New Frontline Approach to Alzheimer’s Diagnosis in Primary Care
A two-step strategy combining a brief, self-administered digital cognitive test with a targeted blood biomarker panel dramatically improves the accuracy of Alzheimer’s disease (AD) diagnosis in everyday clinics. The approach, validated in a recent Nature Medicine study, shows that confirming cognitive impairment before ordering amyloid blood tests reduces false positives, streamlines referrals, and brings a more reliable diagnostic pathway closer to primary care.
The two-step workflow: BioCog first, then biomarkers
Researchers evaluated BioCog, a tablet-based, self-administered cognitive battery, across multiple cohorts in Sweden and the United States. The BioCog test covers immediate and delayed memory tasks, processing speed, and orientation to time, providing a robust assessment of objective cognitive impairment. In secondary care, a six-variable model (BioCog6) achieved an area under the curve (AUC) of 0.96 and 89% accuracy for detecting impairment at a single cutoff. A two-cutoff scheme introduced an intermediate zone that required follow-up, balancing certainty with workflow practicality.
External validation in a primary-care setting (n=403) showed BioCog6 achieved an AUC of 0.93 and 85% accuracy. When the two-cutoff approach was applied, accuracy rose to 90%, with a positive predictive value (PPV) of 91% and a negative predictive value (NPV) of 89%, albeit with an intermediate group representing about 18% of patients. BioCog outperformed standard bedside tools such as the MMSE, MoCA, Mini-Cog, and other cognitive batteries, both in one-cutoff analyses and, where data were available, two-cutoff analyses.
Incorporating blood biomarkers to confirm AD pathology
The second step involves a plasma biomarker panel (APS2) that measures amyloid-beta ratios (Aβ42/Aβ40) and phospho-tau (p-tau217 and non-p-tau217). When used after BioCog-confirmed impairment, the two-step workflow could identify biomarker-verified clinical AD with about 90% accuracy. In this setup, only patients who screen positive for cognitive impairment proceed to biomarker testing, reducing unnecessary testing and focusing resources on those most likely to have AD pathology.
Why this matters for patients and clinicians
Early and accurate diagnosis of AD is crucial as disease-modifying therapies target amyloid pathways and require careful patient selection. Traditional brief cognitive screens can miss subtle impairment in busy clinics, leading to delayed diagnoses or unnecessary referrals. By confirming impairment first, clinicians can improve predictive value and reduce false positives that may lead to inappropriate treatments or anxiety for patients and families.
The study found that primary care pathways using BioCog plus APS2 were superior to standard PCP evaluations relying on clinical judgment and imaging alone. Even when Demographics were adjusted, the BioCog-first strategy consistently outperformed conventional approaches. The two-step method aligns with international guidance calling for efficient, scalable frontline workflows that balance accuracy with feasibility in real-world settings.
Limitations and the path forward
While the BioCog-APS2 approach is promising, researchers caution that further validation in diverse languages and cultures, as well as longitudinal studies, are needed before widespread adoption. The authors emphasize that digital testing should complement clinical judgment, not replace it. Additionally, ensuring accessibility and maintaining user-friendly administration across varied primary care environments will be essential for broad implementation.
Practical implications for clinics
For clinics, the two-step workflow offers a scalable pathway to more accurate diagnoses and more efficient use of specialist referrals. The self-administered nature of BioCog reduces personnel time and standardizes testing, while the selective biomarker testing preserves resources. As evidence grows, this model could become a practical standard of care, helping bring earlier, more confident Alzheimer’s diagnoses into routine clinical practice.
