What are blood-based biomarkers?

Alzheimer's disease develops slowly over time, beginning with a preclinical stage, during which harmful proteins start to accumulate in the brain, yet in the absence of any symptoms. This silent phase can last for up to a few decades. Over time, mild cognitive impairment (MCI) emerges, marked by subtle memory and thinking difficulties that do not yet interfere with daily life. In the final Alzheimer’s dementia stage, severe memory loss, confusion, and difficulty with daily tasks take hold, often accompanied by mood and personality changes.

At the core of the disease are two key pathological hallmarks / proteins:

• Amyloid beta (Aβ) which forms sticky plaques outside the brain cells (called neurons) which leads to the disruption of proper neuron communication.
• Tau that builds inside neurons forming tangles which also results to brain cell death and cognitive decline.

Several risk factors have been identified that influence the risk of developing AD. These risk factors can be grouped into two main categories based on whether they can be changed or not (Livingston et al., 2024).

1. Non-modifiable risk factors – those that cannot be changed, such as increasing age, female sex, familial history of AD, and genetic predisposition (carriership of APOE e4 gene).
2. Modifiable risk factors – These are aspects of health and lifestyle that can be adjusted to help lower the risk of AD. They include heart health factors like high blood pressure and diabetes, exercise, healthy diet, as well as mental and social well-being, such as staying mentally active and maintaining strong social connections.

Current Diagnostics
Currently, diagnosing AD involves a set of procedures that vary depending on the level of care. In Sweden, the diagnostic process typically begins in primary care, where 50–80% of cases are identified using basic cognitive tests and computed tomography (CT) scans. These tests assess thinking abilities such as memory, attention, reasoning, and more complex tasks like mental flexibility. However, while widely used, they are not specific to AD and may miss early signs of the disease.

More advanced diagnostic tools are available in specialist units, including brain imaging techniques like magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, as well as cerebrospinal fluid (CSF) analysis obtained via lumbar puncture. These methods allow for the direct measurement of toxic AD proteins in the brain, providing a more accurate diagnosis. However, they are invasive, time-consuming, costly, and often associated with long waiting times due to limited specialist resources. As a result, many patients face delays in receiving a definitive diagnosis.

To improve early detection and patient access to care, there is a growing need for simple, cost-effective, and disease-specific diagnostic methods that can be integrated into primary care settings. This would help ensure that more individuals receive timely and accurate diagnoses, allowing for earlier intervention and better disease management.

What are the Blood-based Biomarkers (BBMs)?
Blood-based biomarkers are the indicators in the blood which inform about the presence of toxic proteins (molecules). They offer a new, highly sensitive way to detect proteins in the blood that are linked to Alzheimer’s disease, even in its early stages. With a simple blood test, scientists can measure key proteins associated with the disease, making early detection more accessible and less invasive than traditional methods.

Alzheimer’s disease-specific markers in the blood include proteins closely linked to the disease, such as the amyloid beta 42/40 ratio (Aβ42/40) and phosphorylated tau (p-tau). The Aβ42/40 ratio reflects changes in amyloid beta levels, which are associated with plaque buildup in the brain, while p-tau has emerged as a highly reliable indicator of Alzheimer’s-related brain changes.

A major part of the research and development of blood-based biomarkers for Alzheimer’s disease has taken place in western Sweden, specifically at the Neurochemistry lab of the University of Gothenburg, led by Professors Kaj Blennow and Henrik Zetterberg. Their work has been instrumental in advancing the field, helping to refine and validate these biomarkers for potential use in clinical settings. As research continues, blood tests could become a game-changing tool for earlier and more accessible Alzheimer’s diagnosis.

The advantages of blood-based biomarkers over traditional diagnostic methods
Currently, diagnostic methods specific to Alzheimer's disease are primarily available within specialised healthcare settings, which are limited in resources and geographically restricted. Additionally, existing techniques such as MRI, PET, and cerebrospinal fluid (CSF) analysis are costly, invasive, and burdensome. In contrast, blood-based biomarkers offer a non-invasive, cost-effective, and accessible alternative with high disease specificity. Their ease of implementation in primary care settings makes them a promising tool for improving early detection and diagnosis of Alzheimer's disease on a broader scale.

While blood tests are advancing Alzheimer’s diagnostics, their potential extends beyond early detection in clinical practice. They could also be useful in:

• Clinical Trials: Helping to identify and enroll patients in the early stages of AD, improving the efficiency and accuracy of drug testing.
• Monitoring Treatment Response: Assessing whether new therapies, such as lecanemab, are effectively targeting the key proteins—amyloid and tau—that contribute to brain changes in Alzheimer’s disease.

Status quo – Landscape and where REAL AD is in it
Research shows that blood-based biomarkers are highly accurate in identifying Alzheimer’s disease and can even predict cognitive decline before symptoms become severe. However, most studies so far have been conducted in research settings and memory clinics, yet it is still unclear how well these tests will work in the general population, as well as in healthcare settings.

The REAL AD study is helping to bridge this gap by testing whether blood based biomarkers can be used effectively in regular healthcare settings. The study takes place in Western Sweden region and aims to assess how well these blood tests, combined with remote cognitive assessments, can help detect early signs of AD in a general population. Unlike past studies that focused on small, carefully selected research groups, REAL AD works within existing healthcare systems, using established reference methods like CSF analysis and PET scans to confirm its findings. By doing so, it will help determine whether blood based biomarkers can be reliably used in primary care. As part of larger European projects like AD-RIDDLE and PROMINENT, REAL AD is an important step toward making early Alzheimer’s detection more accessible, ultimately improving diagnosis and treatment options for the future.

The Future of Blood Tests in Primary Care
In the near future, primary care physicians may incorporate simple blood tests into routine check-ups to aid in the early detection of Alzheimer’s disease. This advancement could lead to earlier interventions to slow disease progression, better patient stratification for personalised treatment, and increased accessibility of diagnostics, especially in underserved areas.

However, while these tests hold significant promise, they are not yet perfect. Challenges remain in ensuring that they are accurate, work well for everyone, and give reliable results. Different blood tests can produce slightly different results, as well as other health conditions may affect the readings, and more studies are needed to confirm how well they work in real-world settings outside of research contexts (Schöll et al., 2024).

As highlighted in recent work by the leader of the REAL AD study, Michael Schöll, and colleagues, more research is needed to refine these biomarkers before integrating them effectively into clinical practice. Michael Schöll emphasised that while blood tests offer hope for transforming Alzheimer's diagnostics, they should currently be viewed as a valuable addition to existing methods, complementing tools like cognitive assessments and imaging, rather than serving as a standalone solution.