Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation.

Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (ß-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

Replication study of plasma proteins relating to Alzheimer's pathology.

INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

Exploring Cognitive Frailty: Prevalence and Associations with Other Frailty Domains in Older People with Different Degrees of Cognitive Impairment.

BACKGROUND: Cognitive frailty has long been defined as the co-occurrence of mild cognitive deficits and physical frailty. However, recently, a new approach to cognitive frailty has been proposed: cognitive frailty as a distinct construct. Nonetheless, the relationship between this relatively new construct of cognitive frailty and other frailty domains is unclear. OBJECTIVES: The aims of this study were to explore the prevalence of cognitive frailty in groups with different degrees of cognitive impairment, as well as to explore the associations between frailty domains, and if this varies with level of objective cognitive impairment. METHOD: Cross-sectional, secondary data from 3 research projects among community-dwelling people aged ≥60 years, with different degrees of objective cognitive impairment, were used: (1) a randomly selected sample (n = 353); (2) a sample at an increased risk of frailty (n = 95); and (3) a sample of memory clinic patients who scored 0.5 on the Clinical Dementia Rating scale - according to the "original" definition of cognitive frailty (n = 47). Multidimensional frailty was assessed with the Comprehensive Frailty Assessment Instrument - Plus and general cognitive functioning with the Montreal Cognitive Assessment. Descriptive statistics and linear regression were used to determine the prevalence of cognitive frailty and to explore the relationship between cognitive frailty and the other types of frailty in each sample. RESULTS: The prevalence of cognitive frailty increased along with the degree of objective cognitive impairment in the 3 samples (range 35.1-80.9%), while its co-occurrence with (one of) the other types of frailty was most frequent in the frail and community samples. Regarding its relationship with the other domains, cognitive frailty was positively associated with psychological frailty's subdomain mood disorder symptoms in all 3 samples (p ≤ 0.01), while there was no significant association with environmental frailty and social loneliness. The associations between cognitive frailty and the other types of frailty differed between the samples. CONCLUSION: Psychological and cognitive frailty are strongly associated, irrespective of the objective degree of cognitive impairment. In addition, it is shown that cognitive frailty can occur independently from the other frailty domains, including physical frailty, and therefore it can be seen as a distinct concept.

Concordances and differences between a unidimensional and multidimensional assessment of frailty: a cross-sectional study.

BACKGROUND: Many instruments to identify frail older people have been developed. One of the consequences is that the prevalence rates of frailty vary widely dependent on the instrument selected. The aims of this study were 1) to examine the concordances and differences between a unidimensional and multidimensional assessment of frailty, 2) to assess to what extent the characteristics of a 'frail sample' differ depending on the selected frailty measurement because 'being frail' is used in many studies as an inclusion criterion. METHOD: A cross-sectional study was conducted among 196 community-dwelling older adults (≥60 years), which were selected from the census records. Unidimensional frailty was operationalized according to the Fried Phenotype (FP) and multidimensional frailty was measured with the Comprehensive Frailty Assessment Instrument (CFAI). The concordances and differences were examined by prevalence, correlations, observed agreement and Kappa values. Differences between sample characteristics (e.g., age, physical activity, life satisfaction) were investigated with ANOVA and Kruskall-Wallis test. RESULTS: The mean age was 72.74 (SD 8.04) and 48.98% was male. According to the FP 23.59% was not-frail, 56.92% pre-frail and 19.49% frail. According to the CFAI, 44.33% was no-to-low frail, 37.63% was mild frail and 18.04% was high frail. The correlation between FP and the CFAI was r = 0.46 and the observed agreement was 52.85%. The Kappa value was κ = 0.35 (quadratic κ = 0.45). In total, 11.92% of the participants were frail according to both measurements, 7.77% was solely frail according to the FP and 6.21% was solely frail according to the CFAI. The 'frail sample respondents' according to the FP had higher levels of life satisfaction and net income, but performed less physical activities in comparison to high frail people according to the CFAI. CONCLUSION: The present study shows that the FP and CFAI partly measure the same 'frailty-construct', although differences were found for instance in the prevalence of frailty and the composition of the 'frail participants'. Since 'being frail' is an inclusion criterion in many studies, researchers must be aware that the choice of the frailty measurement has an impact on both the estimates of frailty prevalence and the characteristics of the selected sample.

18F-FDG PET, the early phases and the delivery rate of 18F-AV45 PET as proxies of cerebral blood flow in Alzheimer's disease: Validation against 15O-H2O PET.

INTRODUCTION: Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-ß deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18F-florbetapir (eAV45), the 18F-AV45 delivery rate (R1), and 18F-FDG against 15O-H2O PET and assess how they change with disease severity. METHODS: This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed. RESULTS: FDG standardized uptake value ratio, eAV45 (0-2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H2O PET (regional Pearson r = 0.54-0.82, 0.70-0.94, and 0.65-0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36-0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG. DISCUSSION: R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD.

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort.

INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. RESULTS: Eight metabolites were associated with amyloid ß and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. DISCUSSION: PFAMs have been found increased and associated with amyloid ß burden in CSF and clinical measures.

CFAI-Plus: Adding cognitive frailty as a new domain to the comprehensive frailty assessment instrument.

OBJECTIVES: Cognitive frailty is characterized by the presence of cognitive impairment in exclusion of dementia. In line with other frailty domains, cognitive frailty is associated with negative outcomes. The Comprehensive Frailty Assessment Instrument (CFAI) measures 4 domains of frailty, namely physical, psychological, social, and environmental frailty. The absence of cognitive frailty is a limitation. METHOD: An expert panel selected 6 questions from the Informant Questionnaire on Cognitive Decline that were, together with the CFAI and the Montreal cognitive assessment administered to 355 older community dwelling adults (mean age = 77). RESULTS: After multivariate analysis, 2 questions were excluded. All the questions from the original CFAI were implemented in a principal component analysis together with the 4 cognitive questions, showing that the 4 cognitive questions all load on 1 factor, representing the cognitive domain of frailty. By adding the cognitive domain to the CFAI, the reliability of the adapted CFAI (CFAI-Plus), remains good (Cronbach's alpha: .767). CONCLUSIONS: This study showed that cognitive frailty can be added to the CFAI without affecting its good psychometric properties. In the future, the CFAI-Plus needs to be validated in an independent cohort, and the interaction with the other frailty domains needs to be studied.

Randomized controlled trial to evaluate a prevention program for frail community-dwelling older adults: a D-SCOPE protocol.

BACKGROUND: Frail community-dwelling older adults, whom might experience problems regarding physical, cognitive, psychological, social and environmental factors, are at risk for adverse outcomes such as disability, institutionalization and mortality. People in need of help do not always find their way to care and support services and are left undetected. The aim of the D-SCOPE project is to detect frail community-dwelling older adults who previously went unnoticed and to improve their access to care and support. Goal is to increase their frailty-balance, quality of life, meaning in life, life satisfaction, mastery, community inclusion and ageing well in place. METHODS/DESIGN: The study is a prospective, longitudinal randomized four-armed controlled trial with follow-up at 6 months. The study group aims to include 900 community-dwelling older adults aged 60 years and over from 3 municipalities in Flanders (Belgium). While selecting the study group, risk profiles for frailty will be taken into account. Participants will be randomly selected from the census records in each municipality. Data will be collected prospectively at baseline (T0) and at follow-up, 6 months after baseline (T1). At baseline, participants who are at least mild frail on one of the 5 domains of frailty (CFAI-plus) or feel frail based on the subjective assessment of frailty will be randomly assigned to (1) the study group or (2) the control group. A mixed method design with the inclusion of quantitative and qualitative data analyses will be used to evaluate the efficacy and experiences of the detection and prevention program on frailty. DISCUSSION: The study will contribute to an innovative vision concerning the organization of care and support, and a timely and accurate detection and support of community-dwelling older adults at risk for frailty. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, on May 26, 2017, identifier: NCT03168204 .

Detecting frail, older adults and identifying their strengths: results of a mixed-methods study.

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.

[Apathy, depression and cognitive functioning in patients with MCI and dementia]. / De relatie tussen apathie, depressie en cognitief functioneren bij patiënten met MCI en dementie.

BACKGROUND: In dementia, apathy and depression are often seen as one disorder because of the many overlapping symptoms. However, for therapy a correct differentiation is essential. Moreover, apathy and depression are likely both associated with different cognitive deficits and progression of the disease. In this research we give an overview of cognitive domains associated with apathy and depression in MCI patients and report how often both disorders occur in a population sample. METHOD: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to 117 cognitively healthy controls (GC), 97 patients with mild cognitive impairment (MCI) and 50 patients with dementia (DEM). In addition, the Apathy Evaluation Scale clinical version (AES-C) and the Geriatric Depression Scale (GDS) were administered. RESULTS: The number of patients with apathy increased with cognitive decline with respectively 3.4%, 10.4% and 41.5% of patients in the GC, MCI and DEM group. The prevalence of isolated depression was highest in the MCI group (18.8%). Correlation analyses in the MCI group showed that apathy and not depression was associated with a deficit in encoding, attention and global cognitive functioning. CONCLUSION: The prevalence of apathy and depressive symptoms is different in patients with MCI, DEM and GC, and within the MCI group apathy and depression are associated with different cognitive domains.

Identifying frailty risk profiles of home-dwelling older people: focus on sociodemographic and socioeconomic characteristics.

OBJECTIVES: This paper investigates risk profiles of frailty among older people, as these are essential for detecting those individuals at risk for adverse outcomes and to undertake specific preventive actions. Frailty is not only a physical problem, but also refers to emotional, social, and environmental hazards. METHODS: Using data generated from the Belgian Ageing Studies, a cross-sectional study (n = 28,049), we tested a multivariate regression model that included sociodemographic and socioeconomic indicators as well as four dimensions of frailty, for men and women separately. RESULTS: The findings indicated that for both men and women, increased age, having no partner, having moved house in the previous 10 years, having a lower educational level and having a lower household income are risk characteristics for frailty. Moreover, when looking at the different frailty domains, different risk profiles arose, and gender-specific risk characteristics were detected. DISCUSSION: This paper elaborates on practical implications, and formulates a number of future research recommendations to tackle frailty in an aging society. The conclusion demonstrates the necessity for a thorough knowledge of risk profiles of frailty, as this will save both time and money and permit preventive actions to be more individually tailored.

Are depressive symptoms in mild cognitive impairment predictive of conversion to dementia?

BACKGROUND: Depressive symptoms are common in amnestic mild cognitive impairment (aMCI). The association between depressive symptoms and conversion to dementia is not yet clear. This longitudinal study was conducted to ascertain whether depressive symptoms in aMCI patients are predictive of conversion to dementia. METHODS: 35 aMCI patients participated in this study. All participants underwent cognitive testing and were administered the geriatric depression scale (GDS) to determine the presence of depressive symptoms. A score equaling or higher than 11 on the GDS was taken as the cut-off point for presence of significant depressive symptoms. Conversion to dementia was assessed at follow-up visits after 1.5, 4, and 10 years. RESULTS: 31.4% of the patients reported depressive symptoms at baseline. None of the cognitive measures revealed a significant difference at baseline between patients with and without depressive symptoms. After 1.5, 4, and 10 years respectively 6, 14, and 23 patients had converted to dementia. Although the GDS scores at baseline did not predict conversion to dementia, the cognitive measures and more specifically a verbal cued recall task (the memory impairment scale-plus) was a good predictor for conversion. CONCLUSIONS: Based on this dataset, the presence of depressive symptoms in aMCI patients is not predictive of conversion to dementia.

Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies.

BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. METHODS: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. RESULTS: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

Investigating Tissue-Specific Abnormalities in Alzheimer's Disease with Multi-Shell Diffusion MRI.

BACKGROUND: Most studies using diffusion-weighted MRI (DW-MRI) in Alzheimer's disease (AD) have focused their analyses on white matter (WM) microstructural changes using the diffusion (kurtosis) tensor model. Although recent works have addressed some limitations of the tensor model, such as the representation of crossing fibers and partial volume effects with cerebrospinal fluid (CSF), the focus remains in modeling and analyzing the WM. OBJECTIVE: In this work, we present a brain analysis approach for DW-MRI that disentangles multiple tissue compartments as well as micro- and macroscopic effects to investigate differences between groups of subjects in the AD continuum and controls. METHODS: By means of the multi-tissue constrained spherical deconvolution of multi-shell DW-MRI, underlying brain tissue is modeled with a WM fiber orientation distribution function along with the contributions of gray matter (GM) and CSF to the diffusion signal. From this multi-tissue model, a set of measures capturing tissue diffusivity properties and morphology are extracted. Group differences were interrogated following fixel-, voxel-, and tensor-based morphometry approaches while including strong FWE control across multiple comparisons. RESULTS: Abnormalities related to AD stages were detected in WM tracts including the splenium, cingulum, longitudinal fasciculi, and corticospinal tract. Changes in tissue composition were identified, particularly in the medial temporal lobe and superior longitudinal fasciculus. CONCLUSION: This analysis framework constitutes a comprehensive approach allowing simultaneous macro and microscopic assessment of WM, GM, and CSF, from a single DW-MRI dataset.

A search for relevant contextual factors in intervention studies: a stepwise approach with online information.

OBJECTIVE: The 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. DESIGN: Exploratory case study. SETTING: In 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). METHODS: One 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. RESULTS: Three 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. CONCLUSION: The 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.

Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort.

BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD. RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

Validation of replacement questions for slowness and weakness to assess the Fried Phenotype: a cross-sectional study.

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.

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort.

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.