CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease.

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 [Aß]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.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Unlocking Preclinical Alzheimer's: A Multi-Year Label-Free In Vitro Raman Spectroscopy Study Empowered by Chemometrics.

Alzheimer's disease is a progressive neurodegenerative disorder, the early detection of which is crucial for timely intervention and enrollment in clinical trials. However, the preclinical diagnosis of Alzheimer's encounters difficulties with gold-standard methods. The current definitive diagnosis of Alzheimer's still relies on expensive instrumentation and post-mortem histological examinations. Here, we explore label-free Raman spectroscopy with machine learning as an alternative to preclinical Alzheimer's diagnosis. A special feature of this study is the inclusion of patient samples from different cohorts, sampled and measured in different years. To develop reliable classification models, partial least squares discriminant analysis in combination with variable selection methods identified discriminative molecules, including nucleic acids, amino acids, proteins, and carbohydrates such as taurine/hypotaurine and guanine, when applied to Raman spectra taken from dried samples of cerebrospinal fluid. The robustness of the model is remarkable, as the discriminative molecules could be identified in different cohorts and years. A unified model notably classifies preclinical Alzheimer's, which is particularly surprising because of Raman spectroscopy's high sensitivity regarding different measurement conditions. The presented results demonstrate the capability of Raman spectroscopy to detect preclinical Alzheimer's disease for the first time and offer invaluable opportunities for future clinical applications and diagnostic methods.

GOIZ ZAINDU study: a FINGER-like multidomain lifestyle intervention feasibility randomized trial to prevent dementia in Southern Europe.

BACKGROUND: GOIZ ZAINDU ("caring early" in Basque) is a pilot study to adapt the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) methodology to the Basque population and evaluate the feasibility and adherence to a FINGER-like multidomain intervention program. Additional aims included the assessment of efficacy on cognition and data collection to design a large efficacy trial. METHOD: GOIZ ZAINDU is a 1-year, randomized, controlled trial of a multidomain intervention in persons aged 60+ years, with Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score ≥ 6, no diagnosis of dementia, and below-than-expected performance in at least one of three cognitive screening tests. Randomization to a multidomain intervention (MD-Int) or regular health advice (RHA) was stratified by sex, age (>/≤ 75), and cognitive status (mild cognitive impairment (MCI)/normal cognition). MD-Int included cardiovascular risk factor control, nutritional counseling, physical activity, and cognitive training. The primary outcomes were retention rate and adherence to the intervention program. Exploratory cognitive outcomes included changes in the Neuropsychological Test Battery z-scores. Analyses were performed according to the intention to treat. RESULTS: One hundred twenty-five participants were recruited (mean age: 75.64 (± 6.46); 58% women). The MD-Int (n = 61) and RHA (n = 64) groups were balanced in terms of their demographics and cognition. Fifty-two (85%) participants from the RHA group and 56 (88%) from the MD-Int group completed the study. More than 70% of the participants had high overall adherence to the intervention activities. The risk of cognitive decline was higher in the RHA group than in the MD-Int group in terms of executive function (p =.019) and processing speed scores (p =.026). CONCLUSIONS: The GOIZ-ZAINDU study proved that the FINGER methodology is adaptable and feasible in a different socio-cultural environment. The exploratory efficacy results showed a lower risk of decline in executive function and processing speed in the intervention group. These results support the design of a large-scale efficacy trial. TRIAL REGISTRATION: GOIZ ZAINDU feasibility trial was approved and registered by the Euskadi Drug Research Ethics Committee (ID: PI2017134) on 23 January 2018. Retrospectively registered in ClinicalTrials.gov (NCT06163716) on 8 December 2023.

Alzheimer's Disease and Small Vessel Disease Differentially Affect White Matter Microstructure.

OBJECTIVE: Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non-invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE-ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non-demented older adults. METHODS: Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid ß1-42 and p-Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow-up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed-effects model for each tract. RESULTS: AD pathology, APOE-ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE-ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. INTERPRETATION: Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

INTRODUCTION: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from EMIF-AD MBD and ADNI. For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these groups. DISCUSSION: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

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.

Paired plasma lipidomics and proteomics analysis in the conversion from mild cognitive impairment to Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition for which there is currently no available medication that can stop its progression. Previous studies suggest that mild cognitive impairment (MCI) is a phase that precedes the disease. Therefore, a better understanding of the molecular mechanisms behind MCI conversion to AD is needed. METHOD: Here, we propose a machine learning-based approach to detect the key metabolites and proteins involved in MCI progression to AD using data from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Study. Proteins and metabolites were evaluated separately in multiclass models (controls, MCI and AD) and together in MCI conversion models (MCI stable vs converter). Only features selected as relevant by 3/4 algorithms proposed were kept for downstream analysis. RESULTS: Multiclass models of metabolites highlighted nine features further validated in an independent cohort (0.726 mean balanced accuracy). Among these features, one metabolite, oleamide, was selected by all the algorithms. Further in-vitro experiments in rodents showed that disease-associated microglia excreted oleamide in vesicles. Multiclass models of proteins stood out with nine features, validated in an independent cohort (0.720 mean balanced accuracy). However, none of the proteins was selected by all the algorithms. Besides, to distinguish between MCI stable and converters, 14 key features were selected (0.872 AUC), including tTau, alpha-synuclein (SNCA), junctophilin-3 (JPH3), properdin (CFP) and peptidase inhibitor 15 (PI15) among others. CONCLUSIONS: This omics integration approach highlighted a set of molecules associated with MCI conversion important in neuronal and glia inflammation pathways.

Mapa de la enfermedad de Alzheimer y otras demencias en España. Proyecto MapEA / Map of Alzheimer's disease and other dementias in Spain. MapEA Project

Introducción. En el contexto actual de aumento de la esperanza de vida y progresivo envejecimiento de la población cabe esperar un incremento muy significativo del número de personas con deterioro cognitivo y demencia. No cabe duda que España se enfrenta a un reto de preocupantes dimensiones sociosanitarias en las próximas décadas. El proyecto «Mapa de la enfermedad de Alzheimer y otras demencias en España» pretende analizar el estado actual de las herramientas de planificación y organización, actividades de prevención y detección temprana, proceso asistencial y recursos específicos disponibles en las comunidades autónomas para la atención y el cuidado de las personas con deterioro cognitivo y demencia, con el objeto de identificar las áreas de mejora y emitir recomendaciones. Metodología. El grupo de trabajo estuvo formado por un Comité Asesor nacional de 5 expertos y los correspondientes Comités de Expertos de cada comunidad autónoma constituidos por profesionales del ámbito de la Neurología, Geriatría, Psiquiatría y Atención Primaria así como representantes de Asociaciones de Familiares de personas con Alzheimer y otras demencias. Se llevaron a cabo reuniones de cada comité local en las que se revisó la situación actual de la atención de acuerdo con el cuestionario guía elaborado por el Comité Asesor. Resultados. Los planes específicos disponibles en España están en su mayoría obsoletos o no se han llegado a implantar. En líneas generales no se llevan a cabo actividades de prevención ni de detección temprana. Hay una gran heterogeneidad de rutas asistenciales de acceso al diagnóstico, tratamiento y seguimiento de la enfermedad y no todas las pruebas diagnósticas están disponibles en las diferentes regiones sanitarias. En general, los recursos disponibles se consideran escasos y poco conocidos. Conclusiones. El estudio Mapa de la enfermedad de Alzheimer y otras demencias en España ha permitido detectar los principales puntos susceptibles de cambio y optimización tanto en gestión, organización y coordinación de los recursos como en información y formación de las personas implicadas. Además, el estudio ha revelado que en España se dan las condiciones necesarias de disponibilidad de profesionales implicados y capacitados y de existencia de potenciales recursos diagnósticos y asistenciales para encarar este margen de mejora mediante la aprobación y el desarrollo de un Plan Nacional de Alzheimer, respaldado por un compromiso de voluntades políticas profundo y veraz, y que será el marco idóneo para el desarrollo de estas posibilidades (AU)

Introduction. In the current context of increased life expectancy and progressive aging of the population a very significant increase in the number of people with cognitive impairment and dementia is expected. Consequently, Spain will face an enormous social and health problem in the next decades. The Mapa de la enfermedad de Alzheimer y otras demencias en España project aims to analyse plans, prevention and early diagnosis activities, process of care and resources available across the 17 Spanish regions for the management of cognitive impairment and dementia in order to identify improvement areas, as well as to provide a list of recommendations. Methods. The working group consisted of an Advisory Committee of 5 national experts and a Committee of Experts from each region made up of professionals in the field of Neurology, Geriatrics, Psychiatry, and Primary Care, as well as representatives of Family Associations of People with Alzheimer's and other dementias. The Expert Committee of each region held meetings in which the current situation of care was reviewed. Results. Plans available in Spain for dementia management are mostly obsolete or have not been implemented. Prevention and early detection activities are generally not carried out. There is great variability of care process that patients must follow for the diagnosis, treatment, and follow-up of the disease, and not all diagnostic test are available in different regions. In general, resources are considered scarce and unknown. Conclusions. The Mapa de la enfermedad de Alzheimer y otras demencias en España study has been able to detect the main points that require changing n the management, organisation, and coordination of resources, such as information and training of the personnel involved. Furthermore, the study has revealed that, in Spain, the necessary conditions are in place in Spain, such as the availability and capacity of professionals involved, as well as there being the potential diagnostic and health care resources to address this room for improvement through the approval and development of a National Alzheimer's Plan, supported by a deep and truthful political commitment, which will be the ideal framework for the development of these possibilities (AU)

Efectos del tratamiento combinado de fármaco más estimulación cognitiva en la demencia moderada: seguimiento de dos años / Effects of combined pharmacologic and cognitive treatment in the progression of moderate dementia: a two-year follow-up

Objetivos: estudiar la eficacia de un tratamiento combinado (fármaco anticolinesterásico y entrenamiento cognitivo) en los procesos cognitivos de pacientes con demencia moderada después de 2 años de tratamiento. Material y métodos: cincuenta pacientes, 64,0% mujeres, edad media ± desviación estándar de 77,9 ± 6,2 años, diagnosticados de enfermedad de Alzheimer (EA) en estadio FAST ≥ 4. Asignación aleatorizada, ciega, a 4 grupos de tratamiento: grupo 1 (n = 12 individuos) recibió estimulación cognitiva; grupo 2 (n = 13), tratamiento farmacológico; grupo 3 (n = 12), tratamiento combinado (fármaco y estimulación cognitiva), y grupo 4 (n = 13), sin tratamiento. La eficacia terapéutica se evaluó, al cabo de uno y 2 años, mediante las escalas Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale (ADAS-Cog) y Functional Staging of Dementia of the Alzheimer's Type (FAST). Se realiza comparación entre los resultados obtenidos en los distintos grupos tras el seguimiento (ANOVA para medidas repetidas), nivel de significación p < 0,05. Resultados: los grupos de tratamiento mostraron cambios significativamente positivos frente al declive del grupo control para todas las escalas estudiadas al cabo de un año (p < 0,0001). El efecto deletéreo del tratamiento al cabo de 2 años es homogéneo en estos grupos, aunque en el grupo 3 (tratamiento combinado) se aprecia una tendencia al enlentecimiento de su deterioro funcional frente al resto (p no significativa). Conclusión: el tratamiento combinado (farmacológico y cognitivo) en la EA en estadio moderado produce efectos beneficiosos durante el primer año del tratamiento y mitiga el deterioro que se produce al segundo año en relación con otras formas de tratamiento

Objectives: to study the efficacy of combined treatment (anticholinesterase drugs and cognitive stimulation) in improving cognitive function in patients with moderate dementia after a 2-year follow-up. Material and methods: fifty patients (64.0% women, mean age 77.9 years [SD 6.2]) diagnosed with Alzheimer's disease (AD) in functional assessment stage (FAST) ≥ 4 were included. The patients were randomly assigned to 4 treatment groups: group 1 (n = 12) received cognitive stimulation; group 2 (n = 13) received drug therapy; group 3 (n = 12) received combined therapy (drug therapy plus cognitive stimulation), and group 4 (n = 13) received no treatment. The evaluator was blind to treatment allocation. Therapeutic efficacy was evaluated after 1 and 2 years through the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale (ADAS-Cog) and FAST. The results obtained in the distinct study groups were compared after follow-up (repeated measures ANOVA). Statistical significance was set at p < 0.05. Results: at the end of 1 year, the two treatment groups showed significant positive changes compared with cognitive decline in the control group in all the scales studied (p < 0.0001). After 2 years, deterioration was homogeneous in these groups, although group 3 (combined therapy) showed a nonsignificant tendency toward slowing of functional deterioration compared with the remaining groups. Conclusion: combined treatment (pharmacological and cognitive) in moderate-stage AD produces beneficial effects during the first year of treatment and mitigates the deterioration produced in the second year in comparison with other forms of treatment

Educación, reserva cerebral y factores de riesgo de demencia y enfermedad de Alzheimer / Educational attainment, brain reserve, and risk factors for dementia and Alzheimer disease

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Estrógenos y enfermedad de Alzheimer: bases, promesas y realidades / Estrogens and Alzheimer disease: fundamentals, promises and truths

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