Two-step workflow taps cognitive screening before biomarker testing
A new two-step approach to diagnosing Alzheimer’s disease (AD) in primary care shows promise for cutting false positives and streamlining referrals. Researchers tested a brief, self-administered digital cognitive battery, BioCog, first, and reserved amyloid-related blood tests for individuals who showed objective impairment. This “test-then-blood” workflow aims to bring higher diagnostic precision to everyday clinics, aligning with international guidance that endorses confirming cognitive impairment before pursuing biomarker confirmation of AD pathology.
What BioCog brings to frontline care
BioCog is a tablet-based test battery designed for rapid, self-directed use. It combines a ten-word memory task (immediate recall, delayed recall, and recognition), a processing-speed measure, and orientation items to assess current cognitive status. In secondary-care data, a six-variable model (BioCog6) emerged as the strongest predictor of objectively verified cognitive impairment, achieving an area under the curve (AUC) of 0.96 and 89% accuracy at a single cutoff. The model’s components—delayed recall, processing-speed accuracy, immediate recall, total time, age, and delayed recognition—captured subtle cognitive changes that brief paper-and-pencil tests can miss in rushed clinics.
Adding precision with a targeted blood biomarker panel
The second stage uses a plasma biomarker panel (PrecivityAD2) to calculate the Amyloid-Probability Score-2 (APS2) from biomarkers including Aβ42, Aβ40, p-tau217, and non-p-tau217. When used after BioCog-detected impairment, APS2 helped determine whether AD pathology is present in cognitively impaired patients, improving diagnostic certainty beyond traditional clinical evaluation alone. In primary-care settings, this approach yielded compelling performance: an accuracy of 85% with a positive predictive value (PPV) of 87% and a negative predictive value (NPV) of 83% using a single cutoff, and up to 90% accuracy with a two-cutoff scheme that created a modest intermediate zone for follow-up.
Why a two-cutoff approach matters
The two-cutoff strategy balances decisiveness with practicality. Acknowledging the realities of primary care—limited time and resources—the intermediate zone allows clinicians to defer non-urgent biomarker testing and referrals until a patient’s impairment is more clearly defined. This approach reduced false positives seen when blood tests are used in isolation and improved the positive predictive value for identifying true AD cases, especially when impairment is confirmed before biomarker testing.
Performance versus standard care
In an external primary-care cohort of 403 older adults (mean age around 77), the BioCog6-based workflow outperformed standard PCP assessments, which integrated cognitive testing and imaging but lacked routine biomarkers. The single-cutoff BioCog6 model achieved 85% accuracy with strong sensitivity (88%) and specificity (82%). With two cutoffs, accuracy rose to 90%. When BioCog was contrasted with conventional tools such as MMSE, MoCA, Mini-Cog, and other computerized batteries, BioCog consistently showed superior or comparable performance, even after adjusting for demographic factors. Importantly, the two-step pathway identified biomarker-verified clinical AD with about 90% accuracy, a level that reduces unnecessary biomarker testing among patients unlikely to have AD pathology.
Clinical implications and next steps
These findings support a pragmatic, scalable model that brings robust cognitive screening into routine practice before committing patients to invasive or costly biomarker testing. By confirming impairment prior to amyloid measurement, clinicians can better target patients for disease-modifying therapies, such as anti-amyloid approaches, while minimizing false positives that lead to unnecessary referrals and anxiety for patients and families.
However, investigators caution that BioCog should complement clinical judgment, not replace it. Validation across diverse languages, cultures, and longitudinal settings remains essential before widespread adoption. The study’s design and results align with evolving international recommendations and WHO guidance favoring structured pretest evaluation to optimize biomarker use.
Conclusion
The “test first, then blood” pathway demonstrated in Swedish and U.S. cohorts shows that a brief digital cognitive test, followed by a targeted blood biomarker panel, can markedly improve the accuracy of Alzheimer’s diagnosis in primary care. This approach promises earlier, more confident identification of patients who may benefit from disease-modifying therapies while reducing unnecessary testing and referrals in busy clinics.
