Biomarker assays

Alzheimer’s disease

Early diagnosis of Alzheimer’s disease can hugely affect the impact on individuals: it allows access to a wider range of treatments and can help patients and their families manage the condition more effectively. Unfortunately, Alzheimer’s disease can be difficult to diagnose early; symptoms can be mistaken for normal, age-related changes and slow progression means that cognitive decline can be hard to spot. Because of this, research has focused on developing a reliable biomarker-based method of AD diagnosis. Whereas diagnosis used to rely on symptom observations, PET scans and cerebrospinal fluid analysis are now used to identify disease biomarkers. However, these methods can be inaccessible, expensive, and invasive, especially when compared to the ease of a blood test.

Reliable blood-based biomarker testing is expected to revolutionize diagnosis by lowering cost and improving access. Faster, earlier diagnosis would accelerate clinical trial recruitment, aiding the development of new therapies.

The exhaustive search for a reliable blood-based biomarker seems to be over, at least for now. Ptau217–a form of phosphorylated tau– performs similarly to CSF tests in identifying abnormal amyloid and tau¹, correlates with PET measures of aggregated tau, and can be used to stratify patients into different stages of AD progression². It shows up early in AD disease progression (even before the onset of symptoms), making it an ideal candidate for blood-based diagnostic testing. Tests to bring ptau217 detection to the clinic are being developed at a breakneck pace, with several already commercially available. None have yet received FDA approval, but some have received FDA Breakthrough Device Designation³.

Ptau217 has low abundance in blood, and sensitive reagents are needed to develop reliable immunoassays. Work will no doubt continue to improve these immunoassays and identify further biomarkers.

Parkinson’s disease

Alpha-synuclein aggregation is a hallmark of PD. The seed amplification assay (SAA) detects disease-associated alpha-synuclein aggregates in biofluids like blood and saliva. The assay has shown high sensitivity and specificity, making it a promising diagnostic tool for Parkinson's disease.  Alpha-synuclein may be particularly useful in differential diagnosis; research indicates that its morphology varies between PD, multiple system atrophy, and Lewy body dementia.

As well as traditional biomarkers, digital biomarkers, like changes in voice and gait, are being investigated for their potential to diagnose and monitor PD. Gait pattern analysis can detect early signs of PD and track disease progression, and voice analysis is being explored as a less invasive digital biomarker.

Understanding disease heterogeneity

AD research has traditionally been dominated by our understanding of the disease as a proteopathy, with amyloid and tau center stage. AD is hugely complicated, with innumerable interactions between different pathways. While amyloid and tau research remains essential, the wider field has shifted to view the disease somewhat more holistically: only 18% of drugs currently in AD clinical trials target amyloid, and only 11% target tau.

There is now an increasing focus on neuroinflammation, synapse/neuronal injury, and the role of the vascular system and blood-brain barrier. As well as opening up new research and therapeutic development avenues, this wider perspective will help to investigate AD heterogeneity and co-morbidities. Lifestyle-related risk factors, like LDL cholesterol, type 2 diabetes, CVD, and poor sleep, as well as other risk factors like untreated sight and hearing loss, are now implicated in AD pathology. GLP-1 agonist drugs like semaglutide are showing neuroprotective effects in AD without affecting amyloid and tau⁴, demonstrating the importance of research into inflammation and indicating exciting new treatment avenues. Another way inflammation is being investigated is in the gut/brain axis: research suggests a link between some types of gut bacteria and Alzheimer’s disease, mediated by neuroinflammation⁵.

References

1.      Ashton, N. J. et al. Diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay for alzheimer disease pathology. JAMA Neurology 81, 255 (2024).

2.      Feizpour, A. et al. Accurate detection and staging of alzheimer’s disease by plasma ptau217 on a high-throughput immunoassay platform. eBioMedicine 109, (2024).

3.      Marisa. FDA Breakthrough device designation of novel ptau 217 blood test. Spear Bio (2025). Available at: https://spear.bio/blog/2025/01/13/spear-bio-secures-fda-breakthrough-device-designation-for-its-novel-ptau-217-blood-test-advancing-scalable-solutions-for-early-alzheimers-disease-diagnosis/. (Accessed: 23rd April 2025)

4.      Mahapatra, M. K., Karuppasamy, M. & Sahoo, B. M. Therapeutic potential of semaglutide, a newer GLP-1 receptor agonist, in abating obesity, non-alcoholic steatohepatitis and neurodegenerative diseases: A narrative review. Pharmaceutical Research 39, 1233–1248 (2022).

5.      Kowalski, K. & Mulak, A. Brain-gut-microbiota axis in alzheimer’s disease. Journal of Neurogastroenterology and Motility 25, 48–60 (2019).