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.
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.
Availability of CSF biomarkers for Alzheimer's disease within 6 months of the blood draw.
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.
Adult patients attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital, Milan, Italy, presenting with subjective or objective cognitive complaints of progressive and suspected neurodegenerative nature.
Cohort
Prospective
Annual blood draw for plasma biomarker measurement
Procedure/SurgeryA 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.
Time to progression to all-cause dementia in MCI patients (primary prognostic endpoint)
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.
Change in MMSE score over time
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.
Conversion from MCI to Alzheimer's disease dementia
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.
Longitudinal change in plasma Abeta42/Abeta40 ratio
Change over time in the plasma Abeta42/Abeta40 ratio, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
Longitudinal change in plasma pTau-181 levels
Change over time in plasma phosphorylated tau 181 (pTau-181) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
Diagnostic accuracy of plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)
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.
Diagnostic accuracy of plasma pTau-181 vs CSF gold standard (sub-study)
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.
Diagnostic accuracy of plasma NfL vs CSF gold standard (sub-study)
Area under the ROC curve (AUC), sensitivity, and specificity of plasma NfL in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
Diagnostic accuracy of plasma GFAP vs CSF gold standard (sub-study)
Area under the ROC curve (AUC), sensitivity, and specificity of plasma GFAP in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
Click on the lead sponsor to view all of their trials.
