{"doi":"10.1111/jnp.12413","title":"Time to align sensitive cognitive assessment with protein biomarkers in Alzheimer's disease","abstract":"In the last decade, Alzheimer's disease research has seen large shifts, particularly regarding diagnostic criteria and the use of protein biomarkers. The Alzheimer's Association (AA) workgroup has recently revised their previous 2018 research criteria (Jack Jr et al., 2018) for diagnosis and staging of Alzheimer's disease to now inform both research and clinical care (Jack Jr et al., 2024a), maintaining a biological definition that primarily relies upon protein biomarkers, such as amyloid and tau levels, to identify the disease even in the absence of cognitive symptoms (e.g. memory and language impairment). In counter-response, the International Working Group (IWG) advocates for an integrative clinical-biological approach, emphasizing that the diagnosis of Alzheimer's disease should not rely solely on protein biomarkers but must also incorporate phenotypic expression such as objective cognitive impairment (Dubois et al., 2021, 2024). The debate over a biological versus clinical-biological definition of Alzheimer's disease has been ongoing for years but was reignited earlier this year after the release of the revised AA criteria (Jack Jr et al., 2024a). Petersen et al. (Petersen et al., 2024). presented a well-balanced comparison of the overlapping standpoints and differences between the AA and IWG frameworks. Proponents of the biological-only approach have argued that focusing on protein biomarkers, such as amyloid and tau, allows for earlier detection of the disease, providing a window for intervention during the preclinical stage before a significant cognitive decline occurs (Jack Jr et al., 2024b). Jack Jr et al (Jack Jr et al., 2024a) highlight that protein biomarkers offer a more standardized and objectively replicable framework, reducing the variability seen in clinical assessments alone. Critics of the biological framework point out significant limitations and risks. Many researchers caution that a protein biomarker-only approach may lead to overdiagnosis, unnecessary anxiety and stigma for individuals who may never clinically express the underlying disease pathology (Petersen et al., 2024). This perspective reflects concerns about the potential psychological, social and ethical ramifications of labelling asymptomatic individuals as having Alzheimer's disease based purely on protein-biomarker positivity, given the variability in symptom progression and the influence of factors such as cognitive reserve (Glymour et al., 2018; Kiselica et al., 2024). While a positive protein biomarker test may justify a diagnosis of a disease, the debate raises the question of whether this diagnosis should be ‘Alzheimer's disease’, the same label traditionally associated with progressive cognitive decline and underlying neuropathology. Using the same term for asymptomatic individuals with abnormal protein biomarkers and symptomatic patients creates both conceptual and practical dilemmas. The AA framework argues that it seeks to ensure scientific accuracy by distinguishing Alzheimer's pathology from Alzheimer's clinical symptoms. However, this goal could still be achieved when using a different label that indicates protein biomarker-positivity as a distinct disease that is a risk factor for dementia (Villain & Planche, 2024). Effective communication requires precise terminology, in which there is little room for lexical ambiguity when discussing a disease that affects millions of people worldwide, including patients, caregivers, clinicians, researchers and industry professionals. Instead, establishing distinct terminology for protein biomarker-positive, asymptomatic individuals would emphasize the presence of Alzheimer's disease-related pathology without implying the presence of clinical disease—as also proposed by the IWG (Dubois et al., 2024). Changing the traditional concept of Alzheimer's disease, rather than adopting a distinct term for asymptomatic individuals with abnormal protein biomarkers, also sidelines the critical role of cogn","journal":"Journal of Neuropsychology","year":2025,"id":538533,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":373276,"name":"Jet M. J. Vonk","orcid":"0000-0002-1808-8843","position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":null,"created_at":"2026-07-19T02:52:21.389196Z","pmid":"39829197","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}