Blood-Based Biomarkers Among Notable Alzheimer’s Advances

There is growing interest in the potential of blood-based biomarkers for Alzheimer’s disease to challenge current clinicians’ concepts of diagnosis and treatment. While there are valid concerns about accuracy, issues of equity, and implementation in clinical practice, the relative simplicity of a blood test compared to imaging or CSF analysis opens the door to earlier diagnosis and more testing, and could create new avenues for treatment development as well as research subjects.

Why It Matters

What used to be called Alzheimer’s disease by symptoms is no longer how we diagnose and treat Alzheimer’s disease. The incorporation of data regarding biological changes to these symptoms in diagnosis and treatment is the new standard. Some of these biomarkers can be measured with a simple blood test. As a result, information about patients beyond those enrolled in research centers can be gathered. There will be enormous implications for patients, clinicians, payers, and health systems. A probable biological diagnosis can be reached in less time, and patients and their specialty healthcare providers will focus on the most appropriate course of treatment in an expeditious manner. Patients can become eligible for current and emerging treatments as well as entry into existing and future clinical trials, provided that documentation of such biological changes can be established.

Early Detection and Systems

While simple tests are often imagined to yield simple results, systems are actually pulled in many different directions as tests become positive earlier in the course of the disease. While detection early in the course of disease may indeed be facilitated by the use of biomarkers measurable in blood, the potential for false positive results and uncertainty increases. Decisions for confirmation, counseling, and treatment need to be made, and a number of systems are involved in these decisions, including the systems that determine who makes the test decisions. Tests also evoke questions about confirmation procedures, about how patients and families will learn results, about how tests will be reimbursed, and about whether or not different populations will have access to these tests. Ultimately, workforce implications and implications for laboratories and their capacities are the bottom line.

Time Gained

Future advances in biological diagnosis will facilitate long-term planning over days or weeks. This will enable appropriate planning for patients’ and their families’ care and finances over that period of time. Patients and their families will have the opportunity to decide whether or not to participate in ongoing research in this field. However, there will be a host of difficult ethical considerations with respect to returning results to patients and families for whom there is no symptomatic treatment for many conditions amenable to blood testing. Patients may learn information that could affect their employment, life insurance rates, and feelings of stigmatization by members of society with whom they come into contact.

Recent Research

The US Food and Drug Administration (FDA) clearance of blood-based biomarkers for Alzheimer’s disease (AD) has been viewed as a cost-effective option for clinicians. They are certainly less expensive than imaging approaches like a PET scan or less invasive than a lumbar puncture, commonly used as diagnostic tools for AD. In a recent paper, however, the limitations of these blood biomarkers as diagnostic tools are highlighted. Several common comorbidities, including chronic kidney disease, obesity, and certain cardiovascular medications, affect levels of these biomarkers, potentially leading to incorrect diagnosis. Additionally, differences in sensitivity and specificity between test platforms may lead to false positives or false negatives, particularly in the hands of primary care clinicians whose pretest probabilities of disease differ from those of specialists in neurology or geriatric psychiatry.

While diagnostic accuracy is important, there are also concerns regarding access and legal protections for individuals who receive a caries risk assessment test result. Patients may receive a preliminary blood test result but no confirmatory testing, and no access to expensive new disease-modifying therapies. Furthermore, biomarkers for caries can have psychological and legal consequences that affect employment, insurance, and long-term care. It will be important for future research to ensure that health care providers have the education and training to provide accurate risk-based caries assessment and management, and that legal protections are in place to protect individuals’ rights. Additionally, research is needed to validate biomarkers in different populations with different diseases.

Who It Affects

Patients & Families

Patients and Families will clearly be affected. Those who report memory problems to their physician will be relieved to find out whether a potentially treatable cause, such as diabetes, is or is not present with a simple blood test. Those who are asymptomatic but worry about future memory loss will be relieved to find out that they are not at increased risk with a simple blood test, for which counseling before and after testing will be indicated. Those who work in caregiving roles and those who plan care (e.g., social workers, geriatric care managers) will be affected, detecting potential contributors to dementia several years before staff would normally detect its impact. As a result, staff and care planners will have different conversations with patients and families about issues such as driving, managing medications, managing finances, and planning for care as dementia advances.

Clinicians

With the impending release of diagnostic tests for Alzheimer’s disease, primary care clinicians will require education regarding testing, as well as referral pathways for diagnostic testing, test results interpretation, and subsequent referral to neurology or memory specialty clinics for evaluation. Neurologists and geriatric psychiatrists can expect to see an increase in the number of patients with biomarker-positive, early disease seeking confirmation of the diagnosis and guidance regarding consideration of disease-directed therapies and clinical trials.

Payers and Healthsystems

Payers and healthsystems will need to consider how screening will impact reimbursement policies and capacity planning. Laboratories will need to scale up to handle the increased volume of complex assays needed for screening as well as for confirmatory testing, counseling and follow-up of individuals screened. Payers and others will need to weigh the benefits and harms of screening and consider the costs to avoid exacerbating existing disparities in access to care for individuals with dementia.

What Changes

• Blood tests enable wider, earlier identification of biological changes associated with Alzheimer’s, making first-line screening more accessible in primary care settings.
• Positive blood results will often trigger confirmatory testing (for example, brain imaging or spinal fluid tests) and specialist referral, shifting workload and resource needs to memory clinics and neurodiagnostic services.
• Expanded use of biomarkers will accelerate and reshape clinical trial recruitment and eligibility, allowing research to focus on earlier disease stages and potentially speed the development of new treatments.
• Health systems will need clear protocols for counseling, consent, result disclosure, and follow-up care to manage uncertainty and protect patients from misinterpretation or misuse of biomarker information.

Additional context and clinical considerations

Blood-based biomarkers for Alzheimer’s disease refer to proteins or other molecules in the blood that indicate that an Alzheimer’s disease process is going on in the brain. These blood-based biomarkers may include indicators of amyloid and tau, two key proteins associated with Alzheimer’s disease, as well as other Alzheimer ’s-related proteins. They also include indicators of neuronal damage or death, such as neurofilament light (NfL) chains. Blood-based biomarkers cannot be used as the sole basis for an Alzheimer’s disease diagnosis, but when used along with clinical/cognitive data and appropriate imaging or cerebrospinal fluid biomarkers, blood-based biomarkers can add value to the diagnosis process.

There are many potential uses for blood-based biomarkers for dementia. Most of these uses revolve around a single key clinical question: what you would do with that result. For individuals with established clinical dementia, a biomarker might be used as supplementary evidence to support a diagnosis and to help choose treatments. For individuals with mild cognitive complaints, a biomarker might inform the intensity of evaluation, suggesting either the need for close monitoring or referral to a memory disorders specialty clinic. For “screened” asymptomatic individuals and their families, one would want to be fairly certain of the prognostic information; to know what, if any, treatment might be indicated; and to know how the biomarker result might affect their lives. The answer would depend upon the available treatments and the individual’s goals and preferences.

Consideration should be given to both the variability between different commercial assays and laboratories as well as the variability between which today’s clinical cut-points actually predict relevant outcomes, which may be different than those currently used. As with any test, reliance on validated tests and thoughtful, clear language on test reports is critical. For particular uses, it may be desirable to prefer more standardized assays with robust quality control processes. Furthermore, it is important to distinguish between Alzheimer’s disease biomarkers that reflect pathophysiology and those that reflect declining physical function. Two individuals with similar biomarker profiles could present with very different disease presentations and have different needs for support and care.

System-level and policy implications

As blood biomarkers for dementia enter the mainstream of medical discourse, they are likely to attract the attention of policymakers in relation to issues of insurance coverage and reimbursement. Since these biomarkers are intended to facilitate early diagnosis and open up access to new treatments or even clinical trials for people with dementia, unequal access is a very real risk, with those able to pay out-of-pocket for the test potentially gaining early access while others are left behind. Once the decision to include blood biomarkers in dementia care pathways has been taken, policymakers will then turn to the question of how to fund the necessary confirmatory trials and subsequent follow-up.

Workforce planning will be challenged as testing identifies more individuals at an earlier stage in the disease, requiring specialist input, including neuropsychologists, genetic counsellors and social support. Primary care will need training in the testing pathway and management of reactions in individuals receiving a diagnosis. Providers must be able to communicate risk to patients to avoid causing undue alarm whilst also avoiding giving false reassurance.

Risks, trade-offs, and equity

Early detection and increased screening are good things, but they also carry the risk of overdiagnosis and the psychological and social effects of screening, such as worrying about a brain-change marker for a disease for which you may never develop symptoms. These tests were validated on certain populations, and using them on other groups carries the risk of producing false positives, causing a lot of unnecessary worry, extra tests, and treatments.

Equity must be a major consideration. Many biomarker studies have lacked representation of certain racial/ethnic populations and thus validation in these populations, as well as data on assay performance in these groups, is critical to ensure equitable deployment of the test. In addition to foundational technical and clinical data and studies to understand test implementation, AACC members note that studies to understand the best methods to communicate results to patients and stakeholders, as well as targeted outreach and education to stakeholders and the public, will be important. Additionally, AACC members highlight the need for policies to ensure that all patients have equitable access to confirmatory testing and treatment.

Looking ahead

Blood-based biomarkers for the diagnosis and monitoring of Alzheimer’s disease will take several years to gradually become clinically useful in practice. Initially, their use will be confined to memory clinics and research centers, but as guidelines, payers, laboratory standards, and technologies evolve, biomarkers will increasingly become part of the diagnosis and management of Alzheimer’s disease, including counseling, treatment, and clinical trials.

Screeners have promise, but for clinicians and health system leaders, there are a host of priorities around uses, informed consent and disclosure, access to confirmatory testing, and preparing the workforce to provide counseling and connections to specialty evaluation and care for patients and families. For policymakers and payers, priorities include making policy and coverage decisions that balance patient access with cost and clinical value to maximize the translation of earlier detection and less invasive diagnosis into better outcomes for patients and families.

Blood-based biomarkers for Alzheimer’s disease represent a significant step forward for Alzheimer’s research. However, these tests must be used to deliver timely, effective, compassionate, and sustainable care and support for people at risk of or living with Alzheimer’s and their carers.

Reference

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC12924664/