bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylomic‐based molecular subtyping of late onset Alzheimer’s Disease
Authors: Laroche Valentin , Reijnders Rick A , Smith Adam R. , Eijssen Lars M.T. , Cavill Rachel , Hove Daniel L.A. , Lunnon Katie , Pishva Ehsan
Published: December 2023

Background

Accumulating evidence shows that the heterogeneity and temporal complexity of Alzheimer’s Disease contribute to the treatment failure. Advances in omics technologies along with development of efficient integrative analytical pipelines, provide a unique opportunity to investigate the drivers of heterogeneity at multiple molecular levels.

Method

We used genome‐wide DNA methylation data generated in postmortem prefrontal cortex samples from two independent biobanks of Brain for Dementia Research (BDR; n = 382) and the UK Brain Bank Network (UKBBN; n = 250). Multiple unsupervised clustering methods including network‐based, Bayesian and Ensemble approaches were applied on DNA methylation data quantified by the Illumina EPIC arrays in the discovery cohort (BDR). Following each clustering methods, distinct features related to the identified subtypes were captured using classification models such as sparse partial least square discriminant analysis and random forest. The most accurate models comprising the distinct features were used to classify the samples in the UKBBN cohort into the appropriate subtypes. Clinical and pathological evaluation of the identified subtypes have been performed for both discovery and replication cohorts

Result

We identified well‐defined cluster of samples in the BDR cohort. We achieved acceptable prediction values in the test data to classify the subgroups using the distinct methylation features related to the identified subtypes (AUC: 0.86 – 0.96). The best performing classification model was applied on the other independent cohort and similarly labelled samples across different cohorts were extensively characterized using relevant clinical and pathological information.

Conclusion

We used state‐of the‐art methods to undertake the first systematic, DNA methylomic‐based subtyping of AD. this is a vital step to unravel the heterogeneity of the disease
Establishing the contribution of genetic risk loci in the Lewy dody diseases
Authors: Imm Jennifer L , Harvey Joshua , Creese Byron , Chouliaras Leonidas , Dempster Emma , Ballard Clive G , O'Brien John T , Aarsland Dag , Mill Jonathan , Pishva Ehsan , Lunnon Katie
Published: December 2023

Background

Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are termed Lewy body diseases (LBDs). These neurodegenerative diseases are classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). Whilst pathologically similar, symptomatic staging is different. Previous genome wide association studies (GWAS) have identified classic Alzheimer’s disease (AD) and PD loci as risk loci in DLB. Therefore, we have used polygenic risk score (PRS) analysis to investigate the contribution of AD and PD variants in the LBDs.

Method

DNA was extracted from bulk brain tissue from 481 individuals (162 controls, 95 DLB, 156 PDD and 68 PD) and genotyped on the Illumina global screening array. After a strict quality control and imputation pipeline, PRSs for multiple relevant traits using reference GWAS summary statistics were calculated using PRSice2.

Result

Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. All groups, including controls are stratified for age and concomitant AD pathology. Assessing multiple PRSs for association with pathological development and clinical outcomes we have identified the contribution of genetic risk from related neurodegenerative and neuropsychiatric disorders in our cohort of PD, PDD and DLB samples.

Conclusion

We have collated a well powered study cohort to interrogate the genetic basis of the Lewy body dementias and the relative contribution of AD and PD risk loci in the LBDs. We are currently generating methylation quantitative trait loci (mQTLs) for this dataset using previously generated matched DNA methylation data in the brain.
Cortical white matter hyperintensities are associated with locus coeruleus atrophy in elder subjects
Authors: Medel Vicente , Vidal Victor , Gonzalez‐Gomez Raul , Vergara Rodrigo , Wainstein Gabriel , Orellana Patricia , Ibanez Agustin , Shine James M , Delgado Carolina , Delano Paul H , Farías Gonzalo
Published: December 2023

Background

White matter hyperintensities (WMHs) are frequently seen on FLAIR MRI images in aging and Dementia. It has been hypothesized that an imbalance in norepinephrine (NE) signaling could lead to a “hypometabolism” by decreasing astrocyte metabolism which has been proposed as an important cause leading to local demyelination.We hypothesize that structural atrophy in human Locus Coeruleus (LC) leading to NE deficiencies could contribute to the pathophysiology of WMHs by affecting astrocytic metabolism through astrocytic beta‐adrenergic 2 receptors.

Method

FLAIR na T1‐MPRAGE images were obtained from healthy elder subjects (n = 108). LC atrophy was calculated using gray matter mask. WMHs were calculated through both manual segmentation done by an expert, as well as with automatic segmentation. Gene‐expression gradient of beta‐adrenergic 2 receptor was obtained from the Allen Human Brain Atlas.

Result

We found that LC atrophy is related to an increase of WMHs, mainly in frontal lobes. We replicated previous findings associating WMHs with Gait speed, where we found that this effect was significantly mediated by LC atrophy in structural correlation analysis. We developed Linear Mixed Model to account for Random Effects in the relation between WMHs local load and the expression of beta‐adrenergic 2 receptor, and found that subjects that had a higher random effect between these variables had significantly less LC atrophy.

Conclusion

WMHs are correlated with LC atrohy, and spatially overlaps with beta‐adrenergic receptor 2 expression. We theorize that LC atrophy and subsequent decreased NE release disrupt normal astrocyte function through the beta 2 adrenergic receptor, leading to defective axonal metabolism and ultimately to axonal degeneration observed through WMHs with neuroimaging techniques.
Ponatinib and dabrafenib reduce the accumulation of necroptosis‐related proteins and neuronal loss in APP23xTAU58 mice.
Authors: Koper Marta J , Moonen Sebastiaan , Ronisz Alicja , Ospitalieri Simona , Rabe Sabine , Staufenbiel Matthias , De Strooper Bart , Balusu Sriram , Thal Dietmar Rudolf
Published: December 2023

Background

Neuronal death is the result of the neurodegenerative process in Alzheimer’s disease (AD). Both histopathological hallmark lesions of AD, i.e., amyloid plaques and neurofibrillary tangles, are associated with reduced numbers of neurons in the brain. To model AD‐like neuronal death, mouse models with transgenic overexpression of the amyloid precursor protein (APP) and the tau protein can be used. Recently, the necroptotic cell death pathway was found to be activated in the AD brain. In this context, the activated necrosome was found in granulovacuolar degeneration (GVD) lesions in neurons. Therefore, the question arises whether inhibition of the necroptosis pathway reduces neuron loss.

Method

We analyzed APP23xTAU58 double transgenic mice for the presence of the activated necrosome in GVD lesions in association with amyloid and tau pathology. APP23xTAU58 mice at 2, 6, and 12 months of age were studied (n = 5‐10 animals/group). Neuronal densities in the subiculum and the amygdala were compared with those of wildtype littermates. To clarify whether necroptosis inhibitors can interfere with neuron death in this model, we treated APP23xTAU58 mice from 2‐6 months either with dabrafenib or ponatinib (n = 5 animals/group) and compared neuronal densities with that of vehicle‐treated mice. Neuronal densities as well as the percentage of necroptosis markers exhibiting neurons in the subiculum and amygdala were assessed.

Result

Six‐ and 12‐month‐old APP23xTAU58 mice showed significantly decreased neuronal densities in the subiculum and amygdala compared to wildtype mice (p < 0.005), as well as an increased number of neurons exhibiting the necroptosis executor pMLKL in GVD lesions (p < 0.0001). Treatment with the necroptosis inhibitors ponatinib and dabrafenib reduced neuronal loss in the subiculum and the amygdala compared to vehicle treatment (p ≤ 0.0002).

Conclusion

These results show that neuron loss in the APP23xTAU58 model is associated with the accumulation of necroptosis‐related proteins. This neuron loss and the expression of necrosome components can be reduced by ponatinib or dabrafenib. Thus, it is tempting to speculate that necroptosis inhibition could be a promising strategy to prolong neuron survival and, by doing so, to slow down cognitive decline in AD patients.

Funding: FWO
Effects of meditation training and non‐native language training on cognition in older‐adults: A secondary analysis of the three‐arm Age‐Well randomized controlled trial
Authors: Demnitz‐King Harriet , Requier Florence , Whitfield Tim , Schlosser Marco , Gonneaud Julie , Ware Caitlin , Barnhofer Thorsten , Coll‐Padros Nina , Dautricourt Sophie , Delarue Marion , Klimecki Olga M , Paly Léo , Salmon Eric , Schild Ann‐Katrin , Wirth Miranka , Frison Eric , Lutz Antoine , Chetelat Gael , Collette Fabienne , Marchant Natalie L ,   Medit‐Ageing Research Group
Published: December 2023

Background

Non‐pharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. We investigated the effects of 18‐months meditation or non‐native language training versus no intervention on cognition in older adults.

Method

Age‐Well was an observer‐blind, randomised, controlled clinical trial with three parallel arms. Cognitively healthy adults aged ≥ 65 years and were recruited in France. Participants were randomised (1:1:1) to a meditation training, non‐native language (English) training, or a no intervention group for 18 months. Cognition (a pre‐specified secondary outcome) was assessed pre‐ and post‐intervention via the Preclinical Alzheimer’s Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Linear mixed models, adjusted for age, sex, and education, evaluated cognitive changes between arms. Baseline neocortical amyloid deposition was added as a fixed effect in a sensitivity analysis. Additional sensitivity analyses assessed intervention effects for participants who attended at least 20% of intervention classes or were classified as ‘responders’.

Results

137 participants were randomly assigned to meditation training (n = 45), non‐native language training (n = 46), or no intervention (n = 46). Two participants were excluded for not meeting eligibility criteria, and one died during follow‐up (Figure 1). A positive effect of non‐native language training was observed on episodic memory relative to the no intervention group (0·32 [95% CI: 0·04‐0·61], p = 0·025), and on PACC5 scores compared to meditation training (0·33 [95% CI: 0·01‐0·66], p = 0·045; Figure 2). In sensitivity analyses, neither the inclusion of amyloid as an additional covariate nor the exclusion of participants who attended <20% of intervention classes affected results. Following exclusion of ‘non‐responders’, evidence for beneficial effects (relative to the no intervention group) on episodic memory became significant for meditation training (0·33 [0·01, 0·66]), and was weakened for non‐native language training (0·30 [‐0·02, 0·62]). No other between‐group differences emerged.

Conclusion

Among cognitively healthy older adults, there was limited evidence for positive effects of 18‐months meditation training on cognition. However, in addition to having real‐life utility, non‐native language learning in late life may have beneficial effects on cognitive domains affected early in Alzheimer’s disease. Studies investigating whether these effects are long‐lasting are warranted.
Olfactory Mucosal Cells of Individuals with Alzheimer’s Disease Display Alterations Similar to the Alzheimer Brain
Authors: Lampinen Riikka
Published: December 2023

Background

A sense of smell is orchestrated in the first place by the cells of the olfactory mucosa (OM), located in the rooftop of the nasal cavity. Impairments in olfaction are implicated in aging but also in Alzheimer’s disease (AD). Here, we describe the observed alterations in cultures of OM cells derived from individuals with late‐onset AD or amnestic form of mild cognitive impairment (MCI) when compared to OM cells derived from their cognitively healthy control subjects.

Method

Primary cultures of OM cells were harvested from biopsies of OM derived from cognitively healthy individuals and individuals with late‐onset AD or amnestic MCI and cultured in vitro. First, the cell types present in cultures of OM cells and genes differentially expressed between the OM cells derived from control subjects and individuals AD or MCI OM were assessed by single cell RNA‐sequencing (scRNA‐seq). Next, a total RNA‐seq was applied to a larger cohort of samples. The results of total and scRNA‐seq were further validated with various functional in vitro assays including inductively coupled plasma mass spectrometry (ICP‐MS) and measurements of intracellular ATP levels.

Result

The scRNA‐seq unveiled a total of five distinct cell populations in OM cell cultures. A total of 240 previously AD‐related genes were found to be differentially expressed between the AD and control OM cell cultures. Similarly, the MCI OM cells harbored 224 differentially expressed genes when compared to OM cells derived from their control subjects. Common for both AD and MCI OM cells were the alterations in genes related to mitochondrial function when compared to controls. Additionally, the ICP‐MS revealed increased levels of zinc, calcium and sodium in the AD OM cells in comparison to the OM cells derived from cognitively healthy subjects.

Conclusion

The results implicate the role of olfactory mucosa as a site displaying early alterations related to Alzheimer’s disease.
A feasibility study of a 6‐week online technology‐assisted compassion training (T‐ACTS) to improve mental health in older adults living in the UK during the COVID‐19 pandemic
Authors: Khan Zunera , Da Silva Miguel Vasconcelos , Longworth‐Krafft Miranda S , Kitas Florentia , Palmer Alice , Daly Jessica , Glorioso Danielle , Aarsland Dag
Published: December 2023

Background

The COVID‐19 pandemic led to serious health implications for older adults who may have already significant comorbidities. In addition to the risk related to COVID‐19, self‐isolation and limited social contact may have led to psychosocial impacts, such as increased boredom, frustration, depression and anxiety. These stressors may have had increased effects on other key health outcomes, including worse general well‐being, and diminished quality of life. Therefore, finding techniques to boost older adults’ ability to manage these stressors is vital for better planning of unsettled events of similar nature.

Method

A feasibility study assessing a 6‐week online technology assisted compassion training (T‐ACTS) for older adults (Age 60+ without a diagnosis of dementia, access to internet) living in the UK during the COVID‐19 pandemic. T‐ACTS builds on the Raise Your Resilience intervention by Treichler et al., (2020) [1] with weekly one‐to‐one online sessions by research therapists on empathy, self‐compassion, social connections, acts of kindness, gratitude, self‐efficacy, and positive ageing. Key activities included relaxation, gratitude journaling, and positive social engagement. The data reported on feasibility, demographics and mental health using the Patient Health Questionnaire at pre‐ and post‐intervention. McNemar test reported the difference in depression pre‐and post‐intervention.

Result

Forty‐seven participants gave consent, 35 participants entered the intervention, 25 participants (100% Caucasians, 64% females with age 76/5.74 mean/SD) completed the 6 week intervention; and 10 participants withdrew at different timepoints. Reasons for withdrawals included eligibility (1), IT difficulties (1), intervention content (1), engagement (5) and availability (2). There was a significant difference in levels of depression; pre and post intervention (p = 0.014). Around 70% of the participants found the programme enjoyful very‐much so; 30% some‐what enjoyful. Forty‐three percent found the intervention very‐much useful for setting personal goals, with 57% some‐what useful. Activities that were useful included relaxation exercises, gratitude journaling and acts of kindness.

Conclusion

The T‐ACTS intervention demonstrates feasibility of pragmatic online interventions to improve mental health in older adults, suggesting high potential for further evaluation in a larger sample and implementation for older adults. Future studies are warranted for assessing benefits to other key health outcomes such anxiety and general wellbeing.
ARIA‐E, ARIA‐H, and CAA‐related inflammation: time of reconsiderations?
Authors: Piazza Fabrizio
Published: December 2023

Background

Evidence from published clinical trials suggests that high‐dose of monoclonal antibodies (mAbs) are needed to significantly remove parenchymal‐deposited Aβ plaques. However, high‐dosing mAbs resulted in a 25‐35% increased risk of amyloid‐related imaging abnormalities‐edema (ARIA‐E) and ARIA‐hemorrhage (ARIA‐H) side events. Although most ARIA‐E are incidentally recognized as clinically silent during pre‐planned safety monitoring MRI scans and suggested to be managed by dose reduction or suspension, it is noticeable that half of ARIA‐E progressed to symptomatic at continued dosing and to associate with late occurrence of ARIA‐H. Of particular importance, a few of them aggravated to potentially severe brain injury or death due to fatal CAA‐related events. Increased evidence from natural history studies suggests that ARIA‐E is the iatrogenic manifestation of cerebral amyloid angiopathy‐related inflammation (CAA‐ri), a rare autoimmune encephalopathy due to raised anti‐Aß autoAbs levels in the cerebrospinal fluid (CSF).

Method

Natural history study of CAA‐ri demonstrated that immunotherapy‐related ARIA‐E share several commonalities with the spontaneous occurrence of autoAbs‐related ARIA‐E, including fluid, MRI, and PET biomarker changes and the potential response to treatment outcomes.

Result

The prospective longitudinal monitoring of patients with CAA‐ri provide evidence for a regional and temporal association of ARIA‐E on MRI with focal peaks of neuroinflammation on microglial‐PET imaging. This association was strong in patients with positive CSF markers of AD (ATN positive) and comorbid CAA pathology on MRI, while it was negligible in patients with CAA disease w/o AD (ATN negative). Raised CSF concentrations of anti‐Aß autoAbs were found in all patients at (sub)acute presentation, and reduced within 5 months from the ARIA‐E index event, in parallel with evidence of radiographic resolution of ARIA‐E. At follow‐up MRI scan, the occurrence of new hemorrhagic markers (aka ARIA‐H in trials) were found only in patients with coexisting CAA and AD comorbid pathology. The MRI scales for ARIA commonly used in clinical trials only partially paralleled the clinical, biological, and MRI findings.

Conclusion

This suggests that to mitigate and monitor the risk of ARIA, more sensitive, specific, cost‐effective and easy to interpret diagnostic tools and biomarkers than MRI alone will be needed for precision drug‐dose tailoring.
Implications of ARIA for trial design and monitoring
Authors: Wolters Frank J.
Published: December 2023

Background

Side‐effects of therapy with monoclonal antibodies against Alzheimer’s disease are common, which has important consequences for treatment monitoring. Moreover, adverse effects may affect trial validity through unblinding of participants, but impact on trial results is uncertain.

Method

Literature review, and simulation modelling using observations from published randomised placebo‐controlled clinical trials (RCTs) of monoclonal antibodies against amyloid‐β.

Result

In analysis of simulated trial data, we demonstrate the impact of disclosure of treatment status on cognitive and functional endpoints in RCTs. These analyses show the likelihood that placebo effects after unblinding contribute to the observed treatment effects. We define the most prudent targets for safeguarding causal inference from RCTs, and suggest mitigation strategies for future trial conduct. Furthermore, we consider best practice for treatment selection and monitoring in light of amyloid‐related imaging abnormalities (ARIA). Specifically, we discuss i) the implications of interaction with other, concurrently used medication (e.g. antithrombotic drugs) on treatment safety, and ii) challenges in treatment monitoring on the basis of observed rates of ARIA with monoclonal antibody treatment, as well as background risk of hemorrhagic ARIA in the general population and in placebo‐groups of published RCTs. We end with recommendations for future research on the most pressing ARIA‐related questions for implementation of monoclonal antibodies in routine practice.

Conclusion

Simulated trial data can offer valuable insight in the interpretation and design of RCTs against Alzheimer’s disease. Better understanding of ARIA in different patient groups is needed to guide treatment indication and monitoring.
The ANeED Study: Ambroxol in New and Early Dementia with Lewy bodies
Authors: Chwiszczuk Luiza J. , Rongve Arvid
Published: December 2023

Background

No disease modifying treatment is available for dementia with Lewy bodies (DLB). DLB patients have a rapid disease progression to the end stage of severe dementia, nursing home admission and death as compared to persons living with AD (1). Reported findings suggests reduced glucocerebrosidase (GCase) activity may be involved in pathomechanisms of synucleinopathies. Ambroxol is a well‐known drugs able to enhance GCase activity and thus increases synuclein clearance in CNS (2,3).

Method

The ANeED study is a national, multicentre, phase IIa RCT, placebo controlled clinical intervention trial including patients with prodromal and mild DLB with MMSE >14 (NCT04588285). The drug intervention is 1260 mg/d and treatment duration is 18 month. We additionally stratify participants based on genotypes for APOE and the CSF biomarker amyloid‐beta. Allocation ratio 1:1 for ambroxol and placebo.

Result

The study started in May 2021. As of February 2023, six out of seven sites have started recruitment. Of 47 included patients 38 started treatment with compliance >90%. Five patients completed the blind phase after 18 months and continue in the extended open label phase with ABX for 12 months. Adverse events reported are falls, nausea and sleep disturbances, but the relationship with ambroxol is uncertain. The goal for inclusions is 180 participants. Demographical and clinical data we present in table.

Conclusion

The ANeED study continue to recruit patients as planned. We did not register any serious adverse events related to the study medication. The compliance is high and the tolerability and safety of study medication is good.

References:

1. Rongve A, Soennesyn H, Skogseth R, et al. Cognitive decline in dementia with Lewy bodies: a 5‐year prospective cohort study. BMJ Open. British Medical Journal Publishing Group; 2016;6(2):e010357.

2. Mullin S, Smith L, Lee K, et al. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. American Medical Association; 2020 Apr 1;77(4):427‐34.

3. Silveira CRA, MacKinley J, Coleman K, et al. Ambroxol as a novel disease‐modifying treatment for Parkinson’s disease dementia: protocol for a single‐centre, randomized, double‐blind, placebo‐controlled trial. BMC Neurol. BioMed Central; 2019 Dec 1;19(1):1‐10.
Comparative Toxicogenomics Database: A tool to investigate the effects of environmental exposures on the etiology of Alzheimer’s disease
Authors: Mattingly Carolyn , Wiegers Thomas C , Wiegers Jolene , Sciaky Daniela , Johnson Robin , Davis Allan P
Published: December 2023

Background

Most human diseases involve interactions between genetic and environmental factors. Although the environment is implicated in most chronic diseases, the etiology and mechanisms of action underlying these diseases remain unclear. It is estimated that more than 80,000 chemicals are currently used in commerce, challenging elucidation about chemical mechanisms‐of‐action and prioritization of environmental health research. Integration of diverse data is required to understand environment‐disease associations, mechanisms of chemical action, toxicity prediction and development of effective therapeutic interventions.

Method

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) was launched publicly to address an unmet need for a public data resource dedicated exclusively to advancing understanding about environment‐disease connections. CTD provides a combination of richly annotated data describing chemical‐gene‐phenotype‐disease interactions, exposure information, and novel analysis tools that enable user‐driven discoveries about environmental influences on human health.

Results

Currently, CTD provides >2.5 million manually curated relationships for 16,800 chemicals; 52,000 genes/proteins; 5,500 phenotypes; and 7,200 diseases. The value of CTD has been specifically leveraged for a range of chronic and neurological diseases, including Alzheimer’s disease.

Conclusion

There is growing evidence of environmental influences on the etiology of a range of neuropsychiatric syndromes. This presentation will provide an overview of CTD content and functionality and how it can be used to explore environmental influences on the etiology and underlying mechanisms of Alzheimer’s disease and other disorders.
Implementation of a smartphone application for precision brain health assessment in a rural low socioeconomic setting: The Bogalusa Heart Study
Authors: De Anda‐Duran Ileana , Popp Zachary T , Jones Brayanna , Fernandez‐Alonso Camilo , Low Spencer , Libon David J , Lin Honghuang , Kolachalama Vijaya B. , Au Rhoda , Bazzano Lydia
Published: December 2023

Background

Smartphone apps for digital health with decentralized data collection enable more frequent and precise brain‐health monitoring via the abundance of embedded sensors. Such methods may improve the sensitivity of traditional metrics and representation among diverse populations impacted by health disparities, especially in ADRD studies. Here, we describe a framework for implementing a smartphone‐based digital platform for precision brain health assessment in a longitudinal cohort of Black and White men and women.

Methods

Participants are being recruited as part of a multi‐site study from the Bogalusa Heart Study (BHS), a community‐based cohort in rural Louisiana that began in 1973. The digital platform consists of a smartphone application that is used remotely every three months for two weeks. It includes tasks that assess cognition, speech, gait and balance, and questionnaires that ensure instructions are appropriately followed and to monitor usage experiences. The BHS study personnel handle the initial screening, enrollment, and application setup. To overcome internet connection and time/availability issues, remote phone calls from BHS staff and text messages from a local area code using RingCentral software were implemented. Messages included short reminders, a link to step‐by‐step instructions to complete the application setup, and examples of smartphone tasks. (Figure 1.) Participants could schedule a call to receive phone instructions to complete the process.

Results

A total of 94 participants [age 56 ± 4.5, women n = 60 (69%), Black n = 16 (19%)] have been enrolled in the study thus far. Of those, 77 (82%) registered and set up the application (69 at the study site and 8 remotely via text/phone), and 62 (81%) completed at least one set of tasks. There was no significant difference in completion rates between race [White n = 52 (84%) and Black n = 10 (77%); p = 0.54] and sex groups [women n = 45 (82%) and men n = 17 (85%); p = 0.75].

Conclusion

Results showed that individuals from a rural community‐based cohort are willing to use digital technologies for brain health assessments. These findings highlight the importance of utilizing low‐cost, scalable platforms and adapting research protocols to meet the requirements of specific populations, particularly those from low socioeconomic and underrepresented backgrounds.
Differences in pathology, brain atrophy, and WMHs across APOE subtypes
Authors: Morrison Cassandra , Dadar Mahsa , Kamal Farooq , Collins D Louis
Published: December 2023

Background

The apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer’s disease (AD), while the e2 allele is thought to be protective. As few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype, we do so here.

Methods

We analyzed Alzheimer’s Disease Neuro Imaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load (obtained using Dadar 2018); ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV‐45), and phosphorylated tau (pTau), all downloaded from LONI. Participants were divided into one of four APOE allele profiles (E4 = e4e4 or e3e4; E2 = e2e2 or e2e3; E3 = e3e3; or E24 = e2e4, Fig.1). Linear mixed effects models examined the relationship between APOE profiles and each pathology while controlling for age, sex, education, and diagnostic status.

Results

At baseline (Fig.2), E4 exhibited increased pTau (p<.001) compared to E2 and E3 and smaller HC and EC volumes than all other APOE profiles (p<.01). The E24 group exhibited smaller ventricles than E3 and E4 (p<.05). The E2 group exhibited less amyloid than all other APOE profiles (p<.001), while E4 and E24 had more amyloid compared to E3 (p<.001).

Longitudinally (Fig.3), ventricular enlargement and HC atrophy significantly differed between all profiles (p<.001). Furthermore, E2 was observed to have slower WMH accumulation compared to all other profiles (p<.001), while E4 exhibited faster accumulation compared to E3 (p<.001). The E4 group exhibited increased EC atrophy compared to E3 and E2 (p<.001), and E24 exhibited more atrophy than E2 (p = .015). Amyloid increased faster in the E4 group compared to E3 and E2 (p<.001), while E2 amyloid progressed slower than E3 (p = .005).

Conclusions

APOE E4 positivity is associated with increased baseline and greater accumulation of pathologies and rates of neurodegeneration. APOE E2 positivity is associated with reduced pathology burden (i.e., WMH and amyloid) and less neurodegeneration as measured by ventricle size and hippocampal and entorhinal cortex volume over time. APOE E2E4 is similar to E4 (i.e., increased neurodegeneration and pathology burden) but with a slightly slower rate of change.
Biomarker (Metabolic and Lipids) Determinants of Dementia in Older Adult Population from Nigeria: A Cross Sectional Analysis
Authors: Ucheagwu Valentine A , Giordani Bruno
Published: December 2023

Background

Dementia is determined by underlying biological processes. There is a paucity of studies from Nigeria concerning biomarkers in dementia. We present baseline data from longitudinal study on association of lipid and metabolic biomarkers on dementia.

Method

Three hundred older adults (65‐89 years; mean age: 70.30; female: 202) without stroke participated were assessed using adapted Unified Data Set (UDS 3) neuropsychological test battery. Diagnoses was made using the Jack and Bondi (1961) method (normal cognition, borderline or severe impairment/dementia). Blood samples were used to analyze lipid (total cholesterol, triglycerides, HDL, LDL, and VLDL) and sugar. Hypertension, pulse and BMI were obtained in this cross sectional study. Partial correlations controlling for age, sex, education, and marital status were used to test for associations between biomarkers and cognitive status across entire sample. MANOVA was used to analyze differences in biomarker categories on UDS3 performance.

Result

There were no significant associations between dementia status and metabolic biomarkers (systolic BP, diastolic BP, diabetes, BMI and pulse), though diabetes and BMI showed small effect sizes (0.10).No significant association between lipids biomarkers (total cholesterol (TC), triglycerides (TG), HDL, LDL, VLDL) and dementia were found. Also, no significant associations were found between lipids and metabolic biomarkers on cognitive domains, except for HDL on visual spatial domain (‐0.15).There were small effect sizes (0.10 to 0.12) for TC and HDL on attention and TG and VLDL on language. There were small effect sizes (between 0.15 to 0.18) for BMI on attention; systolic BP, diabetes and BMI on visual spatial; systolic BP, diabetes, BMI and pulse on processing speed, as well as pulse on language. No significant differences were seen on cognitive measures for those diagnosed with or without diabetes or hypertention. When comparing high/low HDL, significant differences were found only for language (0.57).

Conclusion

Our findings stand in contrast to prevailing western studies on the roles of metabolic syndrome and lipids on cognitive status. Though there are pockets of small effect sizes, there was little evidence for metabolic and lipid profiles as determinants of dementia and cognitive performance in older Nigerian adults.
Exposomics for Characterization of Environmental Drivers of AD
Authors: Miller Gary W , Kalia Vrinda , Lai Yunjia , Honig Lawrence S. , Mayeux Richard , Vardarajan Badri N , Lantigua Rafael A. , Lee Annie J , Manly Jennifer J. , Nandakumar Renu
Published: December 2023

In order to provide a comprehensive evaluation of the non‐genetic factors involved in the development of Alzheimer’s disease and related disorders it is necessary to develop a systematic process to capture the range of environmental and social influences. Exposomics has emerged as an approach to do this. Using high‐resolution mass spectrometry and geospatial techniques it is possible to evaluate thousands of external factors (chemical, nutritional, social, environmental) and their corresponding impact on biology. In this presentation, we will describe the steps we are taking to build the required infrastructure. The first aspect is to improve the identification of exogenous and endogenous chemical features by expansion of our high‐resolution mass spectrometry capabilities (automated liquid handling with ThermoFisher Orbitrap‐based technology: HFX, LC‐Exploris 240, GC‐Exploris 240, and IQX Tribrid Mass Spectrometer). We are in the process of analyzing thousands of samples from WHICAP, EFIGA, and RANN using our combined LC/GC Orbitrap platform, to identify significant associations with disease traits (existing and next generation biomarkers, pathology, imaging, clinical features). Initial results from these studies will be presented to demonstrate feasibility of the approach. We have also initiated a series of pilot studies for other AD cohorts, which cover a range of populations with diverse ethnicity, disease stage, and age. These studies have extensive clinical phenotyping and deep molecular phenotyping. The addition of exposomics will leverage these existing studies to uncover novel environmental contributors to AD. We also also developing a platform to distribute workflows via an online EXCEL AD Community Dashboard to other ADRCs and AD research groups interested in incorporating exposomics into their studies. We will also provide guidance on quality control materials, including providing standards as needed. The Community Dashboard would also compile information on ongoing AD studies that are incorporating exposomics, as well as relevant publications. Various tools will be developed to encourage the utilization of this new platform such as user manuals, training programs (in‐person, online) exposomics bootcamps, and scholar exchange through on‐site visits to laboratories. We will deploy an academic research consultancy that will help other interested laboratories to establish the exposomics workflow.
Association of hippocampal neuron loss, pTDP‐43, and Alzheimer’s disease pathology with the presence of cerebral Lewy bodies
Authors: Gawor Klara , Tomé Sandra O. , Ronisz Alicja , Ospitalieri Simona , Vandenberghe Rik , von Arnim Christina , Otto Markus , Thal Dietmar Rudolf
Published: December 2023

Background

The presence of multiple brain pathologies in patients with late‐onset dementia was shown to be a rule rather than an exception. Studies have shown that over half of the patients with Lewy bodies (LB) in the brain also have concurrent Alzheimer’s disease pathology (ADNC). The estimates of pTDP‐43 proteinopathy prevalence vary greatly between studies, ranging from 0‐50%. This disparity may be attributed to different patterns of LB distribution, including brainstem, limbic, and neocortical. In this study, we aimed to investigate the hypothesis that the severity of pTDP‐43 pathology and hippocampal neuronal loss vary depending on the distribution of LBs, independent of co‐existing ADNC.

Method

Paraffin‐embedded sections from 270 brains of older adults with and without dementia were histologically evaluated for amyloid‐beta, pTau, pTDP‐43, and alpha‐synuclein. The severity of ADNC was assessed according to NIA‐AA guidelines. We differentiated cases positive for alpha‐synuclein in the amygdala or neocortex (cerebral LB) from those with pathology restricted to brainstem regions (brainstem LB). The CA1 region from the posterior hippocampus was quantitatively analyzed for pTDP‐43 pathology and overall neuronal density.

Result

Our findings revealed that pTDP‐43 neuronal inclusions were present in the CA1 region in more than 80% of subjects with cerebral LB and high ADNC. The percentage of pTDP‐43 positive neurons was higher in the cerebral LB/AD group than in AD cases without LBs (β = 0.11, p<10−4). We detected a decreased neuronal density in the CA1 regions in cases with cerebral LBs regardless of AD status (β = ‐35.43, p<10−4). LB restricted to brainstem regions had no impact on pTDP‐43 pathology (β = 0, p = 0.99) and neuronal density in the hippocampus (β = ‐12.26, p = 0.15).

Conclusion

Our results support the existence of a distinct subgroup of late‐onset dementia cases characterized by cerebral LBs, ADNC, and severe pTDP‐43 pathology. This finding may explain the variability of pTDP‐43 prevalence estimations in LB patients. By identifying the association between cerebral LBs and neuronal loss in the hippocampus, we also emphasize the importance of stratifying dementia patients based on the pattern of LB distribution. Further research is needed to clarify the functional interactions between pTDP‐43, alpha‐synuclein (LB), and ADNC.
Comparative Effects of Extracts from Leaves of Horseradish Tree Species (Moringa oleifera and Moringa stenopetala) on Memory Index, Monoamine Oxidase activity and Tyrosine Hydroxylase mRNA Expression in Paraquat‐induced Model of Parkinson s disease in Fruit Flies (Drosophila melanogaster)
Authors: Aro Olayemi Philemon , Adefegha Adeniyi Stephen , Ogunsuyi Opeyemi Babatunde , Oboh Ganiyu
Published: December 2023

Background

PD is now understood to be a multi‐system brain condition affecting multiple non‐dopaminergic transmitter systems that grow more prominent as the disease develops. Recent epidemiological and experimental studies have connected pesticides, particularly paraquat, to Parkinson’s disease. Even though the horseradish tree (Moringa oleifera) is a very promising ethnobotanical plant with a wealth of medicinal applications, little is known about the bioactive qualities of alkaloid extracts from its leaves.

Method

This study investigated the comparative modulatory effects of alkaloid extracts of Moringa leaves on the survival rate of paraquat‐induced flies, as well as specific biochemical and genetic markers related to Parkinson’s disease in the heads of the flies

Result

The results showed that the alkaloid extract increased fly survivability (p <0.05). M. Stenopetala (50 mg/ml) extract reduced monoamine oxidase and acetylcholinesterase activity more than M. oleifera. Compared to the paraquat‐induced group, M. Stenopetala also increased the amounts of superoxide dismutase, glutathione‐S‐transferase, catalase, and total thiols. Gene expression data show that the induced group had lower levels of catalase and TH mRNA expression compared to the treated groups. It was shown that M. oleifera had a greater ameliorative impact than M. stenopetala on catalase mRNA expression, whereas M. stenopetala had a considerably greater ameliorative effect on TH mRNA expression than M. oleifera.

Conclusion

In this research, paraquat‐induced fruit flies were treated with alkaloid extracts from Moringa leaves, and the results showed that the M. Stenopetala variety had a more effective therapeutic effect than M. oleifera.
MAPT subhaplotypes and chronic traumatic encephalopathy
Authors: Han Xudong , Petrosky Jillian , Bald Sarah , Zhang Yichi , Sherva Richard , Chung Jaeyoon , Abdolmohammadi Bobak , Durape Shruti , Martin Brett M , Palmisano Joseph N , Farrell Kurt W. , Farrell John , Cherry Jonathan D , Alvarez Victor E. , Huber Bertrand R. , Alosco Michael L , Tripodis Yorghos , Stern Robert A , Stein Thor D. , Farrer Lindsay A. , Crary John F. , McKee Ann C. , Mez Jesse B.
Published: December 2023

Background

Exposure to repetitive head impacts (RHI) is the main risk‐factor for chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by perivascular hyperphosphorylated tau deposition. However, the occurrence and severity of CTE varies widely among those with similar RHI exposure, suggesting other factors, including genetics, may contribute. The MAPT gene, which codes for the tau protein, is implicated in other tauopathies, but has not been investigated in CTE. The 17q21.31 region, containing MAPT, includes a megabase‐long inversion (H1/H2; European ancestry only) and copy‐number variations, including α, β and γ segments, which can be characterized as nine segregating structural subhaplotypes. We investigated associations between these subhaplotypes, CTE, and related clinical and neuropathological outcomes.

Method

458 male brain donors of European ancestry from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank with known RHI exposure from contact sports and/or military service were evaluated for CTE status, CTE stage (0 = absent; 4 = most severe), semiquantitative tau burden (0 = absent; 3 = most severe) across 11 brain regions and dementia based on informant report. Donors were genotyped on ∼5,000 SNPs across the 17q21.31 region in 2 batches. SHAPEIT and IMPUTE2 were used to phase and impute 12 biallelic surrogate markers and then SHAPEIT was used again to estimate 9 subhaplotypes. We tested the subhaplotype associations with CTE and the above outcomes in regression models adjusted for age at death and 10 principal components of population substructure. Results were meta‐analyzed across batches using the inverse variance method in METAL. Permutation testing was used to account for multiple testing and correlated data.

Result

The imputation quality of the surrogate markers was good (info score:0.516‐0.797). There were no significant associations with CTE status. The H1β1γ1 subhaplotype (frequency = 0.39) was significantly associated with dementia (OR = 1.90; padj = 0.019) and semiquantitative tau burden in the amygdala (OR = 1.53; padj = 0.025), entorhinal cortex (OR = 1.50; padj = 0.047), inferior parietal cortex (OR = 1.51; padj = 0.039), middle frontal cortex (OR = 1.48; padj = 0.045), and superior temporal cortex (OR = 1.67; padj = 0.002). H1β1γ1 was nominally associated with CTE stage (OR = 1.35; p = 0.027).

Conclusion

These findings suggest a relationship between MAPT region structural variation and CTE‐related outcomes. Extension in a richly characterized living cohort of elite American football players is ongoing.
Impact of the COVID‐19 pandemic on enrollment at United States Alzheimer’s Disease Research Centers
Authors: Shaaban C. Elizabeth , Lin Hsing‐Hua Sylvia , Ren Dianxu , Lingler Jennifer H
Published: December 2023

Background

Impacts of the COVID‐19 pandemic have been disproportionate by race/ethnicity and sex. We aimed to characterize the impact of the pandemic on enrollment in US Alzheimer’s Disease Research Centers (ADRCs) overall and by race/ethnicity and sex using National Alzheimer’s Coordinating Center (NACC) data.

Methods

We included data on N = 8875 participants (mean age, 69.4 years; 59% female; 9% Hispanic/Latino; 14% Black/African American) from 29 ADRCs with ≥5 years of data and study visits after 2020 (e.g., baseline visits from January 2017‐December 2021). We used interrupted time series (ITS) analyses to assess the relationship of the pandemic on enrollment and calculated projected date of recovery of pre‐pandemic enrollment overall and by race, ethnicity, and sex.

Results

Enrollment dropped to 0% of pre‐pandemic levels in April 2020; through December 2021, enrollment recovered to only 46% of pre‐pandemic levels. Participants enrolled during the pandemic (vs pre‐pandemic) were less likely to be: women, cognitively normal, and able to live independently. They were slightly younger, slightly more educated, and more likely to: be married, be referred by a doctor, nurse, or other professional, and come in for a clinical or mixed clinical and research study evaluation (p’s<0.05). The two groups did not vary by race, ethnicity, living situation (alone or with others), or co‐participant characteristics. ITS demonstrated that the pandemic caused an immediate 79% drop in enrollment rate, with an estimated post‐pandemic increase in enrollment of 0.92%/month, leading to a projected recovery date of January 2026. Due to parallel pre‐ and post‐pandemic enrollment slopes among Black/African American participants, we could not predict a recovery date for this group. Projected recovery varied by ethnicity with Hispanic participant enrollment recovering earlier than non‐Hispanic participant enrollment (January 2022 vs. April 2027), largely because Hispanic participant enrollment was declining nearly 1.5%/month pre‐pandemic. Recovery date projections also varied by sex, with female participant enrollment recovering sooner than male participant enrollment (June 2025 vs. May 2027).

Conclusions

Strategies to speed enrollment recovery should be developed and implemented, with special attention given to Black/African American and Hispanic enrollment. Funders and researchers should be aware of and account for ongoing COVID‐19 impact on ADRD research enrollment.