By Henrik Zetterberg

The global fight against Alzheimer’s disease is at a critical juncture, highlighting the urgent need for scalable Alzheimer’s diagnostics. Projections estimate that an alarming 153 million people will be living with Alzheimer’s or related dementias by 2050.

Even with those alarming numbers, the US FDA approvals of disease-modifying therapies (DMTs) such as Leqembi (lecanemab) and Kisunla (donanemab) for select patients provide reason for optimism. Additional promising DMTs are currently in clinical trials and could become available within the next few years.

Early diagnosis offers the best possible outcome for millions of patients in need. By advancing ongoing research and commercialising clinical testing platforms, researchers, clinicians and industry partners around the world can then accelerate the development of new diagnostics and treatments to improve patient care.

This demand for accessible, accurate and early diagnosis has never been more pressing. While traditional diagnostic methods, such as Positron Emission Tomography (PET) scans and cerebrospinal fluid (CSF) analysis, have long been the gold standard, their invasive nature, high cost and logistical complexity have limited their scalability, making them unsuitable for widespread population screening or routine clinical use.

Studies have shown that blood-based diagnostic tests can match the sensitivity and accuracy of these existing methods. That’s great news. However, there are challenges we must overcome on the way to realising the potential of those tests.

One of the greatest challenges in developing blood-based tests for Alzheimer’s disease is the need to detect biomarkers at extremely low concentrations. Proteins like phosphorylated tau at position 217 (pTau217), a key biomarker of Alzheimer’s disease, accumulate in the brain during early stages of the disease. Yet, only trace amounts cross the blood-brain barrier and enter the bloodstream, requiring ultra-sensitive assays for accurate detection.

The blood-brain barrier is a semi-permeable layer of cells that surrounds the brain and protects it from potentially harmful elements circulating in the blood. Acting like a fine filter, it prevents larger molecules from penetrating or leaving the brain, including disease-related proteins like tau. While essential for maintaining brain health, this barrier makes detecting Alzheimer’s-related biomarkers in blood especially challenging.

Until recently, this limitation presented a significant hurdle for the widespread clinical viability and reliability of blood-based testing for Alzheimer’s. Because pTau217 levels in plasma are so low, they require measurement tools with exceptional sensitivity. Traditional methods often rely on specialised technologies such as Quanterix’s single molecule array (Simoa) technology or Olink’s PCR amplified assays.

However, recent advancements have shown that a high-quality antibody, like the ALZpath pTau217, can power robust assays that run effectively on standard clinical chemistry analysers, significantly increasing scalability and accessibility. Despite these advances, in individuals without Alzheimer’s, pTau217 concentrations are so low that many samples fall below the lower limit of quantification on routine clinical analysers. While a clinician might interpret low concentration as reassuring, the ability to precisely monitor even these low concentrations is crucial to measuring and tracking, especially for monitoring therapeutic response. For instance, when DMTs are initiated early in Alzheimer’s patients, they lead to a reduction in plasma pTau217 levels. To accurately monitor this reduction as concentrations move towards normal levels, ultra-sensitive assays become indispensable.

Furthermore, scientists are working to define what constitutes the earliest biomarker evidence of Alzheimer’s-related brain changes. It is theorised that the first sign may not present as the crossing of a static abnormality threshold, but rather a subtle, individualised increase in pTau217 over time. Measuring this ‘delta change’, with high precision, in the normal range is therefore essential for true early detection.

Another consideration is understanding potential interferences and confounding factors that can impact results in individual patients. While robust pTau217 assays have demonstrated strong resistance to such interference, as testing scales to high volumes (for example, 10,000 tests annually in a clinical lab), the goal of maintaining consistency becomes more complex, as factors such as pre-analytical variability, lot-to-lot differences, routine instrument calibration and day-to-day operational variation can introduce minor fluctuations in assay performance over time. Close collaboration between clinical laboratories and clinicians, combined with participation in external quality control programmes like the Alzheimer’s Association DDSC QC Program, play a key role in identifying and addressing erroneous results.

As these ultra-sensitive blood-based assays become more viable, focus is increasingly turning to ensuring these innovations are accessible at scale.

The availability of new methods on standard clinical chemistry analyzers is instrumental in addressing the longstanding barriers to accessibility, specifically in areas that range in socioeconomic level.

Global diagnostics companies such as Roche, Fujirebio and Beckman Coulter are actively developing sensitive pTau217 assay kits for their platforms, paving the way for significant progress. While universal access remains an ongoing effort, this level of industry engagement from some of the largest players indicates this challenge is far from insurmountable. The global shift to blood-based testing is already underway.  Several US academic and specialty clinics have begun incorporating blood based tau biomarkers into clinical workflows. In Sweden, regional memory clinic networks are piloting these tests and leading centers in countries such as China, Japan, the UAE and the UK are similarly moving toward broader clinical use. This growing international momentum highlights the real-world impact of these diagnostic innovations, including their potential use in clinical trials.

Beyond scientific sensitivity and instrument accessibility, the third crucial pillar for widespread adoption is education. All general practitioners, not just specialists in neurology, must learn how to accurately interpret pTau217 results and discuss them with patients within the broader clinical context.

There are several significant advantages of blood-based testing, it is non-invasive, more comfortable for patients, scalable for population-wide screening and cost-effective compared to current testing practices of PET imaging or lumbar punctures. However, it is essential to remember that pTau217 is a biomarker of Alzheimer’s pathophysiology, not a standalone diagnostic tool. A definitive diagnosis requires a comprehensive evaluation, including medical and family history, brain imaging and other blood chemistry results (eg, thyroid function, B12, folic acid). The pTau217 result from an easy blood test should be interpreted as one part – albeit a significant one – of the holistic diagnostic picture.

Sensitivity and accuracy are essential in Alzheimer’s blood testing because early and reliable detection is vital for meaningful intervention. To fully realise the potential to transform Alzheimer’s diagnostics, we must collectively raise awareness, invest in clinical education and support continued innovation in ultra-sensitive diagnostic tools. It is equally important to drive broad clinical adoption and ensure equitable access to testing across all geographies and socioeconomic groups. These united efforts will accelerate the integration of advanced diagnostics into routine care, leading to earlier disease detection, more effective treatments and ultimately, improved patient outcomes worldwide.