Blood Biomarkers in Alzheimer’s Disease
The AD landscape is complex but evolving addressing diagnosis bottlenecks, infrastructure support/access issues, and cost considerations is crucial for improving patient outcomes.
Barriers to address for improving patient outcomes
Diagnosis
- PCPs are not set up for success to provide adequate workup.
- Current cognitive and functional tests have limitations and require repeat testing to detect decline over time.
- Blood biomarkers (BBMs) can address some of these limitations but have had a slow uptake.
Infrastructure
- Hiring and training required personnel needed to carry out all required steps for diagnosis and medication administration (e.g., staff at infusion and MRI centers).
Support/Access
- Patients’ access to HCPs is limited (e.g., geographic location, HCP limited time).
- Caregiver support is essential and is often overlooked when setting up patient appointments.
Cost
- High cost of approved therapies is a barrier to access for patients even though they are most effective and offer cost savings when introduced early.
- Other factors should be considered, such as care partners’ ability to continue working while the patient remains in the earlier stages longer.
On this page, we will provide an overview on diagnosis with a specific focus on BBMs, including the landscape, available tests, accessibility, accuracy of data, and upcoming pipeline and industry trends.
EXECUTIVE SUMMARY – THE BBM SPACE TODAY
Despite rapid expansion in BBM development, significant hurdles remain to reach broad adoption in AD1
Challenges with Current AD Biomarker Tests2,3
- The gold standard for Aβ and tau measurements involves costly and invasive PET and CSF tests.
- There is a need for less invasive and cost-effective alternatives.
BBM tests1,2,4
- Have the potential to address unmet needs because they:
- Limit the number of patients that require a confirmatory PET scan.
- Help with earlier diagnosis of AD.
- Current limitations include:
- Age-dependent accuracy.
- Results influenced by comorbidities such as hypertension or CKD.
Did you know?
Because of the multiple steps in the diagnosis of AD, the average predicted wait time between clinical diagnosis and treatment is 18.6 months4
4.
EXECUTIVE SUMMARY – THE FUTURE BBM LANDSCAPE
Slow adoption of BBM tests is poised to shift, driven by outcomes of combination targets, greater coverage and reimbursement, and increased investments, reflecting growing confidence in BBMs in AD diagnosis.
Testing for multiple targets yields the most promising outcomes
Previous BBM tests examined individual targets. Recent approvals in the market show a shift toward a stronger emphasis on simultaneously assessing various targets (i.e., Aβ and p-tau 217).
Wider insurance coverage and improved reimbursement will enhance BBM accessibility for AD diagnosis
With the emergence of DMTs, we anticipate that more BBM tests will secure CPT codes, insurance coverage, and reimbursement protocols, accelerating their adoption.
Increasing investments and strategic partnerships underscore a high level of confidence in the potential of BBM testing
These collaborations not only demonstrate a commitment to advancing BBM technologies, but also indicate a growing belief in their ability to make a meaningful impact on AD diagnosis.
Despite an initial sluggish adoption, emerging trends point toward the anticipated expansion of BBMs in clinical practice.
Detailed Findings
Amyloid beta and tau are the primary biomarkers of Alzheimer’s disease, which are currently measured via CSF or PET scans2,5
Amyloid beta (Aβ)6
Plasma Aβ42/40 levels are abnormal during the presymptomatic disease stages making earlier screening and diagnosis possible.
A lower Aβ42/40 ratio corresponds to Aβ presence in the brain.
P-tau
Plasma p-tau levels are related to both the density of Aβ plaques and tau tangles.
P-tau levels increase across the AD continuum, including the asymptomatic phase in sporadic and genetic forms of AD7
Given the multistep nature of AD diagnosis, more accessible testing methods are needed to help with timely and accurate AD diagnosis and intervention
AD often isn’t diagnosed until a patient has progressed to the mild dementia stage of the disease8
About one-third of people with MCI due to AD develop AD dementia within 5 years, and each day >2000 adults may transition to moderate AD9
Progression past the MCI stage can lead to ineligibility for certain AD treatments10
Routine screening of adults >65 or individuals with risk factors for AD could identify more patients before they progress to mild dementia.
More affordable and accessible testing could reduce time from initial cognitive changes to formal diagnosis.
Did you know? Because of the multiple steps in the diagnosis of AD, the average predicted wait time between clinical diagnosis and treatment is 18.6 months15.
Assessment via BBMs have the potential to be an important part of the path to treatment and are a growing focus area
Overview of BBMs
Drivers:
- Enable earlier diagnosis for patients over 65, particularly in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)1
- Reduce misdiagnosis
- Provide greater access to biomarker-based measures compared to expensive and invasive PET/CSF tests
Barriers:
- Lack of regulatory approval for BBMs
- BBMs should complement, not replace, clinical assessments16
- High variability in disease progression among individuals with positive biomarkers17
- BBMs are not yet established in clinical practice, requiring physician education
As the field’s understanding of BBM use and limitations in the AD space increases, so does the number of in-development and commercially available tests
Test | Manufacturer | Availability | Target | Accuracy Data |
---|---|---|---|---|
AD-Detect18 | Quest | Available for use | Amyloid beta, p-tau181, p-tau 217 | Sensitivity: 71 Specificity: 89% |
PrecivityAD19 | C2N | Available for use | Amyloid beta 42/40 ratio | Sensitivity: 88% Specificity: 89% Accuracy: 86% |
PrecivityAD220 | C2N | Available for use | Amyloid beta 42/40 and p-tau 217/np-tau 217 ratio | Sensitivity 88% Specificity 89% |
ALZpathDx21 | ALZpath | Available for use | Amyloid beta and p-tau 217 | Accuracy: 92% |
P-Tau 21722,23 | Mayo Clinic | Available for use | P-tau 217 | Accuracy: 94% |
ALZmetrix TM24 | PharmaKure | Completed clinical trial | Amyloid beta, α-synuclein, p-tau 181, and p-tau 217 | Accuracy: 97% |
Elecsys25,26 | Roche/Lilly | Ongoing clinical trials | Amyloid beta or p-tau 217 | Data not yet released |
LucentAD27 | Quanterix | Research use only | P-tau 217 | Accuracy: >90% |
AB42 and TTAU28 | Siemens Healthineers | N/A | Amyloid beta and tau | Data not yet released |
ALZpath p-tau 21729,30 | Alamar | N/A | Research only | Accuracy: >90% |
Equipment dependent test31 | Fujirebio | Research use only | Amyloid beta (1-40,1-42) and tau (p-181, p-217) | N/A |
Did you know?
A breakthrough device must file for FDA 510(k) clearance when there is low to moderate risk for the device and there is a legally marketed predicated device32.
Scientific evidence has driven companies to offer tests that measure both Aβ and p-tau to obtain a more accurate assessment of AD
Test | Manufacturer | CLIA certified | Availability | Target | Accuracy Data |
---|---|---|---|---|---|
AD-Detect18 | Quest | Yes | Available for use | Amyloid beta, p-tau 181, p-tau 217 | Sensitivity: 71%, Specificity: 89% |
PrecivityAD19 | C2N | Yes | Available for use | Amyloid beta | Sensitivity: 88%, Specificity: 89%, Accuracy: 86% |
PrecivityAD220 | C2N | Yes | Available for use | Amyloid beta 42/40 and p-tau 217/np-tau 217 ratio | Sensitivity 88%, Specificity 89% |
Simoa® ALZpath21 | ALZpath, Quanterix | Yes | Available for use | P-tau 217 | Accuracy: 95% |
ALZmetrix TM22 | PharmaKure | N/A | Completed clinical trial | Amyloid beta, α-synuclein, p-tau 181 and p-tau 217 | Accuracy: 97% |
Phospho-Tau 21722,23 | Mayo Clinic | Yes | Available for use | P-tau 217 | Accuracy: 94% |
Elecsys23,24 | Roche/Lilly | N/A | Ongoing clinical trials | Amyloid beta or p-tau 217 | Data not yet released |
Earlier developed tests were primarily designed to screen for Aβ.
There has been a shift toward the development of tests screening for p-tau 217 and others that simultaneously screen for multiple markers.
C2N, ALZpath, and Quanterix, and Roche and Eli Lilly’s plasma tests for Aβ and p-tau 217 have received the FDA Breakthrough Device Designation23-26,33.
Did you know?
The average review time for breakthrough devices with 510(k) clearance is 152 days34.
Lack of insurance coverage hinders the adoption of BBMs, but the promise of expanded coverage and reimbursement in the future can spur their acceptance and use
CPT Code | Description |
---|---|
0206U | Neurology (Alzheimer’s disease); cell aggregation using morphometric imaging and protein kinase C-epsilon (PKCε) concentration in response to amylospheroid treatment by ELISA, cultured skin fibroblasts, each reported as positive or negative for Alzheimer’s disease DISCERN™, NeuroDiagnostics, NeuroDiagnostics |
0207U | Neurology (Alzheimer’s disease); quantitative imaging of phosphorylated ERK1 and ERK2 in response to bradykinin treatment by in situ immunofluorescence, using cultured skin fibroblasts, reported as a probability index for Alzheimer’s disease DISCERN™, NeuroDiagnostics, NeuroDiagnostics |
0289U | Neurology (Alzheimer’s disease); mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score MindX Blood Test™, MindX Sciences™ Laboratory |
0346U | Beta amyloid, Aβ40 and Aβ42 by liquid chromatography with tandem mass spectrometry (LC-MS/MS), ratio, plasma QUEST AD-Detect™ Beta Amyloid 42/40 Ratio, Plasma, Quest Diagnostics |
0358U | Neurology (mild cognitive impairment); analysis of β-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebral spinal fluid, reported as positive, likely positive, or negative Lumipulse® G βAmyloid Ratio (1-42/1-40) Test, Fujirebio Diagnostics, Inc, Fujirebio Diagnostics, Inc |
0361U | Neurofilament light chain, digital immunoassay, plasma, quantitative Neurofilament Light Chain (NfL), Mayo Clinic, Mayo Clinic |
0393U | Neurology (e.g., Parkinson’s disease, dementia with Lewy bodies); cerebrospinal fluid (CSF), detection of misfolded α-synuclein protein by seed amplification assay, qualitative SYNTap® Biomarker Test, Amprion Clinical Laboratory |
0412U | Beta amyloid, Aβ42/40 ratio, immunoprecipitation with quantitation by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and qualitative ApoE isoform-specific proteotyping, plasma combined with age, algorithm reported as presence or absence of brain amyloid pathology PrecivityAD® blood test, C2N Diagnostics LLC, C2N Diagnostics LLC |
0443U | Neurofilament light chain (NfL), ultra-sensitive immunoassay, serum or cerebrospinal fluid (Effective 04/01/2024) |
0445U | β-amyloid (Abeta42) and p-tau (181P) (pTau181), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology Elecsys® PhosphoTau (181P) CSF (p-tau 181) and βAmyloid (1-42) CSF II (Abeta 42) Ratio, Roche Diagnostics Operations Inc (US owner/operator) |
83520 | Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative; not otherwise specified |
84999 | Unlisted chemistry procedure [when specified as tau protein, amyloid beta peptide testing other than long form Aβ, Aβ1-42, Beta-amyloid (1-42), and Abeta42 in CSF specimen or neural thread protein biochemical testing] |
Coverage & reimbursement is restricted
- BBMs currently lack medical necessity status and require stronger evidence for clinical use
- Due to their novelty, private insurance payers, Medicare, and Medicaid do not currently provide coverage for BBMs
- BBM test manufacturers are actively pursuing reimbursement for their products
BBM CPT codes are limited
Only 2 BBM tests currently have corresponding CPT codes35,36
High OOP Costs for tests
- Patients need to pay out-of-pocket for biomarker tests since they are not covered by insurance
- The cost per test varies by manufacturer; the QUEST-AD Detect test is priced at $399 plus a physician service fee, while the PrecivityAD test costs approximately $1,20037-39
- C2N Diagnostics emphasizes potential cost savings of $643 per identified case of Alzheimer’s disease
The use of BBMs to detect and diagnose Alzheimer’s disease early could lead to an increase in the number of patients receiving potentially life-changing treatment.
The use of BBMs to detect and diagnose Alzheimer’s disease early could lead to an increase in the number of patients receiving potentially life-changing treatment.
BBMs can have a significant impact on the diagnosis and monitoring of Alzheimer’s disease, benefiting both patients and physicians, if current challenges are overcome by:
Allowing for patient identification at the PCP level
Detecting patients in the earliest stages of AD
Limiting the need for a confirmatory PET scan
Leading to early intervention, maximizing the effectiveness of approved therapies
Reducing the burden on caregivers
BBM tests have the potential to shape the AD neurodiagnostic landscape46
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