Blood Biomarkers Highly Accurate in Diagnosing Alzheimer’s

PHILADELPHIA — Amyloid beta (Aβ) and tau protein blood biomarkers are highly accurate in identifying Alzheimer’s disease (AD) in patients with cognitive symptoms attending primary and secondary care clinics, new research showed.

Accurate early diagnosis of AD is important because two monoclonal antibodies donanemab (Kisunla) and lecanemab (Leqembi) are now approved by the US Food and Drug Administration (FDA) for early-stage AD. However, the use of these agents requires amyloid confirmation.

A key finding of the study was that primary care physicians had a diagnostic accuracy of 61%, and dementia specialists had an accuracy of 73%, after completing standard clinical evaluations and before seeing results of the blood test or other AD biomarkers, while the blood test used in the study had an accuracy of 91% for correctly classifying clinical, biomarker-verified AD.

“This underscores the potential improvement in diagnostic accuracy, especially in primary care, when implementing such a blood test,” study investigator Sebastian Palmqvist, MD, PhD, associate professor of neurology at Lund University, Lund, and a consultant at Skåne University Hospital, Malmö, Sweden, told Medscape Medical News.

“It also highlights the challenges in accurately identifying AD based solely on clinical evaluation and cognitive testing, even for specialists.”

The findings were presented on July 28 at Alzheimer’s Association International Conference (AAIC) 2024 and simultaneously published online in JAMA.

The study included two cohorts from primary and secondary care clinics in Sweden. Researchers analyzed plasma samples together at one timepoint in a single batch.

It also included two cohorts from Swedish primary and secondary care clinics where the plasma samples were analyzed prospectively (biweekly) in batches throughout the enrollment period, which more closely resembles clinical practice.

Primary care physicians and dementia specialists documented whether they believed their patients had AD pathology, basing the diagnoses on the standard evaluation that includes clinical examination, cognitive testing, and a CT scan prior to seeing any AD biomarker results.

They reported their certainty of the presence of AD pathology on a scale from 0 (not at all certain) to 10 (completely certain).

Plasma analyses were performed by personnel blinded to all clinical or biomarker data. Mass spectrometry assays were used to analyze Aβ42, Aβ40, phosphorylated tau 217 (p-tau217), and non–p-tau217.

Biomarkers used in the study included the percentage of plasma p-tau217, which is the ratio of p-tau217 relative to non–p-tau217, and the Aβ42 to Aβ40 ratio (the amyloid probability score 2 [APS2]). Researchers determined p-tau217 alone and when combined with the APS2.

The study included 1213 patients with cognitive symptoms — mean age 74.2 years and 48% women. Researchers applied biomarker cutoff values to the primary care cohort (n=307) and the secondary care cohort (n=300) and then evaluated the blood test prospectively in the primary care cohort (n=208) and the secondary care cohort (n=398).

The blood biomarker cutoff value was set at 90% specificity for AD pathology (the 1 cutoff-value approach). A 2 cutoff-value approach (using 1 upper and 1 lower cutoff value) was also used with values corresponding to 95% sensitivity and 95% specificity.

The primary outcome was presence of AD pathology. A positive finding of the Aβ biomarker was defined according to the FDA-approved cutoff value (≤ 0.072). A positive finding of the tau biomarker was defined as a p-tau217 level> 11.42 pg/mL in cerebrospinal fluid.

Researchers calculated the positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy, as well as area under the curve (AUC) values.

Accuracy in Specialty vs Primary Care

When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 when the APS2 was used. In the secondary care cohort, the AUC was 0.96 when the APS2 was used.

When plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 when the APS2 was used. In the secondary care cohort, the AUC was 0.97 when the APS2 was used.

The 2 cutoff-value approach achieved PPVs of 97%-99% in patients with cognitive impairment, which is the target population of currently available anti-amyloid treatments.

Although NPVs were slightly lower in these patients (87%-92% using the APS2), “we argue that a very high positive predictive value is probably more important in diagnosing patients as having Alzheimer’s disease, especially before initiating costly and burdensome anti-amyloid treatment,” the investigators noted.

The PPVs were less than optimal for accurate identification of AD pathology in patients with subjective cognitive decline regardless of the cutoff-value approach used. The researchers pointed out that this could be a disadvantage for clinical trials that include patients with presymptomatic AD but not in clinical practice because there are no clinical criteria for diagnosing AD at the subjective cognitive decline stage.

The NPVs were higher in patients with subjective cognitive decline (91%-94% for the APS2 or percentage of p-tau217 alone). This indicates the blood test would be more useful for ruling out underlying AD when only subtle symptoms are present, the researchers noted.

As for doctors identifying clinical AD, primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 86%-95%) using the APS2.

In the overall population, the diagnostic accuracy using the APS2 (90%; 95% CI, 88%-92%) was not different from that using the percentage of p-tau217 alone (90%; 95% CI, 88%-91%).

Very little was known about how a blood test would perform in a primary care setting, said Palmqvist. “Seeing that the test was just as accurate in primary care (about 90%) as it was in secondary care is really encouraging, especially since primary care is the first, and often final, point of entry into the healthcare system for cognitive evaluations.”

He said he was surprised the biomarkers performed so well in prospective, biweekly analyses throughout the study. “Previous studies have only demonstrated their effectiveness when all collected samples are analyzed at a single timepoint, which does not reflect how a blood test is used in clinical practice,” he said.

He added that he was surprised that the tests were just as accurate in primary care as in a memory clinic setting with referred patients. This, despite older age and higher prevalence of comorbidities in primary care, such as chronic kidney disease (present in 26% of the primary care cohort), can be a confounding factor causing increased concentrations of p-tau217.

Next Steps

The diagnostic accuracy of the blood tests is on par with FDA-cleared cerebrospinal fluid biomarkers, the investigators, with senior author Professor Oskar Hansson, MD, PhD, Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden, noted.

As blood tests are “more time-effective, cost-effective, and convenient” for patients, “they could also potentially replace cerebrospinal fluid tests and PET,” they added.

Palmqvist emphasized that these tests should not be used as stand-alone diagnostic tools for AD but should complement the standard clinical evaluation that includes cognitive testing and a thorough interview with the patient and a spouse or relative.

“This is crucial because Alzheimer’s disease pathology can be asymptomatic for many years, and cognitive symptoms in some patients with AD pathology may primarily result from other conditions. Misinterpreting a positive AD blood test could lead to underdiagnosis of common non-AD conditions.”

With new anti-amyloid treatments possibly slowing disease progression by 30%-40% when initiated early on, a blood test for AD could lead to more people receiving an accurate and earlier diagnosis, said Palmqvist. “This could potentially result in a better response to treatment. Results from drug trials clearly indicate that the earlier treatment begins, the more effectively it can slow disease progression.”

The test used in the study is already available in the United States, the investigators said, and similar test will be accessible in Sweden within a few months. “However, the rollout will probably be gradual and will depend on how international and national guidelines recommend their use, so developing these guidelines will be a crucial next step for widespread implementation, particularly in primary care,” said Palmqvist.

He also underlined the importance of replicating the findings in more diverse populations. “This will help ensure the tests’ reliability and effectiveness across various demographic and clinical contexts.”

An important next research step is to examine how implementing a blood test for AD affects patient care. “This includes looking at changes in management, such as referrals, other examinations, and the initiation of appropriate treatments,” said Palmqvist.

Another study presented at the meeting showed that a highly accurate blood test could significantly reduce diagnostic wait times.

Convincing Research

In an accompanying editorial, Stephen Salloway, MD, Departments of Psychiatry and Neurology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, and colleagues said the study “makes the case convincingly that highly sensitive blood measures of Alzheimer’s disease can be integrated into the clinical decision-making process, including in the primary care setting.”

These tests, they wrote, “can be used to enhance the ability of clinicians to accurately identify individuals with cognitive impairment and dementia due to Alzheimer’s disease.”

“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid.”

A key limitation of the study was the lack of diversity in the study sample. This makes it difficult to generalize the results across other ethnic and racial groups, the editorialists noted. Plasma assays for AD in the United States will require approval from the FDA and coverage by the US Centers for Medicare & Medicaid Services to be widely adopted.

The editorialists also pointed out that advances in the diagnosis and treatment of AD will require important changes to healthcare models, including providing additional resources and staffing.

The study was supported by the Alzheimer’s Association, National Institute on Aging, European Research Council, Swedish Research Council, the GHR Foundation, and other groups.

The study was conducted as an academic collaboration between Lund University and C2N Diagnostics in the United States. Lund University or its affiliated researchers received no funding or compensation from C2N Diagnostics. C2N Diagnostics performed the plasma analyses blinded to any biomarker or clinical data and had no role in the statistical analysis or results.

Palmqvist reported receiving institutional research support from ki:elements, Alzheimer’s Drug Discovery Foundation, and Avid Radiopharmaceuticals and consultancy or speaker fees from BioArctic, Biogen, Esai, Eli Lilly, and Roche.

Hansson reported receiving personal fees from AC Immune, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Roche, Bristol Myers Squibb, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens and institutional research support from ADX, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche.

Salloway reported receiving grants from Biogen, Roche, Lilly, Genentech, Eisai, and Novartis; personal fees from Biogen, Roche, Lilly, Genentech, Eisai, Novo Nordisk, Prothena, AbbVie, Acumen, and Kisbee; and nonfinancial support (travel expenses for conference attendance) from Biogen, Roche, Lilly, and Acumen.