Alzheimer Disease, Cognitive Impairment, Dementia, Mild Cognitive Impairment, Subjective Cognitive Decline
Conditions
Keywords
Alzheimer's disease, Plasma biomarkers, pTau-181, Abeta42, Abeta40, NfL, GFAP, sTREM2, ApoE, Mild Cognitive Impairment, Subjective Cognitive Decline, Dementia, Blood biomarkers, Diagnostic accuracy, Prognosis
Brief summary
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.
Detailed description
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.
Interventions
PROCEDUREAnnual blood draw for plasma biomarker measurement
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.
Sponsors
IRCCS San Raffaele
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(main study and sub-study): 1. Age greater than or equal to 40 years (patients of childbearing age are admitted). 2. Subjective or objective cognitive complaints, progressive in nature and of suspected neurodegenerative origin. 3. Mini-Mental State Examination (MMSE) score greater than or equal to 18. Additional inclusion criterion for the validation sub-study: 4. Availability of CSF biomarkers for Alzheimer's disease within 6 months of the blood draw.
Exclusion criteria
(main study): 1. Secondary forms of cognitive impairment based on medical history, neurological examination, and neuroimaging findings. 2. Pregnancy or breastfeeding. 3. Rapidly progressive cognitive decline occurring over weeks or months, typically indicative of prion disease, neoplasia, or metabolic disorders. 4. Subjects who require a legal guardian or tutor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to progression to all-cause dementia in MCI patients (primary prognostic endpoint) | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in MMSE score over time | 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. |
| Conversion from MCI to Alzheimer's disease dementia | 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. |
| Longitudinal change in plasma Abeta42/Abeta40 ratio | 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. |
| Longitudinal change in plasma pTau-181 levels | 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. |
| Longitudinal change in plasma NfL levels | 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. |
| Longitudinal change in plasma GFAP levels | 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. |
| Longitudinal change in plasma sTREM2 levels | 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. |
| Longitudinal change in plasma Abeta40 levels | 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. |
| Longitudinal change in plasma Abeta42 levels | 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. |
Countries
Italy
Contacts
CONTACTFederica Agosta, MD
CONTACTGiuseppe Magnani, MD
PRINCIPAL_INVESTIGATORMassimo Filippi, Prof, MD
IRCCS San Raffaele
Outcome results
None listed