Skip to main content
OpenTrials
Recruiting

NCT Number: NCT07717567

Blood Tests for Alzheimer's Disease: Can Plasma Biomarkers Diagnose and Predict Disease Progression

BLAD is a prospective, monocentric, observational epidemiological study with an additional procedure (annual blood draw) evaluating the diagnostic and prognostic performance of plasma biomarkers for Alzheimer's disease (AD) in a large cohort of patients attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital, Milan, Italy.

2000 patients will be enrolled and followed annually for 5 years. A validation sub-study (150 patients) will compare plasma biomarkers against CSF biomarkers as the gold standard.

The study aims to establish plasma biomarkers as a less invasive and more cost-effective alternative to CSF analysis and amyloid-PET for the diagnosis and prognosis of AD.

Recruiting

Interested in participating?

Request Info

Key information

Conditions

Alzheimer Disease Brain Diseases Central Nervous System Diseases Cognition Disorders Cognitive Dysfunction Cognitive Impairment Dementia Mental Disorders Mild Cognitive Impairment Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Subjective Cognitive Decline Tauopathies

Age range

40 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

IRCCS Ospedale San Raffaele - Cognitive Disorders and Dementia Center (CDCD)

Milan, Milano, 20132, Italy

Location status: Recruiting

Location contact

Federica Agosta, MD

CONTACT

[email protected]

0226433051

Federica Agosta, MD

SUB_INVESTIGATOR

Federico Coraglia, MD

SUB_INVESTIGATOR

Francesca Caso, MD

SUB_INVESTIGATOR

Gioele Spinelli, MD

SUB_INVESTIGATOR

Giordano Cecchetti, MD

SUB_INVESTIGATOR

Giulia Rugarli, MD

SUB_INVESTIGATOR

Giuseppe Magnani, MD

CONTACT

Giuseppe Magnani, MD

SUB_INVESTIGATOR

Massimo Filippi, Prof, MD

PRINCIPAL_INVESTIGATOR

Roberto Santangelo, MD

SUB_INVESTIGATOR

About this study

In light of the possible advent of disease-modifying drugs for Alzheimer's disease (AD), reliable biomarkers have been developed in recent years to define the presence of AD pathology at the brain level. The current biological gold standards are cerebrospinal fluid (CSF) biomarkers (CSF-Abeta40, CSF-Abeta42, CSF-pTau, CSF-NfL) and amyloid-PET. Both methods have excellent diagnostic properties but are costly and invasive, limiting their use outside of highly specialized centers.

Plasma biomarkers (plasma-Abeta40, plasma-Abeta42, plasma-pTau-181, plasma-NfL, plasma-ApoE, plasma-ApoE4, plasma-GFAP, plasma-sTREM2, and other plasma neurodegeneration biomarkers) represent a potentially less invasive and more economically accessible alternative. Recent studies have shown that plasma biomarkers can differentiate AD from other neurodegenerative disorders with accuracy comparable to CSF and PET, detect AD pathology in MCI patients, and predict future development of AD dementia in patients with SCD or MCI. However, more research is needed before their widespread use in clinical practice.

The BLAD study is designed as a monocentric, prospective, observational epidemiological study with an additional procedure (annual blood draw for 5 years) and a diagnostic accuracy sub-study (not device-based).

Patients will be recruited among those attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital during routine clinical practice. All enrolled patients will undergo annual blood sampling for 5 years in addition to standard clinical assessments.

A sub-population of 150 patients who undergo lumbar puncture as part of their routine diagnostic workup will enter the validation sub-study. Only those whose CSF biomarkers confirm a biological diagnosis of Alzheimer's disease will continue follow-up; others will exit the sub-study.

The equipment for plasma biomarker measurement (CE-marked medical device) and laboratory kits will be provided on free loan by Fujirebio. No clinical or laboratory data will be shared with Fujirebio.

Statistical analyses will include: log-rank test to compare time to AD development between groups above and below the biomarker threshold; linear stepwise regression models, linear mixed-effects models, and multivariable Cox models to assess the prognostic value of plasma biomarkers; longitudinal generalized linear models for repeated measures or Wilcoxon test to assess biomarker dynamics over time. For the validation sub-study, ROC curve analysis will be performed to assess accuracy, sensitivity, and specificity of plasma biomarkers against CSF gold standard.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

(main study and sub-study):

  • Age greater than or equal to 40 years (patients of childbearing age are admitted).
  • Subjective or objective cognitive complaints, progressive in nature and of suspected neurodegenerative origin.
  • Mini-Mental State Examination (MMSE) score greater than or equal to 18.

Additional inclusion criterion for the validation sub-study:

  • Availability of CSF biomarkers for Alzheimer's disease within 6 months of the blood draw.

Exclusion criteria

(main study):

  • Secondary forms of cognitive impairment based on medical history, neurological examination, and neuroimaging findings.
  • Pregnancy or breastfeeding.
  • Rapidly progressive cognitive decline occurring over weeks or months, typically indicative of prion disease, neoplasia, or metabolic disorders.
  • Subjects who require a legal guardian or tutor.

Exclusion criteria

(validation sub-study):

  • Secondary forms of cognitive impairment based on medical history, neurological examination, and neuroimaging findings.
  • Pregnancy.
  • Rapidly progressive cognitive decline occurring over weeks or months, typically indicative of prion disease, neoplasia, or metabolic disorders.
  • Subjects who are unable to give informed consent and require a legal guardian or tutor.

Treatment and study plan

Annual blood draw for plasma biomarker measurement

Procedure

A blood sample is collected once per year for 5 years (additional procedure beyond standard clinical care) for measurement of plasma biomarkers including: Abeta40, Abeta42, Abeta42/Abeta40 ratio, pTau-181, NfL, ApoE, ApoE4, GFAP, sTREM2, and other plasma neurodegeneration biomarkers. Blood draw is a routine clinical procedure with no specific contraindications. The only possible side effect is local hematoma at the puncture site. Plasma biomarker measurement is performed using a CE-marked medical device (Fujirebio, provided on free loan). Results do not modify the patient's standard diagnostic and therapeutic pathway.

Primary outcomes

  1. Time to progression to all-cause dementia in MCI patients (primary prognostic endpoint)

    Time frame: Annually from baseline up to 5 years

    Time to clinical progression to all-cause dementia in patients with Mild Cognitive Impairment (MCI) at baseline, assessed using multivariable Cox proportional hazards models. For each plasma biomarker, patients are divided into two groups (above/below the median) and compared using the log-rank test (cause-specific hazard). The study has greater than 95% power to detect a Hazard Ratio of 2 and approximately 75-80% power for HR of 1.5.

Secondary outcomes

  1. Change in MMSE score over time

    Time frame: Annually from baseline up to 5 years

    Change over time in Mini-Mental State Examination (MMSE) score as a measure of cognitive progression. A decrease of 5 or more points is considered clinically significant progression of cognitive impairment due to AD.

  2. Conversion from MCI to Alzheimer's disease dementia

    Time frame: Annually from baseline up to 5 years

    Rate of clinical conversion from Mild Cognitive Impairment (MCI) to Alzheimer's disease dementia over the 5-year follow-up period, assessed at each annual visit.

  3. Longitudinal change in plasma Abeta42/Abeta40 ratio

    Time frame: Annually from baseline up to 5 years

    Change over time in the plasma Abeta42/Abeta40 ratio, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

  4. Longitudinal change in plasma pTau-181 levels

    Time frame: Annually from baseline up to 5 years

    Change over time in plasma phosphorylated tau 181 (pTau-181) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

  5. Longitudinal change in plasma NfL levels

    Time frame: Annually from baseline up to 5 years

    Change over time in plasma neurofilament light chain (NfL) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

  6. Longitudinal change in plasma GFAP levels

    Time frame: Annually from baseline up to 5 years

    Change over time in plasma Glial Fibrillary Acidic Protein (GFAP) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

  7. Longitudinal change in plasma sTREM2 levels

    Time frame: Annually from baseline up to 5 years

    Change over time in plasma soluble Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

  8. Longitudinal change in plasma Abeta40 levels

    Time frame: Annually from baseline up to 5 years

    Change over time in plasma beta-amyloid 40 (Abeta40) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

  9. Longitudinal change in plasma Abeta42 levels

    Time frame: Annually from baseline up to 5 years

    Change over time in plasma beta-amyloid 42 (Abeta42) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.

Other outcomes

  1. Diagnostic accuracy of plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Area under the ROC curve (AUC), sensitivity, and specificity of plasma Abeta42/Abeta40 ratio in diagnosing Alzheimer's disease, using CSF biomarkers (CSF-Abeta40, CSF-Abeta42, CSF-pTau, CSF-NfL) as the gold standard. Patients are classified as AD or non-AD based on CSF results. An AUC of at least 0.80 is expected, with greater than 95% power to reject H0: AUC=0.50 at alpha=0.05.

  2. Diagnostic accuracy of plasma pTau-181 vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Area under the ROC curve (AUC), sensitivity, and specificity of plasma pTau-181 in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.

  3. Diagnostic accuracy of plasma NfL vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Area under the ROC curve (AUC), sensitivity, and specificity of plasma NfL in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.

  4. Diagnostic accuracy of plasma GFAP vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Area under the ROC curve (AUC), sensitivity, and specificity of plasma GFAP in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.

  5. Optimal diagnostic cut-off values for plasma Abeta40 vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for Abeta40 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  6. Optimal diagnostic cut-off values for plasma Abeta42 vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for Abeta42 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  7. Optimal diagnostic cut-off values for plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for Abeta42/Abeta40 ratio biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  8. Optimal diagnostic cut-off values for plasma pTau-181 vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for pTau-181 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  9. Optimal diagnostic cut-off values for plasma NfL vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for NfL biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  10. Optimal diagnostic cut-off values for plasma GFAP vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for GFAP biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  11. Optimal diagnostic cut-off values for plasma sTREM2 vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for sTREM2 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  12. Optimal diagnostic cut-off values for plasma ApoE vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for ApoE biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

  13. Optimal diagnostic cut-off values for plasma ApoE4 vs CSF gold standard (sub-study)

    Time frame: Baseline (at time of lumbar puncture, within 6 months of blood draw)

    Determination of the optimal diagnostic cut-off values for ApoE4 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.

Study contacts

Contact information is provided by the study sponsor or research team.

Federica Agosta, MD

CONTACT

[email protected]

0226433051

Giuseppe Magnani, MD

CONTACT

Sponsors and collaborators

Lead sponsor

IRCCS San Raffaele

Other

Registry information

Official study title

The Diagnostic and Prognostic Role of Plasma Biomarkers in Alzheimer's Disease

Acronym: BLAD

Important dates

Study start
2023
Primary completion
2032
Study completion
2032
First posted
Jul 21, 2026
Registry last updated
Jul 21, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.