Beyond Single Biomarkers: Toward Integrated Staging in Alzheimer’s Disease

The era of single biomarkers is over: integrated clinical–biological staging is now essential to capture heterogeneity and guide treatment in Alzheimer’s disease (AD). Attention is currently being directed to the mismatch between biological staging and clinical presentations, and to the insights such discrepancies provide for prognosis, therapeutic responsiveness, and individualized care. In this issue of the Journal of Clinical Neurology, Lee and colleagues apply an integrated staging framework that combines tau positron emission tomography (PET)-based biological staging with cognitive performance as quantified using a standardized residual called the W score.¹ Patients were categorized into concordant (W₀), worse-than-expected (W_–), and better-than-expected (W₊) groups. Notably, W₋ patients showed faster cognitive decline, greater risk of clinical progression, higher prevalence of α-synuclein pathology detected using the cerebrospinal fluid (CSF)-based seed amplification assay (SAA), and widespread [18F]-fluorodeoxyglucose (FDG) PET hypometabolism. In contrast, W₊ patients exhibited relative preservation—or even enhancement—of metabolism in prefrontal, parietal, and temporal regions. Although the study only included a small subset of autopsy-confirmed patients, its findings demonstrate that clinical–biological divergence reflects both the burden of copathologies and the presence of compensatory mechanisms, yielding clinically actionable framework for understanding heterogeneity in AD.

These insights are consistent with the evolving therapeutic landscape. While anti-amyloid monoclonal antibodies such as lecanemab and donanemab have been demonstrated to slow disease progression in early AD, treatment responses vary considerably. A consistent finding across trials is that individuals with lower baseline tau burden demonstrate greater therapeutic benefit.²,³ The W-score–based classification introduced by Lee et al.¹ provides an important framework that captures heterogeneity not explained by tau alone, by identifying individuals whose clinical course is either worse or better than predicted for a given tau burden. The study further underscores the decisive influence of copathologies. Lewy-body pathology as identified using the CSF-based α-synuclein SAA was most common in the W_– group and linked to accelerated decline and occipital hypometabolism. The benefit of antiamyloid monotherapy may be reduced for such patients, underscoring the need for multimodal strategies and realistic expectations. More broadly, copathologies highlight the role of resilience and compensation—reflected in the W₊ group’s preserved function—in shaping prognoses. Importantly, ongoing debates over diagnostic boundaries, such as distinguishing AD with parkinsonism from dementia with Lewy bodies, remind us that heterogeneity arises not only from biomarkers or outcomes but also from the definitions themselves.⁴,⁵

Another important factor to consider is that system-level factors determine how such staging frameworks can be implemented in practice. Although the use of FDG PET is decreasing, the W-score framework underscores its renewed value in capturing clinical—biological mismatches. Amyloid PET in South Korea is relatively inexpensive and widely accessible, enabling its integration into routine practice. The advent of disease-modifying drugs has made amyloid PET central to patient selection and risk prediction, as supported by the national expert consensus.⁶ This example illustrates how healthcare systems strongly influence biomarker adoption and treatment pathways: affordable amyloid PET results in its rapid integration into care, whereas its use in settings with higher costs or reduced reimbursement remains restricted to specialized centers. It is therefore clear that system-level factors can either enable or hinder the broader application of integrated staging.

Together the above-described considerations indicate that the W₋/W₀/W₊ framework represents more than a conceptual refinement—it provides a clinically applicable paradigm for patient stratification and therapeutic decision-making. W₊ patients, who are characterized by preserved or compensatory brain metabolism, may derive greater benefit from time-limited antiamyloid regimens guided by biomarker clearance or treatment responses. In contrast, W₋ patients often exhibit copathologies, for whom multimodal diagnostic workup and intensive nonpharmacological interventions should be prioritized alongside pharmacotherapy.

Challenges remain. Tau PET—the foundation of this framework—remains costly, restricted to specialized centers, and in some countries (including South Korea) is not yet approved for routine clinical use. The autopsy-confirmed sample was small, and W scores as currently defined reflect cross-sectional assessments. Longitudinal validation will be needed to capture the dynamics of clinical–biological divergence, and multicenter replication across diverse populations will be essential before broad adoption. Nonetheless, the overarching implication is clear: maximizing therapeutic benefits and addressing the realities of mixed pathologies require the field to move beyond unidimensional paradigms toward integrated staging. The W₋/W₀/W₊ shared clinical framework provides a valuable tool for recognizing heterogeneity, estimating disease trajectories, and providing patients with the most-appropriate therapeutic combinations at the optimal times.

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.