bluuebunny/crossref_metadata_2025 huggingface dataset:
P‐tau217 is the earliest plasma marker of dementia of the Alzheimer’s type in older primary care patients
Authors: Kleineidam Luca , Oezdemir Selçuk , Martino‐Adami Pamela , Weinhold Leonie , Koehler David , Chatterjee Madhurima , Pentzek Michael , Weyerer Siegfried , Bickel Horst , Wiese Birgitt , Riedel‐Heller Steffi G. , Scherer Martin , Blennow Kaj , Zetterberg Henrik , Schmid Matthias , Ruiz Agustin , Peters Oliver , Jeromin Andreas , Wagner Michael , Ramirez Alfredo , Schneider Anja
Published: December 2023

Background

Blood‐based biomarkers of Alzheimer’s disease (AD) may provide an avenue for early identification of individuals at risk for AD dementia, which is a crucial task for implementing upcoming disease‐modifying therapies in clinical practice. Among blood‐based biomarkers, P‐tau217 has shown a particular sensitivity to amyloid pathology and utility for differential diagnosis of AD. However, less is known about the association of P‐tau217 with dementia risk in older primary care patients.

Method

To address this question in an extreme phenotype design, we measured plasma P‐tau217 using the validated ALZPath pTau217 assay developed on the Single molecule array (Simoa) technology in 184 patients (median age = 83 years) free of dementia at blood draw who converted to clinically diagnosed dementia of the Alzheimer’s type (DAT) during up to eight years of follow‐up. Furthermore, P‐tau217 was measured in 184 age‐ and sex‐matched cognitively normal controls that stayed free of any cognitive impairment during follow‐up. All participants were derived from the primary care‐based AgeCoDe‐cohort. In addition, Aβ42/Aβ40, P‐tau181, NfL, and GFAP were quantified using Simoa technology.

Associations between P‐tau217 and conversion to DAT were assessed using conditional logistic regression and compared to associations of conversion to DAT with Aβ42/Aβ40, P‐tau181, NfL, and GFAP. The influence of time to DAT diagnosis on the associations was assessed by generalized additive models.

Result

P‐tau217 was strongly associated with conversion to DAT (ORper‐1SD‐increase [95%‐CI] = 10.29 [5.16‐20.41], p = 2.0*10−11, N = 368). This association was present irrespective of whether DAT‐converter showed MCI (ORper‐1SD‐increase [95%‐CI] = 3.49 [1.34‐9.12], p = 1.1*10−2) or no MCI (ORper‐1SD‐increase[95%‐CI] = 16.07[6.54‐39.71], p = 1.3*10−9) at blood draw. No other marker showed a similarly strong association with conversion (second‐best performance: GFAP; ORper‐1SD‐increase [95%‐CI] = 1.36 [1.19‐1.54], p = 2.15*10−2).

Patients converting to DAT eight years after blood draw already presented with elevated P‐tau217 levels compared to their matched controls. Other markers (GFAP, P‐tau181) started to show differences in individuals converting to DAT four years after blood draw.

Conclusion

P‐tau217 is the most sensitive plasma marker for risk of conversion to DAT in older patients from primary care patients in comparison to plasma P‐tau181, Aβ42/Aβ40, NfL, and GFAP.
The involvement of GLP1 signaling with the effect of oral galactose in the hypothalamus of sporadic Alzheimer’s disease rat model
Authors: Knezovic Ana , Barilar Jelena Osmanovic , Homolak Jan , Perhoc Ana Babic , Salkovic‐Petrisic Melita
Published: December 2023

Background

Intracerebroventricular (icv) application of streptozotocin (STZ) causes mytochondrial dysfunction, oxidative stress and other metabolic effects, which leads to accumulation of τ‐protein and Aß plaques that makes it suitable for animal model of sporadic Alzheimer’s disease (sAD). We aimed to explore whether acute effect of single oral galactose dose is mediated by glucagon‐like peptide‐1 (GLP‐1) in sAD rat model.

Method

Wistar rats were injected icv with STZ (3 mg/kg) or vehicle only (CTR). One month after the injection, animals were divided into three experiments. First experiment: 200 mg/kg galactose was given orally and CTR animals were sacrificed 30, 60 and 120 min after administration. Second experiment: GLP‐1R antagonist (Exendin 9‐39, 85 µg/kg; GLP1Ra) was administered icv in both groups and animals were sacrificed 30 min after the injection. Third experiment: 30 min prior to oral galactose, rats were injected icv with GLP‐1Ra, and animals were sacrificed 120 min after galactose load. PDH, COXIV, CytC and Casp‐3 levels were measured by Western blot method and lactate, ATP and SOD were measured by ELISA in HPT. Glucose, galactose and GLP‐1 levels were measured in plasma and CSF. Data were analyzed by principal component analysis and Spearman rank correlation.

Result

Metabolic changes were found more pronounced 120 min after single galactose load: reduced levels of Casp‐3 and PDH and increased SOD levels in HPT; increased CSF glucose. GLP1Ra decreased the levels of lactate, COXIV and CytC and increased PDH and Casp‐3 levels in HPT, only in STZ treated animals. CytC was found negatively correlated with ATP and PDH levels in HPT. GLP1Ra decreased the levels of CytC and SOD and increased PDH levels in CTR only after oral galactose.

Conclusion

GLP1Ra might inhibit decreased PDH levels caused by single galactose load. GLP1R central inhibition has more pronounced effect in STZ‐icv treated rats suggesting the involvement of GLP1 signaling in model pathogenesis.

Supported by Croatian Science Foundation and co‐financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).
Clinical proteomic analysis across the Alzheimer’s disease continuum
Authors: Weiner Sophia , Sauer Mathias , Ashton Nicholas J. , Benedet Andrea Lessa , Rosa‐Neto Pedro , Blennow Kaj , Zetterberg Henrik , Gobom Johan
Published: December 2023

Background

Alzheimer’s disease (AD), defined by amyloid‐β (Aβ) and neurofibrillary tau tangles, can be viewed as a continuum, starting with an asymptomatic “pre‐clinical” phase that progresses to a symptomatic clinical stage characterized as mild cognitive impairment (MCI), and finally, AD dementia. Identifying biomarkers reflective of the different disease stages is important to detect individuals at risk of developing AD, to monitor disease progression and the effect of treatments, as well as to determine new therapeutic targets.

Method

We present data from a cross‐sectional tandem mass tag (TMT) proteomic study of cerebrospinal fluid (CSF) samples from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (young adults (n = 22), cognitively unimpaired (n = 54), cognitively impaired (n = 26), MCI (n = 19), AD (n = 19), non‐AD (n = 16), frontotemporal dementia (n = 9); total n = 214); a highly profiled cohort across the AD continuum with clinical and neuropsychological assessments, MRI, and Aβ and tau positron emission tomography (PET). To enhance detection of brain‐derived proteins, we evaluated the use of a TMT booster channel consisting of brain protein extract. Planned statistical analyses include linear regression modelling to compare biomarker distributions across groups, covariating for sex and age where appropriate as well as correlation analyses of biomarker levels with Aβ and tau PET measurements.

Result

Our preliminary data analysis suggests that a set of proteins differed with high significance between amyloid PET negative and positive individuals (Fig. 1), including proteins that showed changes already at the pre‐clinical stage of AD. We will explore the correlation of the identified biomarker candidates with pathological process and disease progression, as well as with Aβ‐ and tau‐PET measurements. Also, protein changes associated with aging and other neurodegenerative disorders will be evaluated. Finally, the use of a TMT booster based on brain protein extract to enhance identification of CSF biomarkers will be assessed.

Conclusion

This study describes the most extensive unbiased proteomic profiling in CSF across the AD continuum, identifying proteins that may serve as novel therapeutic targets and fluid biomarkers for the disease. Additionally, the use of a TMT booster to enhance the detection of brain‐derived proteins was evaluated.
The ABOARD Cohort Panel: public involvement in a Dutch Cohort study on a personalized medicine approach for Alzheimer’s disease
Authors: de Rijke Tanja J. , Smeitink Marlon , Beusink Miriam , Van der Rhee Els , Saaltink Dirk‐Jan , van der Landen Sophie M. , Smets Ellen M.A. , Handgraaf Dédé , de Boer Casper , Meester Hanneke F.M. Rhodius‐ , Schaaij‐Visser Tieneke B.M. , van der Flier Wiesje M. , Visser Leonie N.C.
Published: December 2023

Background

ABOARD is a Dutch public‐private partnership aiming for a personalized medicine approach for Alzheimer’s disease. Within this project, the ABOARD Cohort is initiated: a national prospective data infrastructure with the objective to study the AD disease trajectory using PROMS and linked clinical data. The ABOARD Cohort Panel has been installed to provide advice on the design, execution, and direction of the study. By incorporating the perspective of potential participants the meaningfulness and accessibility of the ABOARD Cohort is ensured.

Method

Recruitment for the panel has been initiated by the Dutch Brain Foundation via social media and newsletters, and approximately 300 people responded with potential interest. To further inform them, we hosted a webinar explaining the ABOARD Cohort Panel. Hereafter, respondents received an official Panel invitation and initial survey (including principles for collaboration), resulting in 59 people signing up as panellists.

Result

Panel members are on average 62 years old, 78% is female, 96% has no migration background, and 52% participated in a panel before. Panellists vary in education level and geographic distribution. The majority has a personal interest in dementia (64%) and/or friends/family with dementia (62%). When asked how they would like to be involved, they indicated wanting to be involved in online questionnaires (100%), online focus groups (56%), and in‐person focus groups (36%). The majority preferred monthly questionnaires (50%) with a duration of 10‐20 minutes (52%). In the first months, panellists provided feedback in online surveys on the ABOARD Cohort information letter and informed consent form. They considered these lengthy, too difficult, and raising questions. An in‐depth live session was held with panellists to test subsequent adjustments, resulting in higher agreement rates on the informed consent procedure of the ABOARD Cohort. Panellists also advised on the communication strategy of the national ABOARD Cohort campaign, which is currently being implemented. In the coming months, panel members will test the usability of the ABOARD Cohort portal and an online cognitive test and advice on dissemination and variables that are being collected.

Conclusion

The ABOARD Cohort Panel incorporates the perspective of potential participants and aims to ensure the meaningfulness and accessibility of the ABOARD Cohort.
Chromosome Y‐haplotype mediates cognitive resilience and differential expression of transposable elements in 5xFAD‐carrying AD‐BXD males
Authors: Boas Stephanie M. , Saul Michael C. , Anderson David , Philip Vivek M. , Ramirez Paulino , Frost Bess , Beck Christine R. , Kaczorowski Catherine C.
Published: December 2023

Background

In Alzheimer’s disease (AD), risk factors and clinical progression differ between sexes. Men have lower post‐diagnosis life‐expectancies 1,2, while women display worsened cognitive decline than men with similar neuropathology3‐5 or shared genetic risk6,7. Investigation of sex‐specific genetic contributions to AD has largely focused on the X‐chromosome, but emerging evidence has also linked somatic Y‐chromosomal instability to age‐linked disease outcomes, including AD8‐10. Notably, the Y‐chromosome contains few coding genes, but is enriched with transposable elements (TEs)11, enigmatic DNA sequences capable of introducing variation into the genome12. Differential expression of TEs has recently been reported in AD13‐15. We hypothesize that TEs could contribute to sex‐specific variation observed in AD onset and progression.

Method

Here, we utilized bulk hippocampal RNAseq and contextual fear memory (CFM) data from a 28‐strain AD‐BXD dataset comprised of male and female 5xFAD‐carrying animals and non‐transgenic (Ntg) littermates to investigate whether expression of coding genes and/or TEs contribute to AD‐relevant sex differences and cognitive outcomes. Data were stratified by sex and Y‐chromosome haplotype (C57BL/6J‐type vs. DBA/2J‐type). TEs were quantified in RNAseq data using TETranscripts16. For each TE, we predicted genomic localization using DFAM17, and calculated sex‐specific heritability.

Result

In 5xFAD animals, C57BL/6J‐type males significantly out‐performed both DBA/2J‐type males and females on a CFM task (Fig.1). TEs identified in this dataset were differentially expressed due to both sex and Y‐chromosome haplotype in 5xFAD animals (Fig.2). Interestingly, Y‐haplotype did not affect Y‐chromosome coding gene expression. We calculated that a large portion of TEs identified in our dataset are highly heritable, with differential heritability associated with sex and 5xFAD‐transgene status (Fig.3)

Conclusion

We report that the C57BL/6J Y‐chromosome confers cognitive resilience in 5xFAD males, which may undermine the utility of models maintained on a homogenous C57BL/6J background as tools for investigating age‐related cognitive decline. We speculate that differential TE expression/activity between Y‐haplotypes and between sexes may account for differential resilience, but further investigation is needed to establish this link directly. Finally, our data suggest that not only are TEs likely influencers of AD risk and disease progression, but that TE expression in disease states may be heritable, rather than stochastically induced.
Concordance between APOE genotyping and proteotyping using the novel Lumipulse G Pan‐ApoE and Lumipulse G ApoE4 RUO assays
Authors: Degrieck Rosina , Denoyette Mario , Delanote Jarne , De Jonge Maarten , Umeda Kazuyuki , Yuri Tatsushi , Umeda Dagmara Minczakiewicz , Bastard Nathalie Le , Sato Hideo , Nojima Hisashi , Aoyagi Katsumi , Vandenbroucke Ina
Published: December 2023

Background

The APOE gene has three different alleles that encode for three different ApoE protein isoforms (APOE2, APOE3, and APOE4), resulting in 6 different phenotypes. Nucleic acid amplification test remains the gold standard for APOE genotyping, however quantification of the ApoE proteins using immunoassays could provide another piece of information, related to the expression levels of the proteins. In this regard, ApoE as a protein biomarker can be used in research to determine its value alone or as part of a panel of plasma biomarkers.

Method

The LUMIPULSE G System is a chemiluminescent enzyme immunoassay platform enabling fully automated processing of samples using ready‐to‐use immunoreaction cartridges. Time to result in these single use test cartridges takes about 30 minutes. The analytical performance of the newly developed Lumipulse G Pan‐ApoE and Lumipulse G ApoE4 RUO assays was determined. Parameters analyzed were precision, sensitivity, linearity, prozone and potential impact of interfering substances. Proof of concept of these novel assays was verified with a set of 230 genotyped plasma samples.

Result

The total within‐lab variability of both assays was ≤8% CV confirming high precision of the LUMIPULSE G system. Using low ApoE concentrated plasma samples, the observed LoD and LoQ (@20% CV) was 0.072 µg/mL (Pan‐ApoE) and 0.152 µg/mL (ApoE4). Linearity was shown across the assay range (0 – 100 µg/mL) for both assays. Neither prozone effect nor significant impact (recovery within 100±10%) of commonly tested endogenous substances (bilirubin, haemoglobin, low and high Protein content, and human anti‐mouse antibodies (HAMA)) was observed. Potential interference was observed for triglycerides and rheumatoid factor (RF) with observed recovery within 100±20%. ApoE proteotyping based on the novel assays resulted in a 99.8% concordance with APOE genotyping (1 discordant result). Moreover, applying the ratio ApoE4/Pan‐ApoE with the measurement values of respective assays, classified correctly between hetero‐ and homozygous E4 carrier status.

Conclusion

The analytical performance studies demonstrate low variability and high sensitivity enabling measurement of pan‐ApoE and ApoE4 in plasma. Pan‐apoE and apoE4 quantification can offer relevant insights into the assessment of subjects at risk for AD or adverse events following anti‐amyloid treatments and should be studied further.
Correlations of p‐tau217, p‐tau181 and tau levels between CSF and plasma that are measured by fully automated immunoassay platform
Authors: Matsumoto Kazuya , Murakami Shun , Mori Asuka , Arai Nari , Ishiki Kengo , Gupta Ishita , Watanabe Shunsuke , Yamashita Kazuto , Ishimoto Tadashi , Kurosaki Masae , Miura Masahiro , Iwanaga Shigeki , Sato Toshiyuki
Published: December 2023

Background

Cerebrospinal fluid (CSF)‐based ATN classification (A: β‐amyloid (Aβ) deposition, T: pathogenic tau accumulation, N: neurodegeneration) is being widely accepted for the characterization of Alzheimer’s disease (AD). However, for the implementation of ATN classification in clinical practice, blood‐based biomarker is preferable in terms of specimen collection ease. Therefore, we have developed the blood‐based biomarker assays that correlate well with CSF levels. We have previously demonstrated that the plasma tau and phosphorylated tau at threonine‐181 (p‐tau181) immunoassays can significantly differentiate between AD, mild cognitive impairment (MCI), and cognitively normal (CN) groups. Here, we evaluated the correlation of biomarker levels between CSF and plasma utilizing the biomarker panel with addition of phosphorylated tau at threonine‐217 (p‐tau217) immunoassay.

Method

We have measured p‐tau217, p‐tau181 and tau using commercially available specimens on a fully automated immunoassay platform, HISCLTM analyzer. The platform can achieve high degree of sensitivity, requires only 30 µl of sample and 17 minutes to complete the measurement per assay. The bio‐analytical performance for the immunoassays was evaluated by measuring lower limit of quantification (LLOQ). The developed immunoassays were used to measure the paired CSF and plasma specimens from AD (n = 10), MCI (n = 35) and CN (n = 9) groups.

Result

The quantitative sensitivity for p‐tau217, p‐tau181 and tau were sufficient to measure plasma specimens in all groups. The plasma biomarker levels were significantly different between the AD and CN groups for all the biomarkers. We have found good correlations of biomarker levels between CSF and plasma for p‐tau217 (rs = 0.594, p < 0.01), p‐tau181 (rs = 0.453, p < 0.01) and tau (rs = 0.326, p < 0.05).

Conclusion

Our results indicated the possibility of detecting plasma p‐tau217, p‐tau181 and tau levels which may reflect the CSF levels. In addition to these assays, we have also developed plasma Ab and neurofilament light chain assays that had demonstrated good correlation with CSF levels. Thus, all the plasma assays developed on the HISCL analyzer could assess ATN classification. The blood‐based biomarker panel using our fully automated assay will accelerate research in the dementia field and may help in appropriate diagnosis of patients with dementia in routine clinical practice.
Associations of 24‐h rest‐activity patterns with plasma markers of neurodegeneration and Alzheimer’s disease pathology in cognitively unimpaired individuals
Authors: Van Egroo Maxime , Beckers Elise , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Jacobs Heidi I.L.
Published: December 2023

Background

Altered 24‐h rest‐activity rhythms have been previously associated with higher burden of Alzheimer’s disease (AD) pathological hallmarks, as measured with positron emission tomography or cerebrospinal fluid collection. Recent developments in fluid biomarkers now allow to non‐invasively measure levels of AD‐related pathology in the plasma. Here, we examined whether actigraphy‐derived 24‐h rest‐activity patterns could be linked to plasma markers of neurodegeneration and AD pathology in a sample of cognitively unimpaired participants.

Method

Ninety‐three asymptomatic individuals (mean age = 59.73 ± 13.74 y., range = 30 – 85 y., 48 females, Table 1) underwent 10 days of actigraphic recordings, and blood drawing. Standard non‐parametric indices of 24‐h rest‐activity rhythm fragmentation (intradaily variability, IV) and stability (interdaily stability, IS) were extracted using the GGIR package (v2.8‐2) in R. Plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), 40 and 42 amino acid‐long amyloid‐β (Aβ40 and Aβ42, respectively), total tau, and phosphorylated tau at threonine 181 (pTau181) or threonine 231 (pTau231) were measured using Single molecule array technology.

Result

Multiple linear regression models adjusted for age, sex, education, and body mass index, showed that worse rest‐activity rhythm fragmentation, as indicated by higher IV values, was strongly associated with elevated levels of plasma NfL (t = 4.53, p < .0001, Figure 1), but also with higher levels of plasma GFAP (t = 2.44, p = .02, Figure 2) and lower plasma Aβ42/40 ratio (t = ‐2.23, p = .03, Figure 2). Similarly, increased day‐to‐day rest‐activity rhythm stability, as indicated by higher IS values, was associated with lower levels of plasma NfL (t = ‐2.37, p = .02, Figure 1). By contrast, no significant relationships were found between IV or IS values and total tau or phosphorylated tau plasma biomarkers (all p > .27).

Conclusion

These findings provide further evidence that disrupted rest‐activity patterns, in particular fragmentation of rest‐activity rhythms, may constitute a sensitive marker of incipient AD pathology and neurodegeneration in cognitively unimpaired individuals. Our study therefore highlights the clinical utility of monitoring rest‐activity patterns for improved detection of individuals at‐risk for neurodegenerative diseases, including AD.
Investigating neuronal senescence marker, p19INK4d, in mouse and human brains
Authors: Hudson Hannah R. , Orr Timothy C. , Orr Miranda E.
Published: December 2023

Background

The cellular senescence stress response allows damaged, toxic cells to survive. Clearing senescent cells is a promising therapeutic approach and has moved to clinical trials for Alzheimer’s disease and related dementias (ADRD). We previously identified a link between the cell cycle inhibitor CDKN2D/p19INK4d and neuronal senescence in human postmortem brains with various levels of AD neuropathology. We hypothesized that senescence could be induced by overexpressing this gene in mouse neurons in vivo.

Method

Adeno‐associated virus 9 (AAV9) with the neuron specific human Synapsin I (hSyn1) promoter was used to deliver experimental Cdkn2d‐GFP, or control GFP gene expression. Precise delivery of 0.5µl of 1013 IU virus into four neuronal populations per mouse, bilateral hippocampal CA1 and cortical layer 5 neurons was accomplished with the assistance of a stereotaxic robot. Male and female wild type, human tau transgenic and mouse tau knockout mice were used (12‐13 months‐old, n = 47). Mice were euthanized at either two weeks or eight weeks post‐surgery to determine the short‐ and long‐term effects of Cdkn2d expression. GeoMx digital spatial profiler was utilized to quantify protein expression between Cdkn2d infected and uninfected neighboring neurons. ROI selection is displayed in Figure 1.

Result

Histological analyses confirmed p19INK4d protein expression in AAV9‐infected cells. GeoMx DSP analyses performed on hippocampus, cortex, and thalamus revealed a protein expression pattern consistent with senescence (i.e., resistance to apoptosis), in Cdkn2d‐expressing neurons of the hippocampus and cortex compared to the un‐infected thalamus (Figure 2). Moreover, proteins associated with apoptosis were higher in the thalamus compared to the cortex and hippocampus.

Conclusions

The data indicates that AAV9‐hSyn1‐Cdkn2d‐GFP is an appropriate method to increase p19INK4d expression in mouse neurons in vivo. Over‐expressing p19INK4d caused neurons to acquire a protein expression signature consistent with senescence. The concomitant expression of apoptosis proteins in the thalamus leads me to hypothesize that the senescent cells in the cortex may cause cell death in the thalamus through the corticothalamic tract. Further studies with increased sample size are needed to confirm the results and continue exploring the effects of Cdkn2d on neuronal senescence, and how tau protein may influence this stress response.
Sexual dimorphisms in longitudinal associations of the blood lipidome with cognitive decline in Alzheimer’s disease
Authors: Marella Bharadwaj , Weinisch Patrick , Huynh Kevin , Risacher Shannon L , Wilhelm Mathias , Kaddurah‐Daouk Rima F. , Meikle Peter J , Kastenmuller Gabi , Arnold Matthias
Published: December 2023

Background

Late‐onset Alzheimer’s disease (AD) is the leading cause of dementia with neither cure nor a clearly understood disease trajectory. Previous studies have shown cross‐sectional and longitudinal associations of the blood lipidome and AD. We previously reported on significant sex differences in the associations of lipids with AD biomarkers and it has been suggested that such sex differences may result in distinct trajectories of AD progression. We performed an association study of sex‐stratified longitudinal lipidomics data with cognitive function to further characterize sexual dimorphisms in lipidomic manifestations of AD.

Method

We used a subset of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset: 1349 individuals (745 males and 604 females) with blood samples and clinical data collected at 10 time points with intervals of 6 to12 months (4145 samples total). We analyzed 749 lipid species measured by quantitative LC‐MS lipidomics profiling (Baker Heart and Diabetes Institute, Melbourne, Australia). We calculated linear mixed models (LMMs) and generalized additive mixed models (GAMMs) to analyze time‐resolved associations between lipids and two composite cognitive scores (ADNI memory and executive function) while adjusting for age, sex (pooled analysis only), BMI, HDL‐C, total cholesterol, copies of APOE ε4, years of education as well as significant medication effects.

Result

We observed a significant difference in lipid concentrations between males and females in line with previous studies, however, these differences were not fully consistent across diagnostic groups. In longitudinal association analyses, we found a substantial fraction of lipid species to have significant sex‐specific associations with cognitive function, which were not observed in the pooled analysis. These lipids were distributed across several lipid classes with enrichment in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and triglycerides (TG). Comparisons between LMMs and GAMMs further indicated that some lipids might have a nonlinear relationship with cognitive trajectories.

Conclusion

Our results suggest that there are substantial sex differences in longitudinal associations of the blood lipidome with cognitive decline resulting in complex and partially nonlinear relationships. The highlighted lipid pathways can serve as a starting point to better characterize sex‐specific molecular changes linked to cognitive decline in AD.
Locus coeruleus microstructural integrity is linked to plasma GFAP concentration and Aβ42/40 ratio in cognitively unimpaired individuals: a 7T MRI study
Authors: Patsyuk Yuliya , Van Egroo Maxime , van Hooren Roy W.E. , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Poser Benedikt A , Jacobs Heidi I.L.
Published: December 2023

Background

Recent autopsy and in vivo MRI studies supported structural integrity of the brainstem locus coeruleus (LC) as a potential indicator of initial AD‐related pathological processes. Importantly, in the earliest stages of the disease, these changes to the neuronal density of the LC are associated with changes to the somatic morphology and dendritic atrophy. Here, we aimed to examine whether LC microstructural integrity, assessed in vivo with advanced diffusion‐weighted magnetic resonance imaging (dMRI), is related to plasma AD biomarkers in a sample of cognitively unimpaired individuals.

Method

Fifty‐seven cognitively unimpaired participants (mean age = 59.3±14.7y; 28 females) (Table 1) underwent a dMRI scanning session using a multi‐shell, high angular resolution acquisition protocol in a 7T scanner. LC microstructure was evaluated by applying the Neurite Orientation Dispersion and Density Imaging (NODDI) biophysical model on the dMRI data, yielding two metrics of microstructural integrity: Neurite Density Index (NDI) and Orientation Dispersion Index (ODI). Additionally, blood samples were analyzed to assess AD plasma biomarkers, including Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau phosphorylated at threonine 181 (pTau181) or threonine 231 (pTau231).

Result

Higher age was associated with lower LC ODI (t = ‐2.77, p = 0.008) but not LC NDI values (t = 0.44, p = 0.658). Multiple linear regressions adjusted for age, sex, and estimated Total Intracranial Volume (eTIV) showed that lower NDI in the LC was associated with higher plasma GFAP levels (t = ‐2.08, p = .04, Figure 1). In addition, we found a negative association between ODI within the LC and Aβ42/40 (t = ‐2.79, p = .007, Figure 2). No significant relationships were found between LC NDI/ODI values and plasma NfL or pTau biomarkers.

Conclusion

Consistent with animal studies, these findings suggest that microstructural changes in the LC are associated with astroglial activation in the earliest stages of the disease. Associations with Aβ42/40 were unexpected but might reflect loss of white matter compartments or changes in lipid density. In future analyses, we will further examine the biological interpretation of the NODDI metrics in subcortical regions, in particular in the context of AD‐related processes.
The extent of Lead‐induced Pathogenesis of Alzheimer’s disease, Synaptic Dysfunction and Cognitive Impairment in Rats
Authors: Iliyasu Musa Omoyine , Ajayi Abayomi
Published: December 2023

Background

The hallmarks of Alzheimer’s disease (AD), like amyloid plaques and neurofibrillary tangles, are constituted of amyloid beta (Aβ) peptide and phosphorylated tau, respectively. Many studies reported the relationship between lead exposure and the progression of AD. However, the extent of lead‐induced pathogenesis and changes in proteins regulating synaptic plasticity in AD is lacking. The proposed study is designed to evaluate the pathogenesis of AD, synaptic dysfunction and cognitive impairment following lead exposure in rats.

Method

Thirty (30) Wistar rats (3 weeks old) will be obtained, acclimatized for one week, and randomly divided into five groups (n = 6). The rats will receive distilled deionized water containing 0% lead acetate [Pb2+] (ddH2O) or 0.5% [Pb2+] (ddH2O + 0.5% Pb2+) solution with a standard rat diet. Group I (baseline) will receive ddH2O for three (3) weeks. Group II (control) will receive ddH2O for nine (9) weeks. Groups III, IV, and V will receive (ddH2O + 0.5% Pb2+) solution for 3, 6, and 9 weeks respectively. Cognitive function will be conducted using 8‐ARWM as well as object recognition tests. The hippocampus will be extracted for immunohistochemical and biochemical studies. The levels of β‐secretase, Aβ42, tau protein (p‐tau), NMDAR subunit NR2B, postsynaptic density protein 95 (PSD‐95), Synaptophysin (SYP), and brain‐derived neurotrophic factor (BDNF) will be determined using Enzyme‐linked immunosorbent assay (ELISA) method. The expression levels of Aβ42, neurofibrillary tangle (NFT), NR2B, PSD‐95, and SYN will be determined using the immunohistochemical method. The expression of β‐secretase and BDNF will be determined using quantitative real‐time PCR.

Result

Lead could affect the levels of β‐secretase, Aβ42, p‐tau, NR2B, PSD‐95, SYP BDNF; the expression of Aβ42, NFT, NR2B, PSD‐95, SYN, and BDNF; and cognitive function.

Conclusion

The results could reveal the extent to which lead‐induced pathogenesis, synaptic dysfunction and cognitive impairment in AD
Blood biomarkers and lifestyle factors in dementia prevention
Authors: Shan Liu , Nishimura Yoshinori , Uchida Kazuhiko
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder with preclinical period that may begin more than 15‐20 years before onset without any clinical symptoms. Risk factors for intervention include obesity in middle age, lack of exercise, hypertension in middle age, diabetes mellitus, smoking, and hearing loss in middle age. Our research indicated that plasma proteins, such as apoA1, transthyretin, and complement C3, may serve as potential biomarkers for mild cognitive impairment (MCI) and Alzheimer’s disease. In this study, we analyzed the associations between risk and protective factors and these plasma protein levels to establish a risk assessment method for dementia.

Method

In present study, we measured blood biomarkers, including apoA1, transthyretin, and complement C3, in 1,736 subjects. We collected medical data from annual health examinations and clinical records of the participants. Additionally, lifestyle questionnaires were incorporated into the research.

Result

Our analyses revealed that the risk values in the composite score indicated by the three blood biomarkers were higher in those with a history of dementia and diabetes than in those without a history of dementia and diabetes. The odds ratios (OR) for MCI were 5.27 (CI: 2.14‐13.2) and 1.59 (CI: 1.04‐2.45), respectively. Smoking exhibited a high‐risk value (OR: 1.87, CI: 1.15‐3.01), while smoking cessation led to higher apoA1 levels than in those who continued to smoke. Utilizing the composite score as an index, we analyzed factors that increase or decrease the composite score based on the receipt diagnosis history, health checkup data, and lifestyle questionnaires. We found that the high‐risk group in the composite score was associated with low HDL cholesterol (OR 0.94), high HbA1c (OR 1.6), and right high frequency hearing loss (OR 2.97). Furthermore, we identified several protective factors against MCI, including regular walking and strong physical exercise, drinking 100% fruit and vegetable juices, and avoiding sweetened beverages, and eating sashimi and miso soup.

Conclusion

Our findings suggest that a firm commitment to lifestyle‐related disease treatment and high‐impact exercise from middle age can help prevent dementia. Additionally, the blood test we used may be useful in presenting specific methods of dementia prevention and evaluating their effectiveness.
Exploring the Potential of Radiomics Features of the Hippocampus in Alzheimer’s Disease Considering Standard versus Parallel Imaging
Authors: Pereira Helena Rico , Ferreira Hugo Alexandre
Published: December 2023

Background

Radiomics features obtained from anatomical magnetic resonance imaging (MRI) have been showing potential as biomarkers for the diagnosis of Alzheimer’s disease (AD). Nevertheless, little is known about how accelerated parallel MRI acquisitions impact such features and their potential in diagnosing AD. Therefore, this study aimed to compare the radiomics features extracted from the hippocampus considering standard and parallel imaging.

Method

A total of 235 age and gender‐matched subjects (128 cognitively normal (CN) and 107 AD) with both T1‐weighted MPRAGE (standard) and accelerated MPRAGE GRAPPA or SENSE images were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Freesurfer was used to process the images and to obtain the volumes of these regions: hippocampus, entorhinal cortex, amygdala, and inferior lateral ventricle (summed bilaterally); and caudal and rostral midfrontal, pars opercularis, pars triangularis, inferior parietal, superior parietal, supramarginal, and superior temporal gyri (all summed into one feature). Using Pyradiomics, the following radiomics features from the bilateral hippocampus were extracted: kurtosis, mean, range, contrast, elongation, flatness, and maximum 3D diameter. To compare the two acquisitions (standard vs parallel), support vector machine models were created to classify AD vs CN. To mitigate AD heterogeneity in ADNI, 5‐fold cross‐validation was used to create 5 train and test sets based on the hippocampus volumes: (each train fold has 80% of 1st quartile AD and 80% 1st quartile CN, and the test fold has 20% of 1st quartile AD and 20% 1st quartile CN volumes, and so on – randomly selected).

Result

Adding radiomics features improved the classification of AD vs CN in both acquisitions (Table 1): the positive predictive value increased from 77.2% to 90.3% in the standard, while the negative predictive value increased to 84.7% to 91.6% in the parallel acquisition. In both cases, models using all volumes surpassed those using only the hippocampus volume by 7.4% (86.0% balanced accuracy, standard) and 4.2% (85.5%, balanced accuracy, parallel) (Table 1).

Conclusion

Radiomics features of the hippocampus improve the performance of the models in both acquisitions, but with different predictive values, confirming their potential. Also, the relevance of other brain regions in AD besides the hippocampus was observed.
GRADUATE I AND II: Revisiting the key findings from two Phase III studies evaluating the efficacy and safety of subcutaneous gantenerumab in early Alzheimer’s disease (AD)
Authors: Lane Christopher , Smith Janice , Perry Richard J , Grimmer Timo , Lansdall Claire J , Voyle Nicola , Delmar Paul , Bittner Tobias , Klein Gregory , Schwab Dietmar , Schneider Andres , Salloway Stephen , Cummings Jeffrey L. , Baudler Monika , Fontoura Paulo , Doody Rachelle S. ,   for the GRADUATE I and GRADUATE II Investigators and the gantenerumab study group
Published: December 2023

Background

Gantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).

Method

Eligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed.

Result

GRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL).

Conclusion

The GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined.
Rescuing impaired cortical‐hippocampal interactions during sleep with 40Hz stimulation directed to hippocampus in 3xTg‐AD/PVcre mice
Authors: Cushing Sarah Danielle , Moseley Shawn C , Stimmell Alina C , Wilber Aaron A
Published: December 2023

Background

In preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired (Allison et al., 2016). We reported similar impairments in 6‐month 3xTg‐AD female mice on a virtual spatial‐reorientation‐task (VM) that requires memory for using landmarks to navigate (Cushing et al., 2020). Memory replay during sleep is critical for learning related plasticity (Ego‐Stengel & Wilson, 2009; Jadhav et al, 2012; Maingret et al, 2016), and hippocampal‐cortical dysfunction is a potential mechanism for memory impairments in AD (Gennaro et al, 2017; Khan et al, 2014). Consistent with this hypothesis, we previously found deficits in hippocampal‐parietal cortex (HPC‐PC) coordination during sleep coinciding with impairments on the VM (Cushing et al, 2020). 40Hz stimulation has been shown to clear AD pathology in mice (Iaccarino et al, 2016; Martorell et al, 2019), and improve functional connectivity in preclinical AD patients (He et al, 2021), but see (Soula et al, 2023).

Method

Thus, we assessed HPC‐PC coordination in 3xTg‐AD/PVcre mice learning the VM. We implanted a 16‐tetrode recording array targeting PC and HPC and an optical fiber targeting HPC. Daily recording sessions of rest‐task‐rest commenced as mice learned the VM, followed by HPC optogenetic stimulation, with either 40Hz or SHAM stimulation. We assessed sleep quality metrics, delta waves (DW) in PC, and HPC markers of memory replay (SWRs) during slow wave sleep (SWS).

Result

In SHAM stimulated mice SWR‐DW cross‐correlations were reduced, similar to 3xTg‐AD mice (Cushing et al, 2020); while in the 40Hz stimulated mice, this phase‐locking was rescued. Furthermore, the 40Hz stimulated mice have restored performance on the VM compared to SHAM mice. However, this rescued HPC‐PC coupling no longer predicted performance as in NonTg animals (Cushing et al, 2020). Instead, DWTs independently predicted performance in 40Hz animals, but not SHAM animals. We also found paradoxical reduction of amyloid beta in contralateral PC and ventral CA1, but no reduction in contralateral dorsal CA1, synaptically closer to where stimulation occurred.

Conclusion

Thus, 40Hz stimulation of HPC rescued learning and memory related functional interactions in the HPC‐PC network during sleep and as a consequence rescued impairments in spatial navigation, despite a decoupling between HPC‐PC coupling and learning and memory.
Creating National Dementia Caregiver Profiles: A Pilot Study
Authors: Sivananthan Saskia , Whate Alexandra , Apostolides Haridos , Armstrong Joshua J.
Published: December 2023

Background

There will be an estimated 1 million people living with dementia (PLWD) in Canada in 2031, with a further 613,500 Canadians thrust into the role of caregiver to support them. These unpaid caregivers, who tend to be spouses or adult children, shoulder significant physical, mental, emotional, and financial burdens while caring for their loved ones. Yet there is almost no information available nationally on caregivers of people living with dementia and their needs

Method

The First Link® program by the Alzheimer Society offers tailored support and connection to caregivers reaching ∼200,000 clients nationally. Consistent quantitative data will be collected from 30,000 individuals across 5 pilot provinces. The pilot recruitment ensures representation and inclusivity of all communities served by the Society. A framework and data set were agreed to through a collaborative community of practice approach engaging provincial Societies, subject matter experts and PLWD. Data sharing agreements were established for automated, secure, de‐identified data transfers into a centralized data repository.

Result

The framework includes a common dataset with demographic (race, ethnicity, gender identity, sexual identity), health status, level of stress/caregiver burden, confidence/preparedness to deliver care, quality of life and connections to local supports. Through an individualized tailored approach, each pilot site receives training in consistent data collection processes as well as equity, diversity, inclusion and belonging sensitivity training. This approach allowed staggered onboarding while ensuring all front‐line staff are trained for longitudinal data collection with 100% uptake. The next step will be engagement to develop caregiver profiles that highlight demographic characteristics, insights into current supports, and priorities for future programming for this population, and allow for subgroup analysis that provides further information on the different sizes of each provincial site, as well as styles of First Link® delivery, healthcare connectedness, and geography.

Conclusion

Over time, this comprehensive dataset will provide insight into the effectiveness of caregiver resources that are currently being provided (e.g., public education, community support groups, crisis support), including ease of access for caregivers, and establish a Canada‐wide surveillance system for caregivers of PLWD
Stable Isotope Labelling Kinetics tracing of Neurofilament Light in stem cell‐derived neurons and humans
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Coulton John , Zetterberg Henrik , Elbert Donald L , Bateman Randall J. , Mills Kevin , Wray Selina , Paterson Ross W.
Published: December 2023

Background

Neurofilament light (NfL) is a neuronal cytoskeletal protein that is released into the extracellular environment from degenerated axons. As such, NfL levels in cerebrospinal fluid (CSF) and serum have been proposed as a promising biomarker of neurodegeneration, yet the metabolism of NfL in human neurons is unknown. Kinetic protein labelling can provide protein half‐lives and rates of production and clearance in vitro and in vivo.

Method

Using a stable isotope tracer (13C6‐leucine), we labelled two lines of pluripotent stem cell‐derived neurons and human study participants with primary tauopathies (n = 9). We collected neuronal lysates and conditioned media every three days during the labelling (“pulse”) and post‐labelling (“chase”) phases. CSF samples were collected across five visits, scheduled around 4, 14, 20, 60 and 120 days post‐labelling. We measured the ratio of labelled to unlabelled NfL using targeted mass spectrometry workflows to quantitate the rates of protein labelling (fractional synthesis rate) and label loss (fractional clearance rate), together providing the protein turnover rate.

Result

The average half‐life of NfL in cell lysates was four days (± 1.06 SD, n = 3 independent biological replicates). The turnover of extracellular NfL in neuronal conditioned media was slower than that found in neuronal lysates, suggesting that NfL is a rather stable protein in the extracellular milieu in vitro. In contrast, analysis of CSF from the in vivo tauopathy cohort detected low labelling of NfL (0.04 – 0.36%) by 120 days (n = 5), indicating that in vivo turnover is exceptionally slower than in vitro and that extended CSF collection and analysis >120 days post‐labelling is crucial to capture NfL production and clearance in vivo. To this end, additional analysis of healthy controls and patients with Alzheimer’s disease (control and AD cohorts; n = 24), which include CSF collection up to 219 ‐ 444 days post‐labelling, is ongoing.

Conclusion

Tracking of both intracellular and extracellular NfL in neurons derived from healthy control individuals, as well as cells with mutations implicated in neurodegenerative diseases, are expected to shed light into the dynamics of NfL turnover in both physiological and pathological conditions. This will be critical for interpreting NfL in response to disease‐modifying therapies.