Longitudinal Profiling of Plasma-Derived Glial Extracellular Vesicles in Alzheimer's Disease

Fondazione Policlinico Universitario Agostino Gemelli IRCCS48 enrolled

Overview

This project aims to longitudinally profile plasma-derived GDEVs and plasma biomarkers of neuroinflammation across three stages of the AD continuum (Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Dementia), exploring their association with biomarkers of amyloidopathy, tauopathy and neurodegeneration, cognitive status and clinical outcome over time. Moreover, GDEVs - collected from subjects at different disease stages - will be used to treat human neurons derived from induced pluripotent stem cells (iPSCs) from healthy controls in order to assess the induced differential neurotoxic or priming effects. This dual translational approach may help identify early pathogenic signatures of neuroinflammation and elucidate their role in disease progression.

The primary goal of the project is to longitudinally profile plasma-derived GDEVs and neuroinflammation biomarkers to better understand their role in AD progression and to investigate novel, non-invasive blood-based biomarkers for improved diagnosis, prognosis, and disease monitoring. The study will focus on key stages of the AD continuum, investigating the relationship between neuroinflammation and established indicators of core AD pathology, cognitive decline, and clinical progression over time. An innovative dual translational approach will test the effects of disease-stage-specific GDEVs on healthy human iPSC-derived neurons, assessing their neurotoxic or priming effects and revealing their direct biological impact. This combined approach aims to identify early neuroinflammation signatures and investigate novel diagnostics and therapeutic targets. A multidisciplinary approach will be adopted to achieve the following four objectives: Objective 1: To profile changes in plasma-derived GDEV cargo and neuroinflammation biomarkers across the AD continuum, from cognitively normal individuals to those with SCD-AD, MCI-AD and Dem-AD. Objective 2: To investigate the relationship between GDEVs/neuroinflammation biomarkers and fluid biomarkers of amyloidopathy, tauopathy, and neurodegeneration. Objective 3: To assess their association with clinical and cognitive markers of AD progression, identifying biological profiles predictive of cognitive decline and clinical progression rate. Objective 4: To assess the neurotoxic or priming effects of GDEVs from different disease stages on human iPSC-derived neurons from healthy subjects.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: ALLMin age: 55 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * For Ctrl: Individuals with no subjective or objective cognitive complaints, normal performance on standardized neuropsychological assessments, and normal AD biomarkers. * For SCD-AD: Individuals reporting persistent self-perceived cognitive decline in the absence of objective cognitive impairment on standardized neuropsychological assessments and with preserved functional independence in activities of daily life, with abnormal AD biomarkers * For MCI-AD: Individuals showing evidence of persistent cognitive decline, either self-reported or observed by an informant, with objective cognitive impairment on standardized neuropsychological assessments and with preserved independence in daily activities, with abnormal AD biomarkers * For Dem-AD: Individuals with substantial progressive cognitive impairment affecting multiple domains and/or associated neuropsychiatric symptoms, confirmed by objective cognitive impairment on standardized neuropsychological assessments and a clear functional decline impacting independence, abnormal AD biomarkers * For all subjects: Informed consent form signed by subject or caregiver Exclusion Criteria: * Exclusion criteria will be age \<55 or \>80 years, lack of a reliable study partner, previous or concomitant neurological diseases, major psychiatric disorders, medical conditions potentially able to interfere with cognitive functions, previous participation in experimental studies with amyloid targeting agents, significant systemic inflammatory diseases or use of immunosuppressive medication.

Outcomes

Primary Outcomes

Longitudinal changes

Longitudinal changes in plasma-derived GDEV cargo and neuroinflammation biomarkers across the Alzheimer's disease continuum

Time frame: 24 months

Disease-stage-specific molecular signatures

Identification of disease-stage-specific GDEV molecular signatures associated with progression along the AD continuum

Time frame: 24 months

Secondary Outcomes

Associations between biomarkers

Identification of associations between GDEV/neuroinflammation biomarkers and established fluid biomarkers of amyloidopathy, tauopathy and neurodegeneration

Time frame: 24 months

Relationships with Clinical Measures

Evaluation of the rate of correlations between plasma GDEV profiles and clinical measures of disease severity, including global cognitive performance, domain-specific cognitive decline, functional impairment and clinical staging (evalauted through neuropsychological assessments and clinical scales)

Time frame: 24 months

Predictive Value

Exploration of the predictive value of baseline and longitudinal GDEV/neuroinflammation profiles in predicting clinical progression along the AD continuum

Time frame: 24 months

Neurotoxic or priming effects

Assessment of the prevalence of neurotoxic or priming effects of GDEVs from different disease stages on human iPSC-derived neurons from healthy subjects, comparing the biological effects of GDEVs across disease stages

Time frame: 24 months

Longitudinal Profiling of Plasma-Derived Glial Extracellular Vesicles in Alzheimer's Disease

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts