Early Alzheimer’s Detection with the PrecivityAD™ Blood Test

[madman]

What is the PrecivityAD™ Blood Test?

PrecivityAD™ Blood Test for Early Alzheimer’s Detection​

Executive Summary​

The PrecivityAD™ blood test, developed by C2N Diagnostics, represents a significant advancement in the early detection and management of Alzheimer’s Disease (AD). Utilizing high-precision mass spectrometry, the test identifies specific biomarkers in the blood to determine the likelihood of amyloid plaques in the brain—a definitive pathological hallmark of AD.

Key findings from clinical research and real-world application indicate that the test:

• Addresses Critical Bottlenecks: Provides a high-throughput alternative to Amyloid PET scans and Cerebrospinal Fluid (CSF) analysis, which are limited by cost, geographic availability, and invasiveness.
• Delivers High Accuracy: Achieves an Area Under the Curve (AUC) of 0.88, with a 92% sensitivity for identifying amyloid pathology.
• Influences Clinical Decision-Making: Significantly increases physician confidence in diagnosis and leads to more appropriate management, including the reduction of unnecessary AD medications in patients who test negative for amyloid.
• Identifies Early Pathology: Evidence suggests the blood test can detect biochemical changes in amyloid levels before they are visible on a traditional PET scan.

The Clinical and Systemic Challenge​

The Growing Burden of Cognitive Impairment​

Alzheimer’s Disease and Mild Cognitive Impairment (MCI) represent a major global health crisis. In the United States alone:

• Prevalence: 6 million Americans have clinical AD or MCI.
• Progression: There is a roughly 10% annual conversion rate from MCI to overt Alzheimer’s.
• Scale: Approximately 15 million Americans with MCI could benefit from early diagnostic testing.
• Global Impact: Dementia affects roughly 47 million people worldwide.

The Diagnostic Gap​

A critical distinction exists between dementia (a clinical manifestation of symptoms) and Alzheimer’s Disease (the underlying pathological cause). AD accounts for 60% to 70% of all dementia cases. Without precise biomarker testing, clinicians often rely on "wait and see" approaches because causes of cognitive impairment are frequently multifactorial, particularly in early stages. Currently, less than 5% of people with cognitive impairment undergo objective AD biomarker testing.

System Preparedness and Bottlenecks​

Simulation analyses indicate that the healthcare system is ill-prepared for the introduction of disease-modifying therapies.

• Specialist Shortages: There is a significant shortage of neurologists and memory care specialists.
• Wait Times: Projections suggest a 2.1-year wait time for patients to see a specialist and receive a precise diagnosis if a new therapy were available today.
• Access Barriers: 60 million Americans lack access to specialized facilities capable of performing Amyloid PET scans.

Technical Methodology: The PrecivityAD™ Test​

The PrecivityAD™ test is a mass spectrometry-based assay designed to quantify specific peptides and genetic markers to calculate an Amyloid Probability Score (APS).

Primary Analytes and Markers​

Marker	Function and Significance
Amyloid Beta 42/40 Ratio	Measures the concentration of Aβ42 and Aβ40. A lower ratio indicates that Aβ42 is being "sequestered" into plaques in the brain, reducing its presence in the soluble pool (blood).
APOE Status	Identifies specific peptides to infer the Apolipoprotein E (APOE) allele status (ε2, ε3, or ε4).
Age	Incorporated into the algorithm as a known risk factor for amyloid accumulation.

The Role of APOE​

APOE4 is the strongest genetic risk factor for sporadic late-onset AD. The risk is amplified based on the number of alleles:

• One Allele: 2x to 4x increased risk.
• Two Alleles ("Double Dose"): 8x to 12x increased risk. Conversely, the APOE2 allele is considered protective against the disease.

The Amyloid Probability Score (APS)​

The test uses a logistic regression model to produce a score from 0 to 100.

• High Score (Close to 100): High likelihood of amyloid pathology.
• Low Score (Close to 0): High negative predictive value, effectively ruling out AD. As noted in the source: "If a person doesn't have amyloid, they don't have Alzheimer's disease."

Clinical Validation and Performance​

Accuracy and Sensitivity​

Validation studies involving 686 individuals (average age 73) compared the blood test against the reference standard of Amyloid PET scans.

• AUC Performance: 0.88 when combining the Aβ 42/40 ratio, APOE status, and age.
• Sensitivity: 92%.
• Specificity: 77%.
• Positive Predictive Value (PPV): 86%.
• Negative Predictive Value (NPV): 86%.

Detection of Pre-PET Pathology​

Research indicates that the blood test may be more sensitive than PET imaging in the earliest stages of disease. Patients who test "positive" via the blood test but "negative" via PET scan have a high hazard ratio for converting to PET-positive status over time. This suggests the blood test captures biochemical signals that precede visual observations on a scan.

Real-World Clinical Utility​

The Quip 1 Study evaluated how the test impacts physician behavior and patient care. The results demonstrated a marked shift in clinical confidence:

• Diagnostic Confidence: For patients with high APS scores, physician confidence in an AD diagnosis rose from 71% to 98%.
• Correction of Misdiagnosis: For patients with low APS scores, the likelihood of an AD diagnosis dropped from 61% (pre-test) to 15% (post-test).
• Medication Management: Utilization of AD-specific medications decreased from 50% to 22% in the low-score group, preventing unnecessary treatment for patients without the disease.
• Reduction in Secondary Testing: The availability of the blood test led to a significant decrease in the demand for more invasive CSF lumbar punctures and expensive PET scans.

Regulatory Status and Future Outlook​

Current Status​

• Accreditation: Offered under CAP/CLIA certification.
• Regulatory Designations: Holds a CE Mark and an FDA Breakthrough Device designation.
• Quality Standards: ISO 13485 compliant.
• Intended Use: The test is not a standalone screening tool for asymptomatic individuals. It is intended for patients already experiencing cognitive impairment who are being evaluated by a clinician for AD.

Future Initiatives​

C2N Diagnostics is expanding its focus beyond amyloid to provide a more comprehensive brain biomarker profile:

• Tau Multi-Analyte Assay: A new mass spectrometry-based assay for tau proteins is currently being introduced and validated.
• Global Health Preparedness: A flagship initiative is underway involving 4,000 people across six countries (Brazil, Jamaica, Japan, Mexico, Scotland, and the U.S.) to evaluate how blood-based biomarkers can improve health system readiness for Alzheimer’s care.

Measuring tau and Yau phosphorylation by mass spectrometry

Join Joel B. Braunstein, MD, MBA (CEO, C2N Diagnostics) at ADLM (formerly AACC) 2022 for a Thermo Fisher Scientific sponsored workshop titled "Diagnostic Performance and Real-World Clinical Experience with the PrecivityAD™ Blood Test to Aid in Early Diagnosis of Alzheimer’s Disease".

 

[madman]

PrecivityAD®

precivityad.com