Blood Tests for Alzheimer's Disease: Can Plasma Biomarkers Diagnose and Predict Disease Progression (BLAD)
The Diagnostic and Prognostic Role of Plasma Biomarkers in Alzheimer's Disease
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.
調査の概要
状態
詳細な説明
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.
研究の種類
入学 (推定)
連絡先と場所
研究連絡先
- 名前：Federica Agosta, MD
- 電話番号：0226433051
- メール：agosta.federica@hsr.it
研究連絡先のバックアップ
- 名前：Giuseppe Magnani, MD
研究場所
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Milano
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Milan、Milano、イタリア、20132
- 募集
- IRCCS Ospedale San Raffaele - Cognitive Disorders and Dementia Center (CDCD)
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コンタクト：
- Federica Agosta, MD
- 電話番号：0226433051
- メール：agosta.federica@hsr.it
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コンタクト：
- Giuseppe Magnani, MD
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主任研究者：
- Massimo Filippi, Prof, MD
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副調査官：
- Federica Agosta, MD
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副調査官：
- Giuseppe Magnani, MD
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副調査官：
- Giordano Cecchetti, MD
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副調査官：
- Francesca Caso, MD
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副調査官：
- Roberto Santangelo, MD
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副調査官：
- Gioele Spinelli, MD
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副調査官：
- Giulia Rugarli, MD
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副調査官：
- Federico Coraglia, MD
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
サンプリング方法
調査対象母集団
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
コホートと介入
グループ/コホート |
介入・治療 |
|---|---|
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Main Study Cohort
2000 adult patients attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital with subjective or objective cognitive complaints of progressive and suspected neurodegenerative nature.
All patients undergo annual blood sampling for 5 years in addition to standard clinical follow-up.
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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.
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Validation Sub-study Cohort
150 patients from the main cohort who undergo lumbar puncture as part of their routine diagnostic workup and have CSF biomarkers for Alzheimer's disease available within 6 months of blood draw.
Only those with CSF biomarkers confirming a biological diagnosis of Alzheimer's disease continue longitudinal follow-up in the sub-study.
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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.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Time to progression to all-cause dementia in MCI patients (primary prognostic endpoint)
時間枠：Annually from baseline up to 5 years
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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.
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Annually from baseline up to 5 years
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Change in MMSE score over time
時間枠：Annually from baseline up to 5 years
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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.
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Annually from baseline up to 5 years
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Conversion from MCI to Alzheimer's disease dementia
時間枠：Annually from baseline up to 5 years
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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.
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Annually from baseline up to 5 years
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Longitudinal change in plasma Abeta42/Abeta40 ratio
時間枠：Annually from baseline up to 5 years
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Change over time in the plasma Abeta42/Abeta40 ratio, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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Longitudinal change in plasma pTau-181 levels
時間枠：Annually from baseline up to 5 years
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Change over time in plasma phosphorylated tau 181 (pTau-181) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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Longitudinal change in plasma NfL levels
時間枠：Annually from baseline up to 5 years
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Change over time in plasma neurofilament light chain (NfL) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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Longitudinal change in plasma GFAP levels
時間枠：Annually from baseline up to 5 years
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Change over time in plasma Glial Fibrillary Acidic Protein (GFAP) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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Longitudinal change in plasma sTREM2 levels
時間枠：Annually from baseline up to 5 years
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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.
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Annually from baseline up to 5 years
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Longitudinal change in plasma Abeta40 levels
時間枠：Annually from baseline up to 5 years
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Change over time in plasma beta-amyloid 40 (Abeta40) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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Longitudinal change in plasma Abeta42 levels
時間枠：Annually from baseline up to 5 years
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Change over time in plasma beta-amyloid 42 (Abeta42) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Diagnostic accuracy of plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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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.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Diagnostic accuracy of plasma pTau-181 vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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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.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Diagnostic accuracy of plasma NfL vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Area under the ROC curve (AUC), sensitivity, and specificity of plasma NfL in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Diagnostic accuracy of plasma GFAP vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Area under the ROC curve (AUC), sensitivity, and specificity of plasma GFAP in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Optimal diagnostic cut-off values for plasma Abeta40 vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for Abeta40 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Optimal diagnostic cut-off values for plasma Abeta42 vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for Abeta42 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Optimal diagnostic cut-off values for plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for Abeta42/Abeta40 ratio biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Optimal diagnostic cut-off values for plasma pTau-181 vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for pTau-181 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
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Optimal diagnostic cut-off values for plasma NfL vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for NfL biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
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Optimal diagnostic cut-off values for plasma GFAP vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for GFAP biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
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Optimal diagnostic cut-off values for plasma sTREM2 vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for sTREM2 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Optimal diagnostic cut-off values for plasma ApoE vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for ApoE biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Optimal diagnostic cut-off values for plasma ApoE4 vs CSF gold standard (sub-study)
時間枠：Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for ApoE4 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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協力者と研究者
スポンサー
捜査官
- 主任研究者：Massimo Filippi, Prof, MD、IRCCS San Raffaele
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
その他の研究ID番号
- BLAD
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