Exploring pre-test probability bias in Alzheimer’s disease

Authors: Ryan Patrick and Joe Volpe, PhD

The recent availability of blood-based biomarkers (BBMs) for Alzheimer’s disease (AD) has begun to reshape how healthcare providers evaluate and triage patients presenting with signs of potential cognitive impairment. When used appropriately, BBMs provide powerful biological insights that can meaningfully support clinical decision-making and patient care.

However, as commercial access to BBMs expands, so does the potential for inappropriate use, increasing the risk of patient misclassification. This underscores the need for improved education, clearer clinical guidance, and more deliberate integration of BBMs—particularly in primary care settings.

Clinical utility of Alzheimer’s blood testing

To date, much of the peer-reviewed literature evaluating BBMs has focused on their analytical and diagnostic performance relative to reference standards—most notably positron emission tomography (PET) imaging. Comparatively fewer studies have examined their clinical utility, that is, their ability to improve patient outcomes and inform real-world clinical decision-making.

Clinical utility implies more than analytical accuracy. The “correct test” is one applied to the appropriate patient, at the right time, and in the appropriate clinical context. Robust clinical utility evidence supporting BBM use in routine practice would facilitate responsible adoption, improve patient care pathways, and strengthen the case for coverage by both government healthcare programs and commercial insurers in the United States.

BBMs in the context of an Alzheimer’s diagnosis

Biological markers associated with AD do not always correspond to the clinical manifestation of Alzheimer’s dementia. Reflecting this distinction, the International Working Group (IWG) on Alzheimer’s Disease characterizes AD as a clinical–biological continuum rather than a purely pathological entity. Under this framework, AD is defined by the coexistence of clinical symptoms and biological evidence of disease.

BBMs hold promise to expedite the diagnostic process and enrich care pathways, particularly for patients with mild cognitive impairment (MCI). By identifying individuals with biological evidence of Alzheimer’s pathology, BBMs may facilitate earlier referral and more informed triage. Nevertheless, confirmation of abnormal BBM results using established reference standards, such as PET imaging or cerebrospinal fluid (CSF) biomarkers, remains recommended. Furthermore, diagnosis, staging, and treatment decisions (including consideration of anti-amyloid and other emerging therapies) still require thorough clinical assessment of symptoms.

Although biological findings and clinical symptoms are conceptually distinct, they are inherently linked through pre-test probability, a construct that critically influences test interpretation.

Pre-test probability of Alzheimer’s disease and its importance in primary care

Pre-test probability refers to the estimated likelihood that a patient has a specific disease prior to diagnostic testing. It is informed by disease prevalence as well as patient-specific factors , including clinical presentation, age, and genetic risk. 

Disease prevalence, and therefore pre-test probability, varies substantially by care setting. Neurology clinics and memory care centers, where patients are often referred due to cognitive symptoms, will have a relatively high prevalence of AD. In contrast, primary care settings generally encounter lower AD prevalence, even among symptomatic individuals. In many cases, AD prevalence in primary care more closely resembles that of the general population.

This distinction is particularly relevant for BBMs because pre-test probability directly influences the predictive value of test results. For any diagnostic test with fixed sensitivity and specificity, positive and negative predictive values will vary depending on the population in which the test is applied.

Although direct evidence of pre-test probability bias in AD is limited, studies in other common conditions—such as pneumonia, breast cancer, cardiac ischemia, and urinary tract infections—suggest that clinicians frequently overestimate pre-test probability. An analogous bias in AD, particularly in primary care, would be concerning. Overestimation of pre-test probability combined with the use of highly sensitive BBMs (e.g., pTau-217) in low-likelihood populations may substantially reduce positive predictive value (PPV), increasing the risk of misclassification. Conversely, underestimation of pre-test probability may lead to dismissal of clinically meaningful symptoms and delays in intervention, which are especially consequential given the benefits of early detection and care.

Optimizing pre-test probability in clinical practice

Successful integration of BBMs in primary care begins with appropriate patient selection and deliberate assessment of pre-test probability. Most AD blood tests are recommended for patients aged 55 years or older who present with symptoms of cognitive impairment. Primary care providers can increase confidence in appropriate test utilization by focusing on two foundational steps: symptom confirmation and exclusion of alternative causes of cognitive impairment.

Impact of pre-test probability on BBM selection

Limitations of use

In general, use of BBMs in asymptomatic patients may complicate clinical evaluation, lead to misleading results, and cause unnecessary distress. Importantly, while BBMs provide valuable biological information, they are intended to inform referral and triage decisions rather than establish a definitive diagnosis of AD in isolation.

Future directions for neurodegenerative blood testing

As the adoption of neurodegenerative blood tests increases, the continued emphasis on education, clinical context, and appropriate use is essential. Pre-test probability, and the biases that can distort it, must remain key considerations in the interpretation of biomarker data and triage decisions for patients presenting with cognitive symptoms.

As an industry leader in neurodegenerative testing, Labcorp remains committed to expanding access to innovative diagnostic tools in AD and other neurodegenerative conditions. Looking ahead, addressing unmet diagnostic needs in areas such as concussion recovery, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) represent a continued priority. With the field rapidly evolving, the responsible integration of emerging biomarkers will enable earlier recognition, more precise triage, and ultimately, more informed management for patients facing neurodegenerative conditions and disease.