Two-step workflow could reshape Alzheimer’s detection in primary care
A recent study published in Nature Medicine proposes a practical, scalable approach to diagnosing Alzheimer’s disease (AD) in everyday clinics: first confirm cognitive impairment with a brief digital tool, then use a targeted blood biomarker panel to verify amyloid pathology. This “test then blood” strategy aims to reduce false positives, streamline referrals, and move accurate diagnoses closer to patients’ primary care offices.
Why a two-step approach matters
Alzheimer’s disease is the leading cause of dementia, driven by amyloid deposition, tau pathology, and neurodegeneration. While advanced tests like amyloid PET scans or cerebrospinal fluid analysis can confirm pathology, they are costly, invasive, or not readily available in many settings. Traditional brief cognitive assessments (eg, MMSE or MoCA) can miss early impairment in busy clinics, leading to under- or over-referral for specialist testing.
The study emphasizes a sequence: establish objective cognitive impairment before ordering biomarker tests. This pre-test filter helps improve the positive predictive value of biomarker results, ensures that only patients with verified impairment proceed to biomarker testing, and reduces unnecessary follow-ups.
The BioCog digital test and the role of biomarkers
Researchers developed BioCog, a tablet-based, self-administered cognitive battery. It assesses a short list of cognitive domains, including immediate and delayed memory, processing speed, and orientation. The primary-care workflow integrates BioCog first, followed by a plasma biomarker panel (APS2) that analyzes Aβ42, Aβ40, p-tau217, and non-p-tau217 to infer amyloid status.
BioCog’s data-informed thresholds were selected to balance sensitivity and specificity. In a secondary-care cohort, a six-variable BioCog model demonstrated superb discrimination for cognitive impairment. When applied in external primary care settings, the BioCog-first approach outperformed standard clinician assessments in accuracy and predictive values, even after adjusting for age and other demographics.
Key study findings
In a diverse primary-care sample (n≈403), the BioCog6 model achieved an AUC of about 0.93 and accuracy around 85% with a single cutoff. A two-cutoff scheme created an intermediate zone, guiding additional evaluation for roughly 18% of patients. Importantly, the BioCog-first pathway followed by APS2 biomarker testing yielded a high overall accuracy and strong predictive values for identifying biomarker-verified clinical AD, surpassing physician assessment alone and blood testing without prior cognitive filtering.
Specifically, the two-step workflow achieved about 90% accuracy in identifying AD pathology when impairment was first confirmed, with a believable balance of sensitivity (84%) and specificity (92%). Compared with standard PCP evaluations, the two-step method reduced false positives and unnecessary referrals, which is critical in the era of Aβ-targeting therapies that require careful patient selection.
Clinical implications and practical considerations
The two-step model aligns with international guidance that favors confirming cognitive impairment before pursuing biomarker confirmation. It offers several practical benefits for primary care:
- Standardized, digitized cognitive assessment reduces variability in frontline testing.
- Efficient triage of patients who actually bear biomarker-predictive risk, preserving specialist resources for those most likely to benefit.
- Potential acceleration of access to disease-modifying therapies for eligible patients with accurate, early diagnosis.
Still, clinicians are cautioned that digital tests should augment, not replace, clinical judgment. Validation across languages, cultures, and longitudinal follow-up remains essential to confirm durability and generalizability of the approach.
Conclusion: bringing reliable Alzheimer’s diagnosis to the clinic floor
Ultimately, the study suggests that a brief, self-administered digital cognitive battery, used as a front-end filter, can improve the precision of subsequent blood biomarker testing for Alzheimer’s disease in primary care. The two-step “test-then-blood” pathway promises to cut false positives, streamline referrals, and move accurate diagnosis closer to everyday clinics—an important step toward timely, patient-centered care in a rapidly aging population.
