Alzheimer’s Blood Tests Together Improve Accuracy, Cut Overdiagnosis

A combination of two blood tests improved Alzheimer’s disease triaging and reduced overdiagnosis in people with asymptomatic Alzheimer’s pathology, a prospective cohort study showed.

Together, the two tests — one assessing the ratio of phosphorylated tau 217 to non-phosphorylated tau (%p-tau217), the other measuring microtubule-binding region-tau243 (eMTBR-tau243) — identified people with established Alzheimer’s disease with an accuracy of 81%, a positive predictive value (PPV) of 84%, a negative predictive value (NPV) of 77%, and a sensitivity of 82%, reported Niklas Mattsson-Carlgren, MD, PhD, of Lund University in Sweden, and co-authors.

Positive eMTBR-tau243 was associated with worse longitudinal cognitive decline and longitudinal tau tangle accumulation in p-tau217-positive patients. In this group, eMTBR-tau243 had an accuracy of 87%, a PPV of 76%, and an NPV of 90% for identifying individuals with high tau-PET load, Mattsson-Carlgren and colleagues said in Lancet Neurology.

The proportion of false-positive test results for established Alzheimer’s disease fell from 43% with %p-tau217 alone to 16% with %p-tau217 and eMTBR-tau24 combined, the researchers noted.

Two-step testing, with %p-tau217 as an initial test to identify Alzheimer’s pathology followed by eMTBR-tau243, could refine diagnostic accuracy, Mattsson-Carlgren and colleagues suggested. Plasma eMTBR-tau243 also could help identify individuals with high tau burden who might have less benefit from amyloid-targeting therapies.

“Plasma p-tau217 is excellent to identify presence of amyloid pathology, which is a core feature of Alzheimer’s disease. But amyloid pathology presents early, before clinical symptoms. By combining p-tau217 with eMTBR-tau243, which increases later in disease, in correlation with aggregated tau pathology, we can increase our confidence that Alzheimer’s is not only present, but also contributes to symptoms,” Mattsson-Carlgren told MedPage Today.

“Individuals with isolated increased p-tau217 without increased eMTBR-tau243 may be more likely to have Alzheimer’s in very early stage, without clear relevance to the current symptoms,” he pointed out.

“This type of fine-grained understanding of how different aspects of Alzheimer’s disease are present and explain symptoms has not been possible with blood tests before,” he added. “If these methods can be used in clinical practice, it will enable objective biological staging of Alzheimer’s, which can guide patient management.”

Plasma p-tau217 can reflect abnormal amyloid pathology decades before Alzheimer’s symptom onset, but also can be abnormal when amyloid is a co-pathology in other diseases, noted Nicholas Ashton, PhD, of Banner Alzheimer’s Institute in Phoenix.

“Therefore, interpretation of p-tau217 in isolation might increase the risk of overdiagnosis, especially in a preclinical population or when amyloid pathology is not the primary driver of the clinical syndrome,” Ashton wrote in an accompanying editorial.

A growing demand for fast diagnostic testing coupled with the need for sufficient accuracy is a fundamental challenge facing the Alzheimer’s field, Ashton observed. “Blood biomarkers clearly address the former, but their ability to reliably inform clinical care remains under scrutiny, despite recent regulatory approvals,” he said.

A sequential framework of p-tau217 and eMTBR-tau243 tests could move the field toward biologically informed diagnosis and stratification, he pointed out. “As disease-modifying treatments become more available, the ability to distinguish early amyloid positivity from tau-driven symptomatic disease will be essential, not only for treatment selection, but also for avoiding both overdiagnosis and missed opportunities for timely intervention,” Ashton wrote.

Mattsson-Carlgren and co-authors evaluated 572 adults with cognitive symptoms — 142 participants with subjective cognitive decline, 259 with mild cognitive impairment, and 171 with dementia — in the Swedish BioFINDER 2 study. About half (51%) were female.

Overall, 350 people had positive plasma %p-tau217. Of these, 341 people (97%) were amyloid-positive by cerebrospinal fluid biomarkers or PET. Just over half — 194 of 350 participants (55%) — also were positive for eMTBR-tau243.

The overall findings were validated in an independent cohort of both cognitively impaired and unimpaired patients from the Knight Alzheimer Disease Research Center (ADRC) at Washington University in St. Louis, the researchers said.

The study has several limitations, they acknowledged. The main sample was made up of Swedish participants, though results were consistent in the Knight ADRC cohort. Cross-validation in other populations and primary care settings is essential, they added.

The eMTBR-tau243 marker also needs further work, Mattsson-Carlgren noted. “The next step is to investigate whether the test can be simplified, and whether it can be used more widely — in primary care, for example,” he stated.

Please enable JavaScript to view the comments powered by Disqus.