bluuebunny/crossref_metadata_2025 huggingface dataset:
Key considerations when developing and implementing digital technology for early dementia detection
Authors: Wilson Sarah , Tolley Clare , Ardle Ríona Mc , Beswick Emily , Slight Sarah
Published: December 2023

Background

The World Health Organisation (WHO) promotes using digital technologies to accelerate global attainment of health and well‐being. This has resulted in an increase in research exploring how digital technology can be used to aid early detection of dementia and to support the successful implementation of new technology into healthcare systems, including the English National Health Service (NHS). We conducted a qualitative study to understand the key considerations amongst healthcare professionals (HCP) when developing and implementing digital technology for the early detection of dementia in the NHS.

Method

We recruited primary and secondary care HCPs from various NHS clinical networks. We explored participants’ views on early dementia detection, using digital technology to aid this approach, and any potential implementation challenges. An inductive thematic analysis approach was taken to identify themes using QSR N‐Vivo (Version 1.6.1). Themes were refined by the authors.

Result

Eighteen semi‐structured interviews were conducted with seven secondary and 11 primary care HCPs. Key themes included considerations for healthcare users and digital technology. Some healthcare professionals felt early detection of dementia would provide healthcare users with the opportunity to future‐plan, for example by “tak[ing] out lasting powers of attorney” (P3 Primary Care Physician (PCP)). Whilst others were concerned “if we’re now looking at screening people who don’t have symptoms, […] the waiting list for memory clinics [referring to secondary care] would dramatically increase” (P6 PCP) which could negativity affect healthcare users. The use of digital technology to aid early detection raised concerns surrounding health equity, to ensure that we are “not excluding people who already are in digital poverty” (P5 PCP). Many HCPs also felt it was important to consider how “dementias have different features” (P14 PCP), so they “would want a tool that tests different modalities” (P6 PCP) to help differentiate between diagnoses.

Conclusion

These results will inform future research in developing and implementing digital technology for early dementia detection. Work is needed to explore how best to support patients receiving information about their early detection of dementia, and the HCPs involved in this process. Research is needed to develop digital inclusion strategies to promote health equity.
AI‐guided patient stratification for neurodegenerative disorders using unsupervised trajectory modelling
Authors: Burkhart Michael C. , Lee Liz Yuanxi , Vaghari Delshad , Venton Jenny , Thomas Spencer , Smith Nadia , Everson Richard , Tino Peter , Kourtzi Zoe ,   the Early Detection of Neurodegenerative diseases initiative
Published: December 2023

Background

Predicting neurodegenerative disorders early has major implications for timely clinical management and patient outcomes. Despite advances in medical technology, we still lack tools to precisely stratify patients for targeted interventions. Here, we propose an unsupervised modelling approach based on mixtures of state space models that learns from longitudinal multimodal (brain imaging, cognitive) data to stratify patients into clusters with different clinical outcomes. Our approach has the potential to support dementia prediction based on cost‐effective, non‐invasive digital measures alone.

Method

We trained (with cross‐validation, 4 components selected with elbow method) a mixture of linear Gaussian state space models on 571 trajectories (2‐4 assessments) from ADNI comprising a) state variables: neuroimaging biomarkers (temporal lobe gray matter density, β‐amyloid) and b) observations: cognitive tests (ADNI‐Mem, ADNI‐EF, MoCA, & ADAS‐13) collected at regular 2‐year intervals. The model clustered individuals based on longitudinal changes in biomarkers and the relationship between biomarkers and cognitive scores (figure 1). We validated model‐derived clusters against clinical outcomes (unseen by the model) based on each individual’s final assessment.

Result

Our unsupervised modelling approach effectively stratifies individuals by clinical outcome. Cluster A comprises 65% healthy controls and 33% stable MCI patients (individuals with MCI who do not convert to AD in a 3‐year period) while cluster D comprises 77% Alzheimer’s patients (table 1). Profiling these clusters using MMSE score validates our approach: individuals in cluster A maintain high memory scores over 6 years whereas individuals in cluster D decline (figure 2). Further, we find that our model maintains good stratification when tested a) with a single rather than multiple assessments and b) with cognitive data only (i.e. without biomarkers). These results enhance the clinical utility of our approach, as collecting longitudinal and biomarker data may prove challenging in clinical settings.

Conclusion

Our modelling approach robustly stratifies patients by clinical outcome when trained on longitudinal multimodal data and tested using cognitive scores alone. Our approach has strong potential to generalize to other non‐invasive and cost‐effective data (e.g. digital markers from wearable technologies), enhancing the translational impact of our AI‐guided tool for early and precise patient stratification in clinical practice.
A new therapeutic approach to Tauopathies: targeting presynaptic tau with antisense oligonucleotides to Synaptogyrin‐3
Authors: Carrano Nicolo
Published: December 2023

Background

The protein Tau is central to several neurodegenerative disorders (“tauopathies”). “Tau‐tangles” (aggregations of the Tau protein) are a key hallmark of Alzheimer’s and many other diseases and Tau‐protein is mutated in several forms of dementia. In all these conditions, Tau causes complex, multifactorial defects in neurons that lead to cognitive decline. Under normal conditions, Tau is attached to axonal microtubules, but under pathogenic conditions it detaches and spreads throughout the neuron, including synapses. Work from my lab indicated that when Tau is present at pre‐synaptic terminals it binds to and clusters synaptic vesicles and identified Synaptogyrin‐3 as a physical interactor of Tau. My lab demonstrated that the partial loss of Synaptogyrin‐3 (Syngr3) restores working memory and rescues synaptic degeneration in mice that express pathogenic P301S Tau (“PS19”), a well‐accepted model for tauopathy that recapitulates features seen in patients, including synaptic loss, neuroinflammation and cognitive decline. Partial (and complete) loss of Syngr3 is benign in mice and fruit flies. Based on this, we pursued a radical alternative and innovative approach, supported by strong pre‐clinical data, to tackle Tau‐induced cognitive decline.

Method

We designed and synthetized oligonucleotides covering the whole Syngr3 transcript, and tested their activity in Neuro2A cells and primary cortical murine neurons in transfection and unassisted uptake conditions.

Result

Through this screen we found several active molecules, that were able to significantly downregulate Syngr3 transcript and protein levels. To find the best candidates, we performed dose‐response curves and time course evaluations in primary murine neurons, and we found several molecules that targeted different regions of the Syngr3 transcript with good activity, potency, and no evident toxic effects.

Conclusion

We found several molecules that induce an effective and sustained reduction of Syngr3 expression. As part of the pre‐clinical evaluation, these molecules will be tested in vivo in PK/PD and acute toxicity studies in WT mice, to determine the best administration dosage and therapeutic window. Finally, we will evaluate the effect of our best candidates in a therapeutic setting, treating PS19 tau mice to assess if the acute removal of the protein can alleviate presynaptic tau toxicity and revert tau induced synaptic and cognitive defects.
Non‐economic aspects of social deprivation and cognitive health in old age
Authors: Rodriguez Francisca S , Hoffmann Wolfgang , Peters Oliver , Priller Josef , Schneider Anja , Fliessbach Klaus , Düzel Emrah , Buerger Katharina , Teipel Stefan , Laske Christoph , Jessen Frank ,   DELCODE study team
Published: December 2023

Background

It is well established that socioeconomic disadvantages such as low income are associated with a higher risk for poor cognitive health in old age. Under the concept of social deprivation, researchers have recently started exploring a broader concept of social embedding including, for instance, unemployment and asset ownership. However, little known of other characteristics of social deprivation and to what extent they are associated with cognitive health.

Method

Participants of the multicenter DZNE Cognitive Impairment and Dementia Study (DELCODE) were asked to complete a questionnaire on four characteristics of social deprivation, (1) Conditions of the living environment, (2) Regional accessibility, (3) Neighborhood support, (4) Family social support. A total of N = 296, 48.3% male, M = 70.8 (SD = 5.8) years old, n = 97 cognitive healthy, n = 161 subjective cognitive decline (SCD), n = 38 mild cognitive impairment (MCI)) returned the questionnaire. Using confirmatory factor analysis, we excluded questions with non‐significant loadings and with coefficients <0.5. The latent scores were saved and a sum score was calculated. The scores were categorized into tertiles (high, medium, low).

Result

Results from logistic regression (adjusted for age, gender, education, family status, depression, diabetes, hypertension, hypercholesterol, cerebrovascular diseases, heart disease, and body mass index) indicated that those with low (compared to high) social deprivation had a significantly reduced risk for SCD (OR = 0.38, p = 0.006) and MCI (OR = 0.25, p = 0.018). Of the individual factor scores, only Neighborhood support was significantly associated with SCD (OR = 0.48, p = 0.030) and MCI (OR = 0.32, p = 0.049).

Conclusion

Our findings suggest that social deprivation and, in particularly, neighborhood support such as visits, helping out, and receiving/giving advice can play an important role in cognitive health in old age. Accordingly, individuals with a high risk for age‐related cognitive impairment might benefit from being embedded in a supportive neighborhood.
A target enablement package for modulating the activity of PLCγ2 as a therapeutic strategy for the treatment of Alzheimer’s disease
Authors: Clayton Brent , Bissel Stephanie J , Richardson Timothy I , Massey Steven M , Beck Daniel E , Putt Karson S , Bedford Logan M , Utsuki Tada , Visvanathan Ramya , Mesecar Andrew D , Lendy Emma K , Kaiser Bridget L , Chu Shaoyou , Mason Emily R , Quinney Sara K , Kandasamy Murugesh , Masters Andrea R , Lamb Bruce T , Palkowitz Alan D , Sondek John , Zhang Qisheng
Published: December 2023

Background

Genome‐wide association studies, whole genome sequencing, and gene‐expression network analyses comparing normal to Alzheimer’s disease (AD) brain tissue have identified risk and protective variants in genes essential to microglial function. Among these genes is phospholipase C gamma2 (PLCγ2). The P522R variant of PLCγ2 is associated with reduced risk for AD and has been characterized as a functional hypermorph. Carriers of P522R with mild cognitive impairment exhibited a slower cognitive decline rate. Therefore, activation of the protein PLCγ2 with small molecules has been proposed as a therapeutic strategy to reduce the rate of disease progression and cognitive decline in AD patients.

Method

We evaluated analogs of a reported phospholipase activator and performed a high‐throughput screen using full‐length PLCγ2 and affinity selection mass spectrometry (ASMS). Soluble substrate and liposomal‐based biochemical assays were developed to evaluate activation and inhibition of the enzyme. A Cellular Thermal Shift Assay (CETSA) was developed to confirm target engagement in cells. A high‐content imaging assay measuring phagocytosis, cell number, and nuclear intensity was implemented using the BV2 and HMC3 cell lines to characterize cellular pharmacology and cytotoxicity. Results were recapitulated in primary murine microglia. Active compounds predicted to have drug‐like properties were subjected to assays measuring solubility, cellular permeability, and mouse microsomal stability.

Result

Structurally distinct, novel PLCγ2 activators have been discovered. In preparation for in vivo studies in mice, in vitro absorption, distribution, metabolism, and excretion (ADME) assays have been carried out for activators with sufficient cellular potency and drug‐like properties.

Conclusion

Activation of PLCγ2 is a novel therapeutic strategy for treatment of AD. We identified structurally distinct molecular scaffolds with varying degrees of enzyme activation and cellular activity. Recommendations for use of probe molecules in target validation studies and the development of lead‐like molecules for clinical studies will be made.
Chinese ADNI study:Characteristic AD biomarkers precisely predicts Alzheimer’s dementia: China Aging and Neurodegenerative Initiative (CANDI) study
Authors: Gao Feng , Dai Linbin , Wang Qiong , Shi Jiong , Shen Yong , Aging China ,   Neurodegenerative Initiative (CANDI) Consortium
Published: December 2023

Background

To test the utility of the “A/T/N” system in the Chinese population, we study core Alzheimer’s disease (AD) biomarkers in a newly established Chinese cohort.

Method

A total of 411 participants were selected, including 96 cognitively normal individuals, 94 patients with mild cognitive impairment (MCI) patients, 173 patients with AD, and 48 patients with non‐AD dementia. Fluid biomarkers were measured with single molecule array. Amyloid beta (Aβ) deposition was determined by 18F‐Flobetapir positron emission tomography (PET), and brain atrophy was quantified using magnetic resonance imaging (MRI).

Result

Aβ42/Aβ40 was decreased, whereas levels of phosphorylated tau (p‐tau) were increased in cerebrospinal fluid (CSF) and plasma from patients with AD. CSF Aβ42/Aβ40, CSF p‐tau, and plasma p‐tau showed a high concordance in discriminat‐ ing between AD and non‐AD dementia or elderly controls. A combination of plasma p‐tau, apolipoprotein E (APOE) genotype, and MRI measures accurately predicted amyloid PET status.

Conclusion

These results revealed a universal applicability of the “A/T/N” framework in a Chinese population and established an optimal diagnostic model consisting of cost‐ effective and non‐invasive approaches for diagnosing AD.
Baseline and Six‐Month Actigraphy and Sleep‐monitoring Devices Help Differentiate Between Alzheimer’s Disease and Dementia with Lewy Bodies
Authors: Tsuang Debby W , Brown Karl , Shutes‐David Andrew , Payne Sarah , Jankowski Adrienne , Seto Edmund , Louis Erik K St , Levendowski Daniel J , Wilson Katie
Published: December 2023

Background

Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are challenging to differentiate. Mobile health devices that measure motor and sleep domains between clinic visits may improve differential diagnosis.

Method

Participants with probable AD and probable DLB wore ActiGraph triaxial wGT3X‐BT actigraphy devices on their nondominant wrists for 2 weeks and multichannel Sleep ProfilerX8TM EEG devices on their foreheads for 2 consecutive nights.3 Actigraphy data were processed and scored using GGIR and activity counts in R. The Sleep Profiler characterizes abnormal slow‐wave sleep and non‐REM hypertonia (NRH).

Result

At baseline, participants with DLB (n = 9) had higher UPDRS scores and a higher likelihood of psychosis than participants with AD (n = 8; see Table 1). Using univariate Wilcoxon Rank‐Sum tests, we found that at baseline participants with DLB had lower daily activity counts, higher % time in NRH, and lower % time in REM sleep than participants with AD (unadjusted p‐values < 0.05; See Figure 1).

In a recent 6‐month followup, activity levels were lower on average than baseline activity levels for both DLB (n = 5) and AD (n = 5). at 6‐months, the differences in % sleep in NRH increased between DLB participants (n = 5) and AD participants (n = 3) as average % NRH increase 6% in DLB and decreased 1% in AD (see Table 2). These 6‐month differences are not statistically significant, but data collection are ongoing.

An exploration of methods for processing and scoring actigraphy data revealed that processing can result in wide range of findings. As a result, we have focused on actigraphy outcomes which are more suitable to older participants with dementia.

Conclusion

Participants with DLB demonstrated lower baseline physical activity and higher rates of baseline sleep disturbances than participants with AD; sleep differences between DLB and AD appeared to increase over 6 months.

Actigraphy and sleep‐monitoring devices are well tolerated in participants with dementia and they can reliably collect valid, useful activity and sleep data in between clinic visits.
Cerebral microbleeds in traumatic brain injury associated with differential risk factors and clinical outcomes: the PREVENT‐Dementia study
Authors: Low Audrey , McKiernan Elizabeth , Prats‐Sedano Maria A , Carter Stephen F , Stefaniak James D , Su Li , Dounavi Maria‐Eleni , Muniz‐Terrera Graciela , Jenkins Natalie D , Ritchie Karen , Lawlor Brian , Naci Lorina , Malhotra Paresh A , Thayanandan Tony , Mackay Clare , Koychev Ivan , Raymont Vanessa , Ritchie Craig W , O'Brien John T ,   the PREVENT Dementia group
Published: December 2023

Background

Cerebral microbleeds (CMB) are predictive of increased risk of dementia and stroke. Although commonly regarded as vascular markers, CMB can also stem from non‐vascular aetiologies like head injuries or traumatic brain injury (TBI), although these are often overlooked. Therefore, this study examines CMB in relation to TBI, and their differential causes (i.e., risk factors) and consequences (i.e., clinical outcomes).

Method

In 605 healthy middle‐aged adults (aged 40‐59), CMB were rated on 3T susceptibility weighted imaging (SWI) MRI. TBI was assessed using the Brain Injury Screening Questionnaire (BISQ). TBI+ was defined as at least one blow to the head resulting in loss of consciousness (36.0%; n = 217). Memory was assessed using the COGNITO battery. Interaction analyses examined TBI*CMB interactions on hypertension, gait, and memory. Dominance analysis examined the relative contribution of TBI and vascular risk factors on predicting gait disturbances and memory. All models adjusted for sex, age, education, and study site.

Result

TBI was related to higher CMB count (t = 2.06, p = .039), and were more common in males (48.3%) than females (28.0%) (Χ2 = 28.91, p<.001). Number of TBI events related to poorer memory (t = ‐2.62, p = .009) and gait disturbances (t = 3.54, p<.001). Interaction analyses demonstrated that hypertension (t = ‐2.26, p = .024), memory (t = 2.70, p = .007) and gait (t = ‐2.29, p = .023) were less closely related to CMB in individuals with greater number of TBI events, relative to those with fewer TBIs. Regionally, these interactions were significant for lobar CMB, but not deep subcortical CMB. Within the TBI+ group, dominance analysis demonstrated that number of TBI events outperformed vascular risk factors in predicting gait disturbances (Contribution to R2: TBI = 52.9%, vascular risk = 32.6%) and memory (TBI = 28.7%, vascular risk = 1.2%).

Conclusion

CMB appeared to differ aetiologically and clinically in those with and without TBI. In individuals with TBI, TBI itself was the dominant driver of clinical deficits. When compared to CMB of presumed vascular origins cross‐sectionally, TBI‐related CMB may appear to be less detrimental. However, longitudinal analysis is required to determine how TBI‐related CMB differ in clinical trajectory and downstream pathologies. This study highlights the importance of differentiating between CMB of vascular origins vs. TBI in both research and clinically to aid prognosis and treatment decisions.
Evaluation of the instrument protocol to verify the effects of the iSupport‐Brasil program for caregivers of people living with dementia
Authors: Ferreira Camila Rafael , Ottaviani Ana Carolina , Monteiro Diana Quirino , Cardoso Anabel Machado , Barbosa Gustavo Carrijo , Correa Larissa , Rocha Luana Aparecida , Maciel Luiza Barros , Barham Elizabeth Joan , Monteiro Diana Q , de Cruz Keila Cristianne Trindade , Pavarini Sofia Cristina Iost , Monteiro Diana Q , Oliveira Déborah
Published: December 2023

Background

The World Health Organization (WHO) developed iSupport, an online, psychoeducational program for informal caregivers who assist someone who lives with dementia. The iSupport program is being adapted for use in many countries, and in Brazil, we now need to evaluate the effects of this program. However, there are no Brazilian versions of instruments needed to evaluate some of the expected outcomes (self‐efficacy, mastery, and positive aspects of caregiving) and there are no online versions of the instruments. The objective of this study was to evaluate an online protocol to evaluate the effects of the iSupport program, in Brazil.

Method

An online data‐collection form was developed for use in Brazil, based on the protocol suggested by the WHO and considering protocols being used in other countries. Caregivers who were eligible for using the program were accompanied while completing this protocol, to identify their doubts and difficulties. There were seven participants, in two subgroups, so issues identified by one group could be resolved before testing the protocol with the next. Problems were discussed in research team meetings, and solutions were developed.

Result

Caregivers indicated problems that resulted in the exclusion of instruments that had similar objectives, the modification of response alternatives to better reflect the diversity of people who are informal caregivers, and wording changes to improve the clarity of instructions or items.

Conclusion

This study was important for maximizing the acceptability of the protocol and the usability of the response form we developed for evaluating the Brazilian version of the iSupport program. Thus, community participation in the development of research protocols should help maximize participation rates and the validity of the information gathered, which, in this case, involves the mental health and wellbeing of informal caregivers who assist people living with dementia. Furthermore, this process enabled us to work on cultural and format adaptations of the instruments needed for evaluating the effects of the iSupport‐Brasil program, so that our protocol will be aligned with those being used in other countries to evaluate the effects of the iSupport program.
Study of microRNAs and their targets in exosome from Alzheimer’s and Frontotemporal Dementia patients
Authors: Gerlando Rosalinda Di , Garofalo Maria , Busacca Maria , Francesca Dragoni , Matteo Bordoni , Scarian Eveljn , Perini Giulia , Ramusino Matteo Cotta , Costa Alfredo , Pansarasa Orietta , Gagliardi Stella
Published: December 2023

Background

A central role of RNA metabolism and non‐coding RNAs biogenesis has emerged in Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). We investigated miRNA cargo of Small Extracellular Vesicles (SEVs) derived from plasma of FTD and AD patients, and Healthy Controls (HC). The purpose was to evaluate deregulated miRNAs in patients to identify new peripheral biomarkers and to determine mRNA targets involved in FTD and AD pathogenesis.

Method

SEVs were isolated from plasma of 13 FTD patients, 20 AD and 20 HC by differential centrifugation and characterized by Nanosight and Western Blot. MicroRNA libraries were generated using Small RNA Seq Library Prep Kit (Lexogen) and sequenced on a NextSeq 500 (Illumina). Interaction prediction was carried out on TarBase v.8 database.

Result

We found a total of 339 Differentially Expressed (DE) microRNAs in FTD, and 291 DE microRNAs in AD compared to controls. Interestingly, 74 miRNAs were commonly deregulated: 38 had the same trend and 36 had an opposite trend. In order to find a miRNA biomarker able to discern FTD and AD, we selected 8 DE miRNAs with opposite trend based on fold changes difference and targets. In fact these miRNAs were found to have validated mRNAs target that may be of interest for molecular study of dementia, such as APP and PTEN.

Conclusion

Our data highlight the importance of miRNAs cargo examination in EVs of FTD and AD patients. In fact, their potential is exploitable both for biomarkers discovery and for study of gene expression alteration in dementia pathogenesis.
Neurons and astrocytes derived from human iPSCs to model Alzheimer´s disease
Authors: Palomo Laura Caceres , Trujillo‐Estrada Laura , Oliva Elba Lopez , Vitorica Javier , Gutierrez Antonia , Leon Juan Antonio Garcia
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by presenting a complex pathology, not fully resolved yet. This fact, together with the lack of reliable models, has impeded the development of effective therapies. Recently, several studies have shown that functional glial cell defects have a key role in the pathology of AD. However, this glial dysfunction, currently, cannot be correctly modeled using the available animal models, so we hypothesized that cells derived from Alzheimer’s patients can serve as a better platform for studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different types of neural cells, which can be used for disease modeling, identification of new targets and drugs development.

Method

We have a collection of hiPSCs derived from patients with sporadic forms of AD stratified based on APOE genotype. We have differentiated these cells towards neural cells and mature them to neurons or astrocytes using a serum‐free approach, to assess intrinsic differences between those derived from AD patients or healthy controls.

Result

We have implemented a serum‐free approach and generated neural precursors and astrocytes from all the lines tested. We observe differences at the phenotypic level and a reduced capacity to differentiate towards neural lineage in those lines derived from APOE4 carriers.

Conclusion

Our preliminary data suggest intrinsic differences in the neural differentiation capacity between cell lines derived from APOE4 or APOE3 carrier subjects. Further experiments would contribute to elucidate novel pathogenic pathways associated with neurodegeneration and susceptible of therapeutic modulation, likely contributing to the development of new effective drugs against AD.

Acknowledgments: This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co‐financed by FEDER funds from European Union, through grants PI21/00915 (to AG) and PI21/00914 (to JV); by Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA20‐FEDERJA‐048 (to JAGL), PY18‐RT‐2233 (to AG) and US‐1262734 (to JV) co‐financed by Programa Operativo FEDER 2014‐2020, University of Malaga (B1‐2020_04) to JAGL and Programa Operativo de Empleo Juvenil SNGJ4‐11 to LCP.
Nanobodies: a promising tool to perturb ApoE4 activity in Alzheimer’s disease pathology
Authors: Vandevelde Laure , Zwaenepoel Olivier , Gettemans Jan , Braeckmans Kevin
Published: December 2023

Background

The APOE‐ε4 allele encoding for apolipoprotein (apo) E4, an isoform of the APOE gene, is the strongest genetic risk factor for Alzheimer’s disease (AD). The exact mechanism by which apoE4 increases this risk is not fully understood. However, apoE4 has a very different structure than the other isoforms, apoE2 and apoE3, and it is suggested that this different structure contributes to the development of AD1. More efforts are still needed to further understand how apoE4 contributes to AD pathogenesis. Single domain antibodies or nanobodies are versatile tools to reveal new information on apoE4 and its pathological effects in AD.

Methods

Nanobodies are routinely obtained from immunized camelids, or from naïve libraries. Nanobodies need to be characterized by i.e. immunoprecipitation with apoE2, apoE3 and apoE4 and their affinity can be determined via an Octet device. Via laser‐induced photoporation, nanobodies can be delivered into living induced pluripotent stem cell derived APOE‐ε4 homozygous neurons. Nanobodies can be tagged with a fluorophore via click chemistry and derivates can be made by equipping them with a degradation or delocalization tag (cloning).

Results

Llama immunization will lead to a set of ApoE‐targeting nanobodies which will be further reduced to a couple of nanobodies after their further characterization (specificity and affinity). Given the high similarity between apoE isoforms, it is to be expected that some nanobodies will cross‐react with different isoforms. Because nanobodies recognize conformational epitopes it is likely that ApoE4 nanobodies can be generated.

Delivery of the nanobodies into apoE4 expressing neurons allows to manipulate endogenous apoE4 and as such our approach does not require expression modulation of the target: the protein can be degraded or it can be trapped/relocated to different regions or organelles in cells. We aim to perturb apoE4 in a way that typical AD pathologies seen in AD neurons are ameliorated and as such gain more insight about the pathophysiology of apoE4 effects in AD.

Conclusion

Nanobodies are excellent tools to uncover new biological information concerning apoE4.

References:

1 Najm, R., Jones, E. A., & Huang, Y. (2019). Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Molecular neurodegeneration, 14(1), 1‐13.
Unpuzzling the relationship between hypertension, stroke, and Alzheimer’s disease – an observation from the Australian Imaging Biomarkers and Lifestyle Study
Authors: Ma Liwei , Chu Chenyin , Zhuo Yuanhao , Sun Jiaqi , Masters Colin L , Jin Liang , Pan Yijun
Published: December 2023

Background

Alzheimer’s disease (AD), hypertension and stroke are common diseases in elderly people, but whether they are intrinsically linked with each other remains uncertain. The aim of this study was to investigate the risks of people who have hypertension and stroke to develop mild cognitive impairment (MCI) and AD, and if hypertension and stroke are risk factors for AD.

Method

The longitudinal data was retrieved from the Australian Imaging Biomarkers and Lifestyle Study (AIBL). The prevalence of hypertension and stroke was compared between cognitively normal (CN) participants, participants who were CN but subsequently diagnosed with MCI/AD during the study (refer to as participants exhibited cognitive decline), and participants with AD confirmed at recruitment.

Result

The prevalence of hypertension (odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.05 ‐ 1.77, p = 0.018) was significantly higher in participants exhibited cognitive decline than CN participants. Interestingly, the prevalence of hypertension (OR = 0.88, 95% CI = 0.70 ‐ 1.11, p = 0.287) was comparable between CN and AD participants. This observation suggested that hypertension is a risk factor for the progression of cognitive decline. The prevalence of stroke was significantly higher in participants exhibited cognitive decline (OR = 2.04, 95% CI = 1.10 ‐ 3.79, p = 0.024) and AD participants (OR = 3.43, 95% CI = 2.09 – 5.64, p<0.001) than CN participants. This observation suggested that stroke is a risk factor for the progression of cognitive decline and AD.

Conclusion

This preliminary study demonstrated that hypertension and stroke are risk factors for the progression of cognitive decline, and stroke is a risk factor for AD. Given the elevated risk in cognitive decline, the cognitive function of elderly people with hypertension or history of stroke should be monitored for timely detection of MCI and AD.
Bidirectional associations between quality of life and cognitive function over 17 years: Evidence from the English Longitudinal Study of Ageing (ELSA)
Authors: John Amber , Desai Roopal , Marchant Natalie L , Woodward‐Carlton Barbara , Saunders Rob , Bell Georgia , Gonzalez Aida , Gaysina Darya , Richards Marcus , Stott Joshua
Published: December 2023

Background

Depression and anxiety are well recognised as risk factors for dementia and poorer cognitive outcomes. However, considerably less is known about the relationship between quality of life and cognitive function over time. Quality of life is not simply the absence of mental health problems, but instead is a related but distinct construct. In particular, it is unclear whether poorer quality of life precedes cognitive decline, or vice versa or whether there is a bidirectional relationship. This is of import because understanding directionality allows us to start to plan interventions around dementia risk reduction. The aim of this study was to test bidirectionality between quality of life and memory in a large, nationally representative sample of people aged 50+ without cognitive impairment.

Method

Data were used from the English Longitudinal Study of Ageing (ELSA), a longitudinal cohort comprising 12,099 people over the age of 50 and their partners. Repeated measures of quality of life and memory (immediate and delayed) were available nine times over a 17‐year period. Cross‐lagged models were fitted to test for bidirectionality between quality of life and memory function.

Result

The fully adjusted model revealed that higher quality of life was significantly associated with higher subsequent immediate memory scores at all time‐points, and with higher subsequent delayed memory scores at all except the final time‐point. There was no consistent evidence that memory was significantly associated with subsequent quality of life.

Conclusion

These results extend previous research by providing evidence for the temporal association between quality of life and memory in a population‐based sample of people aged 50+. Specifically, results suggest that quality of life is consistently associated with later memory function over nearly two decades, though the study did not provide evidence that the association operates in the opposite direction. The lack of consistent evidence for a relationship between cognitive function and subsequent quality of life may be due to the exclusion of people with cognitive impairment and adjustment for depressive symptoms. Better quality of life may act as a protective factor in retaining memory function from middle to later adulthood.
Developing a classifier to screen for mild cognitive impairment and Alzheimer’s disease using machine learning approaches
Authors: Chu Chenyin , Ma Liwei , Zhuo Yuanhao , Sun Jiaqi , Masters Colin L , Goudey Benjamin , Jin Liang , Pan Yijun
Published: December 2023

Background

Machine learning classifier is a powerful tool that has been recently applied to datasets of Alzheimer’s disease (AD). The majority of approaches developed to classify people with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) from cognitively normal (CN) people have made use of expensive or invasive measurements, discouraging the clinical use of these tools. In the current study, we aimed to develop a classifier to screen for MCI and AD using data that can be routinely collected at low cost (e.g. blood pressure, ApoE genotype).

Method

Database of the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) was used (n = 14553 data entries). Dataset was split into two parts: training (80%) and testing (20%). A decision tree was first employed to screen for factors (i.e. clinical parameters) that can effectively discriminate CN, MCI, and AD (Step 1). To further refine factor selection, the association between the factors (from screening) and health status (CN, MCI, AD) were assessed using linear and logistic regression methods. Factors that were rejected by the hypothesis test (i.e. non‐obvious relationship with MCI or AD) and those require high cost for collection were removed (Step 2). The remaining factors were used for the construction of the classifier, where decision tree, Gaussian Naïve Bayes and second‐order polynomial approaches were employed.

Results

The selected factors for classifier construction were ApoE genotype (p<0.001), medical history of stroke (p<0.001 AD, p = 0.223 MCI), diabetes (p<0.001) and depression (p<0.001), and systolic blood pressure (p<0.001). Three models were used to construct the classifier, and the differential accuracy ranges between 74.1 – 84.2% for CN, 25.3 – 50.2% for MCI, and 47.8 – 73.4% for AD (Table 1). Accuracy from second‐order polynomial model was lower than that from the decision tree and Gaussian Naïve Bayes model.

Conclusion

The classifier developed in the current study is yet to be optimized, especially for MCI. In future study, the performance of our classifier will be evaluated using other AD datasets for generalizability. This classifier can potentially be used by the clinicians as an MCI/AD screening tool for at‐risk population prior to requesting costly diagnostic tests.
Automatic assessment of classical Alzheimer’s disease biomarkers in paired cerebrospinal fluid and plasma samples
Authors: Bellomo Giovanni , Megaro Alfredo , Toja Andrea , Nardi Giovanna , Wojdala Anna , Filidei Marta , Paoletti Federico Paolini , Gaetani Lorenzo , Parnetti Lucilla
Published: December 2023

Background

A/T/(N) cerebrospinal fluid (CSF) biomarkers, i.e., amyloid‐β 1‐42 and 1‐40 ratio (Aβ42/Aβ40, A), tau phosphorylated at threonine 181 (p‐T181‐tau, T), and total tau (N), define molecular diagnosis of Alzheimer’s disease (AD). Automated platforms have brought a significant achievement in reducing the pre‐analytical variability. Measuring such biomarkers in blood might allow longitudinal sampling for disease monitoring, in view of disease‐modifying therapies. Along with this premise, to test the agreement between CSF and plasma measurements, we assessed Aβ42, Aβ40 and p‐T181‐tau with Lumipulse® G600II automated platform in paired CSF and plasma samples from 224 patients.

Method

We selected 224 plasma samples collected from subjects with different clinical diagnosis (see Table 1), for whom CSF measurements were performed between 2018 and 2021. Both plasma and CSF were collected at the time of lumbar puncture following international guidelines. ATN CSF profiles have been defined according to cutoff values measured in our lab. One‐way analysis of variance with post‐hoc Tukey test was applied to determine statistically significant differences among groups, linear regression and correlation analysis were applied to determine degree of agreement between CSF and plasma biomarkers, and ROC analysis was applied to test the ability to differentiate AD‐like CSF profiles (A+/T+) from normal CSF profiles (A‐/T‐).

Result

Distributions of Aβ42/Aβ40 ratio and p‐T181‐tau for the different A/T groups are shown in Figure 1. Plasma Aβ42/Aβ40 ratio was found to be significantly decreased in A+/T‐ and A+/T+ subjects as compared with A‐/T‐ and A‐/T+; p‐T181‐tau was found to be significantly increased in A+/T+ subjects as compared with all the other A/T profiles. Plasma Aβ42/Aβ40 ratio and p‐T181‐tau showed moderate correlation with their CSF equivalents (r = 0.62 and 0.60, p << 0.001, respectively). Both biomarkers could detect AD‐like CSF profiles (A+/T+) with an area under the ROC curve > 0.8 (see Figure 2).

Conclusion

The automated assessment of Aβ42/Aβ40 and p‐T181‐tau in plasma can satisfactorily reflect the CSF A+T+ status. Larger cohorts are needed to verify the concordance of plasma with CSF biomarkers
Genome‐Wide Mediation Analysis Reveals the Genetic Underpinnings of the Neuromorphometric Endophenotypes of Alzheimer’s Disease
Authors: Shen Li
Published: December 2023

Background

Alzheimer’s disease (AD) is a common neurodegenerative disorder. AD has high heritability, estimated to be 58%‐79% from twin studies. The strong genetic basis motivates the investigation of AD etiology. AD progression can be captured, in part, by brain volumetric variations, quantified by magnetic resonance imaging (MRI). Brain volumetric variations have been used to capture in vivo imaging biomarkers of AD. Advances in recent brain imaging genetics studies provide an opportunity to elucidate the neuropathogenesis of AD.

Method

We performed a genome‐wide mediation study (GWMS) investigating genetic effects on AD classification that are mediated by regional brain volumes. Specifically, we downloaded the genotyping and raw T1‐weighted brain MRI data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We extracted 145 regions of interest (ROIs) using a multi‐atlas parcellation method (MUSE) from voxel‐wise regional volumetric maps (RAVENS) generated from the MRI scans. We downloaded, integrated, aligned, imputed, and annotated the genotyping data from ADNI 1, GO, 2, and 3 studies. After quality control that excluded low‐quality SNP variants and genetically similar subjects, we performed a genome‐wide association study (GWAS) on 18,366,758 variants and 145 ROI‐level volumetric QTs with 1,382 individuals adjusted for age, sex, and population structure. We prioritized 12,733 significant SNP‐ROI GWAS signals and performed GWMS of AD on those prioritized SNPs with ROIs as mediators.

Result

We found that 35 unique SNPs significantly influenced AD classification mediated by 13 ROI‐level volumetric QTs after false discovery rate correction – in total 218 significant mediation signals. Among all the significant mediation signals, there were 214 partial mediations and 4 full mediations. Chromosome 19 showed the most significant mediation signals. The hippocampus and amygdala in both hemispheres had the most (n = 30) mediation signals, followed by the left entorhinal area with 28 signals (Figure 1).

Conclusion

Our GWMS of AD identified various SNP variants influencing AD classification via the mediation of ROI‐level volumetric QTs. Complementary to the traditional GWAS analyses, the GWMS analyses can help to explain the genetic underpinnings of the neuromorphometric endophenotypes of AD and provide valuable guidance for AD precision medicine.
CSF Biomarkers and [18F]flutemetamol PET‐Derived Centiloids in Patients with SCD or MCI
Authors: Battle Mark R , Buckley Chris J , Farrar Gill , Janelidze Shorena , Palmqvist Sebastian , Ossenkoppele Rik , Smith Ruben , Hansson Oskar
Published: December 2023

Background

CSF biomarkers are well characterised as surrogate markers for amyloid deposition and neurofibrillary tau tangles reflecting pathological features of Alzheimer’s disease. Amyloid PET images provide a visual and quantitative assessment of brain amyloid burden. In diagnostic workup these biomarkers are considered interchangeable, however their relationship is not fully understood.

Methods

Centiloid (CL) values for 387 [18F]flutemetamol images from the Swedish BioFINDER I study were derived following the methods of Klunk et.al. (Alzheimer’s & Dementia, 2015). Subjects, comprising Controls, SCD and MCI (Table 1), were ranked by Centiloid values (lowest to highest) and the average for each consecutive group of 30 subjects calculated. Corresponding CSF biomarker values (Aβ42/40 and pTau181) were plotted for each group.

Results

Subjects in groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) Aβ 42/40 ratio of 0.144 (±0.033, range 0.051 to 0.236, n = 240) with no statistically significant differences between groups (Fig. 1A). A statistically significant fall in CSF Aβ42/40 ratio between the 29.0 CL and 47.3 CL groups (from 0.134 (±0.041, 0.066 to 0.236) to 0.088(±0.031, 0.045 to 0.183), p<0.0001) was observed. The average CSF Aβ42/40 ratio value for all subjects ranging from 66.3 Cl to129.8 CL was 0.072 (±0.017, 0.030 to 0.127, n = 117) with no statistically significant difference in CSF levels across these CL bands.

Subjects in the groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) pTau181 value of 48.9 pg/mL (±15.9, 22 to 138) with no statistically significant difference between groups (Fig. 1B). A statistically significant (p<0.05) increase between 29.0 CL (47.3±19.3, 24 to 116 pg/mL) and 47.3 CL groups (67.8±29.4, 24 to 175 pg/mL) was observed. For all Subjects from 66.3 CL to129.8 CL mean pTau181 levels were 79.6 (±30.3, 32 to 209 pg/mL) with no statistically significant difference across these CL bands.

Conclusions

Comparison of [18F]flutemetamol image quantitation and CSF biomarkers indicates CSF Aβ42/40 and pTau181 starts to show amyloid positivity at approximately 30‐40 CL units. Recent comparisons between visual rating and Centiloids from PET imaging indicate visual positivity from approximately 20 CL units indicating sensitivity of amyloid PET imaging for the detection of early amyloid deposition.
Ex vivo identification of transcriptional regulation landscape and potential therapeutic targets against ER stress using Alzheimer’s disease patient‐derived dermal fibroblast: findings from BICWALZS cohort
Authors: Son Sang Joon , Kim Yeojin , Yoon Sunwoo , Park Sunghong , Cho Yong Hyuk , Nam You Jin , Roh Hyun Woong , Hong Chang Hyung , Hong Sunhwa
Published: December 2023

Background

Endoplasmic reticulum (ER) stress is considered as a central pathophysiology for neurodegeneration in Alzheimer’s disease (AD). Many studies using in vitro cell line or in vivo mouse model have shown the possible association between ER stress and neurodegeneration. However, that connection was not elucidated well in AD patient‐derived cell or brain organoids. In this study, we aimed to identify transcriptional regulation landscape and potential therapeutic targets against ER stress using AD dementia patient‐derived dermal fibroblast.

Method

For the purposes of ex vivo research, we performed skin biopsy and stabilized dermal fibroblasts in vitro. Total of 20 AD dementia patients and 22 cognitively normal older adults were assessed. All of AD dementia patients were amyloid positive on PET imaging, APOE e4 carrier, and cognition was imparied. On the contrary, all of cognitively normal older adults were amyloid negative on PET imaging, and APOE e4 non‐carrier. We applied thabsigargin (10 nM) to dermal fibroblast for 24 hours to promote ER stress. After that, to identify transcriptional regulation landscape against ER stress, RNA sequencing was performed.

Result

Total of 252 transcripts (up = 162, down = 90) were commonly differentially expressed in both of AD dementia and cognitively normal older adults derived dermal fibroblast by ER stress‐thabsigargin. These transcripts were enriched in GO categories related to protein folding in ER, response to ER stress, and ERAD pathway. Interestingly, 80 transcripts (up = 33, down = 47) were only differentially expressed in AD dementia dermal fibroblast by ER stress‐thabsigargin. These transcripts were enriched in GO categories related to cell division, miotic cell cycle, and microtubule‐based movement. Total of 60 transcripts (up = 41, down = 19) were only differentially expressed in cognitively normal older adults dermal fibroblast by ER stress‐thabsigargin. These transcripts were enriched in GO categories related to cholesterol biosynthesis process, DNA replication checkpoint, and cAMP‐mediated signaling.

Conclusion

We identified transcriptional regulation landscape by ER stress‐thabsigargin in AD dementia and cognitively normal older adults dermal fibroblast. Further bioinformatic analysis with computational tools and validation experiments will be performed to find potential therapeutic targets against ER stress.