals in later life span is difficult. Finding out modifiable factors which mediate the relationship between resilience and successful ageing can be alternative way to promote successful ageing. The aim of this study was to examine the mediating role of community participation.

Method

Convenience sampling was applied to recruit community‐dwelling older adults aged 60 or older who could self‐rate the questionnaire independently. Online and on‐site surveys were conducted using the same questionnaire. Total scores of Korean version of the Connor‐Davidson Resilience Scale (CD‐RISC) and Community Integration Measure (CIM) were used respectively to measure resilience and community participation. Sum score of the satisfaction across four areas‐ subjective health; subjective memory; social relationships; socioeconomic status was used to measure successful ageing. Mediation analysis using SAS 9.4 was conducted to examine the mediating role of community participation in relationship between resilience and successful ageing.

Result

Data from 284 individuals was analyzed (Mean age: 67.99 ± 7.28; Female: 50.70%). Mean scores of CD‐RISC, CIM, and successful ageing were 60.70, 36.65, 13.05 respectively. A total effect of resilience on successful ageing was statistically significant (β = 0.038, 95% CI = 0.027 to 0.049) after controlling for gender, age, education, living status, employment status, disabilities, depression and chronic disease. Community participation mediated the relationship between resilience and successful ageing (β = 0.006, 95% CI = 0.002 to 0.010). Mediating role of community participation explained 16.44% of total effect of resilience on successful ageing.

Conclusion

Assisting older adults to increase community participation can be considered as a community‐based health care service to promote successful ageing. Further studies to examine causality among resilience, community participation, and successful ageing is necessary to strengthen the evidence of effect of active community participation on successful ageing.
Lower serum vitamin D aggravates hippocampal neurodegeneration related with amyloid pathology
Authors: Park Junha , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Jun‐Young , Sohn Chul‐Ho , Lee Yun‐Sang , Kang Kyoung Mi , Lee Dong Young
Published: December 2023

Background

Previous studies reported the associations between vitamin D deficiency and increased risk of Alzheimer’s disease (AD) dementia in older adults, but little is known how vitamin D is involved in the pathophysiology of AD. Thus, we aimed to examine the association and interaction of serum vitamin D level with in vivo AD pathologies including beta‐amyloid (Aβ) and neurodegeneration in nondemented older adults.

Method

Nondemented older adults consisting of cognitively normal and mild cognitive impairment groups were recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25(OH)D, and multimodal brain imaging including Pittsburgh compound‐B (PiB) positron emission tomography and magnetic resonance imaging at baseline. Global PiB retention was measured for Aβ biomarker, and hippocampal volume adjusted for intracranial volume (HVa) was used for neurodegeneration biomarker. Age, sex, apolipoprotein E (APOE) e4 positivity was controlled as covariates in all analyses.

Result

A total 428 participants (mean age [SD]: 70.54 [7.97], female [N, %]: 182 [43%]) were included for analysis. Serum 25(OH)D levels were directly associated neither Aβ deposition nor HVa. However, serum 25(OH)D level had significant moderation effect on the association between Aβ and hippocampal neurodegeneration, in that lower serum 25(OH)D level significantly exacerbate the negative association between global Aβ retention and HVa (β = 34.612, p = 0.008) (Figure).

Conclusion

The present findings suggest that lower serum vitamin D level may increase AD dementia risk by aggravating Aβ‐related neurodegeneration.
Red flags and symptom overlap in anti‐IgLON5 disease and dementia with Lewy bodies – a systematic review
Authors: McWilliam Oskar , Gramkow Mathias H. , Blaabjerg Morten , Clemmensen Frederikke Kragh , Hasselbalch Steen G. , Frederiksen Kristian Steen
Published: December 2023

Background

Anti‐IgLON5 disease is a rare but potentially reversible cause of cognitive impairment, sleep disturbances, dysautonomia, and movement disorders. It is a type of autoimmune encephalitis (AE) but unlike other AEs anti‐IgLON5 disease has an insidious onset and prominent tau pathology. Anti‐IgLON5 disease mimics neurodegenerative disorders and multiple symptoms overlap with the second most common cause of neurodegenerative dementia, Dementia with Lewy bodies (DLB). The purpose of this review was to assess the overlap in features between anti‐IgLON5 disease and DLB and to identify potential red flags for anti‐IgLON5 disease in patients undergoing diagnostic evaluation for DLB.

Method

We conducted a systematic review of reports on features of anti‐IgLON5 disease from full‐text articles in MEDLINE, Web of Science, and Embase. The reviewed data was compared to consensus criteria for DLB.

Result

We included 57 studies with a total of 125 cases of anti‐IgLON5 disease. The median age was 61 years at diagnosis, with a median symptom duration of 3.5 years. Ten % (13/113 cases) presented with cognitive dysfunction. REM‐sleep disorder was diagnosed in 43% (17/39 cases), and movement disorders were present in 73% (80/110 cases) of which parkinsonism was identified in 21% (18/85 cases). In 47% (25/59 cases), psychiatric disturbances were reported, and hallucinations were observed in 37% (11/30 cases). Dysautonomia was reported in 56% (42/75 cases). Regarding red flags for anti‐IgLON5 disease, bulbar symptoms were observed in 75% (82/109 cases) and respiratory insufficiency was in 60% (32/66 cases). Brain MRI was normal in 56% (40/72 cases) and routine cerebrospinal fluid examination was normal in 63% (36/57 cases). Anti‐IgLON5 antibodies were positive in serum in all cases, where serum was tested and positive in cerebrospinal fluid in 96% (71/75 cases).

Conclusion

We found a significant overlap between symptoms in anti‐IgLON5 disease and DLB including cognitive dysfunction, REM‐sleep disorders, parkinsonism, and an insidious onset over several years. We propose that anti‐IgLON5 disease should be considered in atypical DLB cases with bulbar or respiratory symptoms. Our study contributes to the emerging knowledge on symptoms and biomarkers in anti‐IgLON5 disease.
Dementias Platform UK: Bringing genetics into life
Authors: Leonenko Ganna , Bauermeister Sarah , Stevenson‐Hoare Joshua O , Baker Emily A , Gallacher John , Escott‐Price Valentina
Published: December 2023

Background

DPUK is a data repository bringing together a wide range of population and clinical cohorts from the UK, Europe and South Korea. It enables data discovery, variable selection, and data access for multi‐modal, multi‐cohort analysis in a shared and secure environment. Neurodegenerative dementias are group of diseases with highly heterogeneous pathology and with an overlapping genetic component that is poorly understood. Combing genetic data from different studies is important due to the increase in power this provides, but this presents an additional challenge due to differences in genotyping arrays and lack of overlapping variants.

Method

We have curated and harmonized genome‐wide data from 6 studies (Brains for Dementia Research, EPIC Norfolk, Generation Scotland, Airwave‐chip 1, Airwave‐chip 2, MRC National Survey of Health Development (NSHD)) within the DPUK platform. We created a pipeline that performs rigorous quality‐control (QC) analysis and imputes genetic variance with the 1000 Genome reference panel using the minimac algorithm. Further, standard pruning and thresholding Polygenic Risk Score (PRS) have been generated with 5 summary statistics related to neurodegenerative diseases (clinical AD, clinical/proxy AD, FTD, ALS, PD) for all 6 studies separately and for the combined dataset.

Result

Research‐ready imputed genetic data that have undergone QC and the PRS, based upon the latest neurodegenerative GWAS, are available for the 6 cohorts separately, and for the combined dataset of 60,670 individuals.

Conclusion

Preparing multiple datasets to a common standard for research‐readiness increases scientific opportunity and allows the wider research community to access and process data at scale and pace.
Widespread transposable element dysregulation in human brains with Alzheimer’s disease
Authors: Feng Yayan , Hou Yuan , Zhou Yadi , Leverenz James B , Pieper Andrew A. , Cheng Feixiong
Published: December 2023

Background

Transposable elements (TEs), known as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. However, transposable element (TE) dysregulation of quantitative trait loci (QTL) has not been well‐characterized in human disease, such as Alzheimer’s disease (AD).

Method

In this study, we present the first catalog of transposable element quantitative trait loci (teQTLs) in human brains. By leveraging large‐scale RNA‐sequencing (RNA‐seq), whole‐genome sequencing (WGS), and various QTL data (xQTL) from three brain biobanks with Alzheimer’s disease (AD), we comprehensively characterize TE dysregulation across diverse AD pathobiology, including Tau, amyloid beta, APOE genotypes, and sex differences. We further integrate different types of QTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls to identify AD likely causal genes regulated by brain teQTLs through colocalization analysis. Regulatory roles of brain teQTLs are dissected via long‐range cell type‐specific enhancer‐promoter chromatin interaction maps.

Result

Joint‐analysis of WGS and RNA‐seq data identified 77,335 genome‐wide significant TE expression QTLs (teQTLs) in human AD brains. Colocalization analysis of teQTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls identified key AD likely causal genes regulated by brain teQTLs. This identified new AD risk genes, including complement C1q tumor necrosis factor‐related protein 4 (C1QTNF4) and farnesyl‐diphosphate farnesyltransferase 1 (FDFT1). A TE from Plat_L3 subfamily (chr11: 47605296‐47605575) suppressed expression of C1QTNF4 (its nearest gene) via long‐range enhancer‐promoter chromatin interaction in neurons. We identified that a TE from AluSz6 subfamily (chr8: 11834847‐11835127) increased expression of FDFT1 (its nearest gene) via microglia‐specific long‐range chromatin looping. Expression perturbation of FDFT1 and C1QTNF4 were significantly correlated with Braak staging score of AD patients. We further identified that individuals with AD risk allele APOE4 displayed elevated expression of AluSz6 and FDFT1 in patient induced pluripotent stem cells (iPSC)‐derived microglia and superior frontal gyrus (SFG) microglia compared to APOE3 individuals.

Conclusion

These findings demonstrate widespread TE dysregulation in human brains and teQTLs offer a useful QTL analytic approach to identify AD risk genes and other complex diseases if broadly applied.
Isoform characterisation & splicing signatures of AD‐risk genes using long‐read sequencing
Authors: Leung Szi Kay , Castanho Isabel , Jeffries Aaron , Moore Karen , Dempster Emma , Brown Jonathan T , Bamford Rosemary , Hannon Eilis , Mill Jonathan
Published: December 2023

Background

An increasing number of studies implicate a role for alternative splicing in development and neuropathology of Alzheimer’s disease (AD). However, it has been historically challenging to characterise splicing events, due to the inherent limitations of traditional RNA‐sequencing (RNA‐Seq) to capture full‐length transcripts critical for transcriptome assembly. In this study, we use two complementary targeted long‐read sequencing approaches, Pacific Biosciences (PacBio) isoform sequencing (Iso‐Seq) and Oxford Nanopore Technologies (ONT) nanopore cDNA sequencing, to profile the cortex of a mouse model of tau pathology (rTg4510) with ultra‐deep sequencing of a panel of 20 genes robustly implicated in AD.

Method

Targeted PacBio Iso‐Seq and targeted ONT profiling were performed on RNA isolated from 24 female rTg4510 transgenic and wild‐type mice, aged 2, 4, 6 and 8 months. Following successful enrichment for target genes using custom‐designed probes (IDT), library preparation were performed for subsequent sequencing on Sequel and MinION. The panel of genes selected for enrichment included genes (i.e. App, Mapt, Snca) and dementia risk genes identified from GWAS analyses. Raw sequence data was processed using a customised bioinformatics, and full‐length reads were merged and annotated with our developed custom scripts (FICLE).

Result

We identify thousands of novel transcripts across the panel of 20 AD‐ and dementia‐associated genes. We reveal unprecedented diversity of alternatively‐spliced isoforms with widespread usage of alternative novel 5’ and 3’ splice sites. We further robust transcriptional and splicing differences in these AD‐risk genes associated with the development of tau pathology. Among these changes, we observed global up‐regulation of Trem2‐associated isoforms and isoform switches in Bin1, further supporting a role for the dysregulation of the immune response in the development of AD pathology.

Conclusion

This represents the first study to comprehensively assess variable AS associated with the development of tau pathology using both PacBio Iso‐Seq and ONT nanopore sequencing. Our analyses confirm the importance of alternative RNA splicing in AD and identify evidence of differential transcript usage, even in the absence of gene‐level expression alterations. Further work will be undertaken to validate and functionally characterise these novel isoforms, and to extend these analyses to human post‐mortem AD brain samples.
DAT1 and BDNF polymorphisms interact to predict cross‐sectional and longitudinal amyloid and tau pathology in cognitively normal older adults
Authors: Ciampa Claire J , Murphy Alice , La Joie Renaud , Jagust William J. , Landau Susan M. , Berry Anne S.
Published: December 2023

Background

Dysfunctional dopamine signaling and disruptions in neurotrophic support are potential exacerbators of Alzheimer’s disease (AD) pathophysiology. A single nucleotide polymorphism (SNP) in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) is associated with greater ventricular expansion and lower scores on the Mini Mental State Exam (MMSE; Roussotte et al., 2015). A polymorphism in the brain derived neurotrophic factor gene (Val66Met in BDNF) is related to greater hippocampal atrophy and more severe episodic memory decline for amyloid positive Met carriers (Lim et al., 2013). However, it is unclear whether and how these polymorphisms directly relate to AD pathology.

Method

We tested a moderated mediation model (Fig. 1) involving both BDNF and DAT1 polymorphisms in a sample of cognitively normal older adults (n = 321) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This mediation involved DAT1 (independent variable), b‐amyloid (Ab; mediator), and tau pathology (dependent variable) with BDNF as a moderator. Ab and tau were measured both cross‐sectionally and longitudinally with positron emission tomography (PET) tracers [18F]Florbetapir/[18F]Florbetaben and [18F]Flortaucipir, respectively.

Result

A significant moderated mediation demonstrated that DAT1 and BDNF interacted to predict cross‐sectional Ab‐PET (p = .02) and tau‐PET (p = .04), such that carriers of both DAT1 C and BDNF Met alleles demonstrated greater pathology (Fig. 2), consistent with previous research associating these variants with AD symptoms. Longitudinal analyses replicated these cross‐sectional results, with DAT1 C and BDNF Met carriers exhibiting greater accumulation of tau pathology (p = .0002) and marginally increased Ab accumulation (p = .07).

Conclusion

Our analyses revealed novel interaction effects between genetic polymorphisms in the DAT1 and BDNF genes. These results suggest that carrying DAT1 CC and BDNF Met results in higher Ab, which then contributes to higher tau pathology. While our analyses do not demonstrate causality, these findings are consistent with current hypotheses of AD in which Ab drives increases in tau pathology (Karran et al., 2011).
The AD/ADRD Interdisciplinary Research Network on Biologically Active Tau Aggregate Polymorphs from Alzheimer’s Disease and Related Dementias
Authors: Kayed Rakez , Kuret Jeff , Keene C Dirk , Eisenberg David S.
Published: December 2023

Background

Tauopathies, including Alzheimer’s disease (AD), are characterized by intracellular lesions composed of aggregated and post‐translationally modified tau proteins. Methods for preparation and biochemical characterization of stable filaments from various tauopathies are well established. In contrast, methods for preparation of soluble oligomeric tau aggregates have not been standardized to the same degree. Additionally, the structures of oligomers which associate most closely with disease propagation and toxicity, are not fully established. The AD/ADRD Resource Network aims to isolate structurally vetted tau filaments and oligomers from human tauopathy cases and distribute them to the research community. In addition, it seeks to bank and distribute detection reagents and associated protocols. The overall mission of the network is to support impactful tauopathy research.

Method

Tauopathies, including Alzheimer’s disease (AD), are characterized by intracellular lesions composed of aggregated and post‐translationally modified tau proteins. Methods for preparation and biochemical characterization of stable filaments from various tauopathies are well established. In contrast, methods for preparation of soluble oligomeric tau aggregates have not been standardized to the same degree. Additionally, the structures of oligomers which associate most closely with disease propagation and toxicity, are not fully established. The AD/ADRD Resource Network aims to isolate structurally vetted tau filaments and oligomers from human tauopathy cases and distribute them to the research community. In addition, it seeks to bank and distribute detection reagents and associated protocols. The overall mission of the network is to support impactful tauopathy research.

Result

Protocols for simultaneous isolation of oligomeric and filamentous tau aggregates have been developed along with analytical and quantitative methods to estimate sample heterogenicity and stability. Resource Network members are establishing cross‐laboratory analytical benchmarks for experiments to ensure rigor and reproducibility of results.

Conclusion

The AD/ADRD Research Network banks rigorously validated preparations of structurally vetted tau aggregates along with directed protocols and reagents. Dissemination of these reagents is expected to maximize rigor and reproducibility of basic research involving tau protein aggregates.
Antemortem visit‐to‐visit blood pressure variability and postmortem cerebrovascular disease lesion burden in older adults without dementia
Authors: Sible Isabel J , Nation Daniel A.
Published: December 2023

Background

Blood pressure management is an accessible therapeutic target for dementia prevention. Beyond the current focus of managing mean levels, there is a burgeoning interest in understanding the variability in blood pressure levels. Emerging research suggests elevated blood pressure variability is associated with increased risk for Alzheimer’s dementia and cerebrovascular disease, including white matter hyperintensities on MRI (e.g., Fazekas score), but relationships with white matter lesions and overall cerebrovascular pathology at autopsy remain understudied. The aim of the current study was to determine whether antemortem blood pressure variability predicts cerebrovascular pathology in older adults without clinical dementia.

Method

1866 older adults from the National Alzheimer’s Coordinating Center study underwent repeated approximately annual blood pressure measurement and autopsy and were free of clinical dementia at study baseline. Visit‐to‐visit blood pressure variability was calculated as variability independent of mean using at least 3 (median 5, range 3 ‐ 15) annual blood pressure measurements. White matter rarefaction was scored as none vs mild/moderate vs severe. An index of overall cerebrovascular lesion burden (range 0‐7) was calculated as the sum of severity (0‐2) of atherosclerosis in the Circle of Willis and arteriolosclerosis, and the presence/absence (0‐1) of microinfarcts, infarcts and lacunes, and microbleeds and hemorrhages. Linear and multinomial logistic regression models examined relationships between blood pressure variability, white matter rarefaction severity, and overall cerebrovascular lesion burden, controlling for age, sex, mean blood pressure, antihypertensive use, and Hachinski Ischemic Score, among other variables.

Result

Elevated blood pressure variability predicted increased severity of white matter rarefaction (OR of mild/moderate [vs none] = 1.21 [1.06, 1.33], p = .004; OR of severe [vs none] = 1.30 [1.07, 1.46], p = .008), and greater overall cerebrovascular lesion burden (ß = .12 [.11, .42]; p < .0001).

Conclusion

Elevated blood pressure variability is related to postmortem cerebrovascular lesion burden, including increased severity of white matter rarefaction, in older adults without clinical dementia, independent of mean blood pressure. Findings are consistent with studies using MRI‐based markers of cerebrovascular disease and may help improve blood pressure as a risk indicator for dementia and cerebrovascular disease.
Infections contribute to proteinopathies in neurodegenerative diseases and in some post‐viral persistent symptoms
Authors: Rheault Sylvie , Duchesne Simon , Belleville Sylvie
Published: December 2023

Background

The failure of therapies directed against amyloid‐beta makes us reconsider the theory of the amyloid cascade in Alzheimer’s disease (AD). Infections are suspected to contribute to the disease process. Co‐infection with herpes simplex virus type 1 (HSV‐1) and cytomegalovirus (CMV) results in a higher odds ratio than an individual heterozygous for APOE 4 to develop AD. The objective is to propose a simplified biological model considering the scientific literature to explain the contribution of infections to proteinopathies resulting in neurodegenerative disease for possible integration into a predictive model.

Method

We performed a narrative review of the literature on the cellular mechanisms affected by HSV‐1, CMV and AD.

Result

We propose an hypothetical model supporting that infections can contribute significantly to the different pathophysiological processes of AD via an increase in the failure of misfolding required to obtain a functional conformation of proteins and a decrease in the clearance of proteins with a potentially toxic conformation. Some important changes also involve immunosenescence, as well as compromise of neurogenesis. Immunosenescence allows latent infections, such as HSV‐1 and CMV, to reactivate, spread, and cause cellular changes favorable to AD development.

Conclusion

The model explains the cellular changes observed in AD. Given that effective treatments already exist for many of the infections, additional studies are urgently needed to detail the specific contribution of each infection.
Inequities in Distal Health Services Outcomes of ADRD: The Role of Race/Ethnicity
Authors: Tarraf Wassim
Published: December 2023

Background

Decades of research point to entrenched health and healthcare disparities by race/ethnicity in the US. These disparities are magnified by illness, particularly so in gradually onsetting late diagnosed progressive diseases such Alzheimer’s Disease and Related Dementias (ADRD). ADRDs impose significant burdens on patients, their families, and their caregivers, have substantial health and social implications, and consume large formal and informal financial resources. The US healthcare system is complex, hard to navigate, and a potential contributor to widening disparities.

Method

We (1) review published work on disparities in health services outcomes among individuals with ADRDs in the context of national survey/observational data, (2) discuss micro, meso, and macro risk and resilience factors that can help reduce or close these disparities, and (3) point to gaps (e.g. in data) needing short and intermediate term focus.

Result

We use findings on distal health services outcomes for ADRD from national survey/observational data (e.g. Health and Retirement Study, and the National Health and Aging Trends Study) focusing on race/ethnicity (and confounding factors).

Conclusion

Addressing the identified gaps can help direct scientific efforts towards interventions and policies that can move us closer to health and healthcare equity in ADRDs.
Multimodal omics analytic framework identifies microglial immunometabolism endophenotypes underlying sex differences in Alzheimer’s disease
Authors: Hou Yuan , Xu Jielin , Bekris Lynn M. , Pieper Andrew A. , Cummings Jeffrey L. , Leverenz James B , Cheng Feixiong
Published: December 2023

Background

Although Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying AD sex differences are incompletely understood.

Method

In this study, we investigated the interplay between cellular metabolism and immune responses (termed the “immunometabolism endophenotype”) by unique integration of single nuclei transcriptomics (snRNA‐seq) and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer’s Disease Research Center. We conduced pathway activity score (PAS) to investigate metabolic alteration in microglia and astrocytes from brain cortex, with PAS > 0 indicating a specific cell type with higher average gene expression within a pathway, relative to all remaining cell types.

Result

We found that female AD subjects had a reduced PAS score within the TNFR2 non‐canonical NF‐kB pathway in microglia compared to male AD subjects, indicating reduced anti‐inflammatory effects of microglia in women. In addition, women with AD also showed lower PAS score within the branched chain amino acid pathway. Integrative sc/snRNA‐seq data analysis also shows sex‐specific metabolic cell‐cell communications among microglia, astrocytes and neurons. For example, male AD subjects have higher metabolic communication between astrocytes and excitatory neurons. In particular, astrocytes show lower PAS distribution across 84 metabolic pathways in women with AD, compared to men with AD. Astrocytes in female AD subjects showed deceased PAS within creatine metabolism pathways and increased PAS within threonine catabolism pathways.

Conclusion

This study demonstrates proof‐of‐concept of microglial immunometabolism underlying sex differences in AD.
The Evaluation on the Challenges of Current Assessment Tools Measuring Caregiver Intensity
Authors: Tkatch Rifky
Published: December 2023

Background

Family members caring for individuals with Alzheimer’s disease demonstrate higher levels of burden and stress than other caregivers. Caregiver intensity is characterized as the number of tasks and hours caregivers care for the recipient and, as a construct, has demonstrated a more comprehensive assessment of the caregiver experience. Furthermore, because caregiver experience is intertwined within the patient journey, current measures of caregiver burden/intensity do not encapsulate the full construct as described and can be difficult to administer in real world settings.

Objective

This session reviews and evaluates current assessment tools measuring caregiver intensity/burden, gaps in measurement, methodology used to implement these measures, associated health economic outcomes, and challenges implementing these measures.

Methods

A systematic review of the current assessment tools including the Zarit Burden Interview‐S, Caregiver‐Perceived Burden Questionnaire, Caregiver Burden Scale and the Caregiver Burden Inventory. Domains within each measure, length and burden to respondent and associated outcomes will be assessed.

Results

Current measures of caregiver burden/intensity have strengths and limitations in their use. Some do not fully capture the caregiver burden/intensity construct, are limited to a single domain, and exclude recipient progression.

Conclusion

The inadequate nature caregiver intensity/burden measurement suggests the construct and its associated clinical, psychosocial, and economic outcomes are likely underreported. The practicality of implementing lengthy and complex measures in a real‐world setting is challenging. Unique approaches that include the intensity of caregiver experience, the patient and caregiver as a “dyadic patient” navigating the patient journey, and multiple domains (financial, social, physical etc.) should be considered. This would provide meaningful information when designing and implementing both caregiver and patient interventions.
Effect of Alcohol Use on Progression to Mild Cognitive Impairment and Dementia
Authors: Joshi Pallavi , Chen Yinghua , Su Yi , Reiman Eric M.
Published: December 2023

Background

Addressing modifiable risk is an important part of a comprehensive strategy to reduce the risk of incident mild cognitive impairment (MCI) and dementia. Alcohol use is one modifiable risk factor with good potential for early identification and intervention. Substantial evidence demonstrates that chronic and heavy alcohol use increases the risk of dementia, but the effect of infrequent alcohol use versus moderate to heavy use on the risk for progression from cognitively unimpaired (CU) to MCI or from MCI to dementia is not known.

Method

We used data from Alzheimer’s Disease Research Center participants at least 65 years of age in the National Alzheimer’s Coordinating Center (NACC) database to examine the relationship between two levels of self‐reported alcohol use on rates of clinical progression from CU to MCI and from MCI to dementia. Cox proportional hazard models were used to characterize and compare rates of clinical progression over 84 months in a) 418 CU and 137 participants who reported no/infrequent use and b) 49 CU and 203 MCI participants who reported moderate/heavy use, after controlling for age, sex, educational level, presence or absence of APOE4, and Hispanic ethnicity. Kaplan‐Meier survival analysis was used to assess the progression odd‐ratio and time to conversion differences between the moderate/heavy alcohol users and no/infrequent users as the primary statistical method, and simple Chi‐square test to secondarily examine prevalence differences.

Result

There was no significant difference in alcohol use in CU and MCI impaired groups at baseline and no significant differences in risk of progression from either CU to MCI (p = 0.14) or from MCI to dementia (p = 0.32).

Conclusion

This study was unable to detect a significant difference between self‐reported low/infrequent and moderate/heavy alcohol use on rates of progression to MCI and dementia. Larger studies could address potential differences with greater statistical power; and emerging blood‐based biomarkers could be used in legacy plasma samples to clarify the extent to which different levels of alcohol use have any preferential impact on Alzheimer’s disease and related disorders.
QEEG‐based TabNet classifier for dementia pathologies: Alzheiemer’s disease and Lewy body disease
Authors: Jeong Hyerin , Park Ukeob , Baik Kyoungwon , Ye Byoung Seok , Kang Seung Wan
Published: December 2023

Background

Early screening and prevention of dementia are widely discussed and studied in the current healthcare paradigm. However, about 70 percent of dementia diagnoses are categorized into Alzheimer’s disease (AD), neglecting the presence and influence of Lewy body. The present study aims to distinguish Alzheimer’s disease dementia (pure AD) and Lewy body dementia (pure LBD) through quantitative electroencephalogram (QEEG)‐based classification algorithm. The mixed dementia that exhibits both AD and LBD related propensities were further tested for the verification of the established classification model.

Method

19 channel EEG data were recorded in accordance with the 10‐20 system in eyes‐closed resting state. The acquired data were bandpass filtered into the range of interest (1‐45Hz) and re‐referenced into common average reference. Artifacts were removed by bad epoch rejection and independent component analysis (ICA) through an automated, cloud‐based QEEG analysis platform iSyncBrain®. Henceforth, sensor‐level features were extracted and computed for the training of TabNet structure. Due to the data imbalance (N = 146, Pure AD = 48, Pure LBD = 102), time window‐based augmentation has been applied to establish the final dataset (N = 7292, Pure AD = 3376, Pure LBD = 3916), which were then split into 8 to 2 ratio for the training and testing of the classification model. In addition, mixed dementia (N = 136) data were used to further validate the model’s performance.

Result

The best classification model yielded test accuracy of 80% with pure AD sensitivity at 80% and pure LBD sensitivity 80%. Moreover, the predicted probability distribution for the mixed dementia data were prominently concentrated around 0.5, which reflect that both pure AD and LBD properties exist.

Conclusion

Along with the promising classification performance of the established classification model, the centered probability distribution of the mixed dementia data reflect that the model can well distinguish the characteristics that are specific to pure AD and LBD.