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INTRODUCTION We investigated blood DNA methylation patterns associated with 15 well‐established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) study using the EPIC array. RESULTS We identified Bonferroni‐significant differential methylation associated with CSF YKL‐40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL‐40 levels correlating with plasma YKL‐40 levels. A co‐localization analysis showed shared genetic variants underlying YKL‐40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co‐methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. DISCUSSION We conducted the most comprehensive epigenome‐wide association study (EWAS) of AD‐relevant CSF biomarkers to date. Future work should explore the relationship between YKL‐40 genotype, DNA methylation, and protein levels in the brain. Highlights Blood DNA methylation was assessed in the EMIF‐AD MBD study. Epigenome‐wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)–relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni‐significant loci were associated with YKL‐40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL‐40 co‐localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single‐nucleotide polymorphisms (SNPs) in YKL‐40 on CSF protein levels.

Objectives The objective of this systematic review was (1) to give an overview of the available short screening instruments for the early detection of Alzheimer’s disease (AD) and (2) to review the psychometric properties of these instruments. Methods First, a systematic search of titles and abstracts of PubMed and Web of Science was conducted between February and July 2015 and updated in April 2016 and May 2018. Only papers written in English or Dutch were considered. All full-text papers about cognitive screening instruments for the early detection of AD were included, resulting in the identification of 38 pencil and paper tests and 12 computer tests. In a second step, the psychometric quality of these instruments was evaluated. Therefore, the same databases were searched again to identify papers that described the psychometric properties of the instruments meanwhile applying diagnostic criteria for the diagnostic groups included. Results Out of 1454 papers, 96 clearly discussed the psychometric properties of the instruments. Eighty-nine papers discussed pencil and paper tests of which 80 were validated in a memory clinic setting. Based on the number of studies (31 articles) and the sensitivity (84%) and specificity (74%) values, the Montreal Cognitive Assessment (MoCA) seems to be a promising (pencil and paper) screening test for memory clinic testing as well as for population screening. Regarding computer tests, validation studies were only available for 7 out of 12 tests. Conclusions A large number of screening tests for AD are available. However, most tests are only validated in a memory clinic setting and description of the psychometric properties of the instruments is limited. Especially, computer tests require further research. The MoCA is a promising instrument, but the specificity to detect early AD is rather low.

INTRODUCTION The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood‐derived DNA methylation as a promising tool for early dementia risk detection. METHODS In conjunction with an extensive array of machine learning techniques, we employed whole blood genome‐wide DNA methylation data as a surrogate for 14 modifiable and non‐modifiable factors in the assessment of dementia risk in independent dementia cohorts. RESULTS We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross‐sectionally, independent of age and sex (P = 2.0 × 10−3). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)‐Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia = 2.59). DISCUSSION Our work shows the potential of employing blood‐derived DNA methylation data in the assessment of dementia risk. Highlights We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level.

INTRODUCTION We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.

Key summary points Aim What is the overall concordance between FRIED-P and FRIED-Q? Findings The concordance between the FRIED-P and FRIED-Q was substantial, characterized by a very high specificity but a moderate sensitivity. Message The FRIED-Q can be used as a step in a sequential process to detect frailty in a large population. Purpose When screening large populations, performance-based measures can be difficult to conduct because they are time consuming and costly, and require well-trained assessors. The aim of the present study is to validate a set of questions replacing the performance-based measures slowness and weakness as part of the Fried frailty phenotype (FRIED-P). Methods A cross-sectional study was conducted among community-dwelling older adults (≥ 60 years) in three Flemish municipalities. The Fried Phenotype (FRIED-P) was used to measure physical frailty. The two performance-based measures of the Fried Phenotype (slowness and weakness) were also measured by means of six substituting questions (FRIED-Q). These questions were validated through sensitivity, specificity, Cohen’s kappa value, observed agreement, correlation analysis, and the area under the curve (AUC, ROC curve). Results 196 older adults participated. According to the FRIED-P, 19.5% of them were frail, 56.9% were pre-frail and 23.6% were non-frail. For slowness, the observed sensitivity was 47.0%, the specificity was 96.5% and the AUC was 0.717. For weakness, the sensitivity was 46.2%, the specificity was 83.7%, and the AUC was 0.649. The overall Spearman correlation between the FRIED-P and the FRIED-Q was r  = 0.721 with an observed agreement of 76.6% (weighted linear kappa value = 0.663, quadratic kappa value = 0.738). Conclusions The concordance between the FRIED-P and FRIED-Q was substantial, characterized by a very high specificity, but a moderate sensitivity. This alternative operationalization of the Fried Phenotype—i.e., including six replacement questions instead of two performance-based tests—can be considered to apply as screening tool to screen physical frailty in large populations.

Background The debate on frailty in later life focuses primarily on deficits and their associations with adverse (health) outcomes. In addition to deficits, it may also be important to consider the abilities and resources of older adults. This study was designed to gain insights into the lived experiences of frailty among older adults to determine which strengths can balance the deficits that affect frailty. Methods Data from 121 potentially frail community-dwelling older adults in Flemish-speaking Region of Belgium and Brussels were collected using a mixed-methods approach. Quantitative data were collected using the Comprehensive Frailty Assessment Instrument (CFAI), Montreal Cognitive Assessment (MoCA), and numeric rating scales (NRS) for quality of life (QoL), care and support, meaning in life, and mastery. Bivariate analyses, paired samples t-tests and means were performed. Qualitative data on experiences of frailty, frailty balance, QoL, care and support, meaning in life, and mastery were collected using semi-structured interviews. Interviews were subjected to thematic content analysis. Results The “no to mild frailty” group had higher QoL, care and support, meaning in life, and mastery scores than the “severe frailty” group. Nevertheless, qualitative results indicate that, despite being classified as frail, many older adults experienced high levels of QoL, care and support, meaning in life, and mastery. Respondents mentioned multiple balancing factors for frailty, comprising individual-level circumstances (e.g., personality traits, coping strategies, resilience), environmental influences (e.g., caregivers, neighborhood, social participation), and macro-level features (e.g., health literacy, adequate financial compensation). Respondents also highlighted that life changes affected their frailty balance, including changes in health, finances, personal relationships, and living situation. Conclusion The findings indicate that frailty among older individuals can be considered as a dynamic state and, regardless of frailty, balancing factors are important in maintaining a good QoL. The study investigated not only the deficits, but also the abilities, and resources of frail, older adults. Public policymakers and healthcare organizations are encouraged to include these abilities, supplementary or even complementary to the usual focus on deficits.

ObjectiveThe aim of the present study is to describe a stepwise approach to study which contextual factors might moderate the effect of healthcare interventions and to test feasibility of this approach within the D-SCOPE project.DesignExploratory case study.SettingIn the D-SCOPE project, a complex intervention by means of home visits was set up to improve access to tailored care in three municipalities (Ghent, Knokke-Heist and Tienen).MethodsOne designed and tested an approach including five steps: (1) a theoretical/conceptual discussion of relevant contextual factor domains was held; (2) a search was done to find appropriate web-based public datasets which covered these topics with standardised information; (3) a list of all identified contextual factors was made (inventory); (4) to reduce the long list of contextual factors, a concise list of most relevant contextual factors was developed based on the opinion of two independent reviewers and (5) a nominal grouping technique (NGT) was applied.ResultsThree public web-based datasets were found resulting in an inventory of 157 contextual factors. After the selection by two independent reviewers, 41 contextual factors were left over and presented in a NGT which selected 10 contextual factors. The NGT included seven researchers, all familiar with the D-SCOPE intervention, with various educational backgrounds and expertise and lasted approximately 1 hour.ConclusionThe present study shows that a five-step approach is feasible to determine relevant contextual factors that might affect the results of an intervention study. Such information may be used to correct for in the statistical analyses and for interpretation of the outcomes of intervention studies.NCT03168204

Background Event-based modeling (EBM) traces sequential progression of events in complex processes like neurodegenerative diseases, adept at handling uncertainties. This study validated an EBM for Alzheimer’s disease (AD) staging designed by EuroPOND, an EU-funded Horizon 2020 project, using research and real-world datasets, a crucial step towards application in multi-center trials. Methods The training dataset comprised 1737 subjects from ADNI-1/GO/2, using the EuroPOND EBM toolbox. Testing datasets included a research cohort from University of Antwerp (controls, CN ( n  = 46), subjective cognitive decline, SCD ( n  = 10), mild cognitive impairment, MCI ( n  = 47), AD dementia, ADD ( n  = 16)) and a real-world cohort from 9 Belgian Dementia Council memory clinics (CN ( n  = 91), SCD ( n  = 66), (non-amnestic) naMCI ( n  = 54), aMCI ( n  = 255), and ADD ( n  = 220). Biomarkers included: 2 clinical scores (Mini Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT)); 3 CSF-biomarkers (Aβ 1−42 , P-tau 181 , total-Tau); and 4 magnetic resonance imaging (MRI) biomarkers (volumes of the hippocampi, temporal, parietal, and frontal cortices) computed with icobrain dm. The naMCI and aMCI groups were compared by EBM stage proportions, and the model’s effectiveness at patient level was evaluated. Results The research cohort’s maximum likelihood event sequence comprised CSF Aβ 1-42 , P-tau 181 , T-tau, RAVLT, MMSE, and cortical volumes. The clinical cohort’s order was frontal cortex volume, MMSE, and remaining cortical regions. aMCI subjects showed higher staging than naMCI, with 54% in the two most advanced stages compared to 38% in naMCI. In the research cohort, 10 outliers were identified with potential mismatches between assigned stages and clinical or biomarker profiles, with CN ( n  = 4) and SCD ( n  = 2) subjects assigned in stage 4, one control in stage 9 with abnormal imaging, and three aMCI cases in stage 0 despite clinical or volumetric signs of impairment. Conclusions This study highlights the generalizability of EuroPOND’s AD EBM model across research and real-world clinical datasets, supporting its use in multi-center trials. aMCI subjects generally reside in more advanced stages than naMCI, who may not necessarily have AD, demonstrating utility for precision recruitment/screening. Highlights EBM for AD staging is generalizable and reliable across research and real-world clinical datasets. Amnestic MCI subjects exhibited higher EBM scores than non-amnestic subjects, indicating utility for precision recruitment and screening in clinical trials. Tailored EBM models for distinct AD subtypes and diverse neurodegenerative diseases are imperative for accurate staging and understanding varied disease trajectories.

This paper aims to give an overview of the different sources of income and the expenditures of community-dwelling older adults and to what extent they can make ends meet to explore the affordability of care and support at home. Despite research on the affordability of residential care, evidence on the cost of ‘ageing in place’ is still missing. 173 questionnaires were gathered within a non-random sample of community-dwelling older adults (60+). Both frequencies and bivariate tests (to explore whether there are certain risk groups with low incomes and high expenditures) were performed on the data. Results indicate the variety of income sources, the necessity of financial compensations to make ends meet and that especially older women and older tenants are at risk for facing financial difficulties. Also, this research indicates that ‘ageing in place’, especially for older adults with care needs, is not always affordable and can be a challenge within our ageing society.