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The assay is scalable and non-invasive, yet it relies on a ratio of two markers that are unstable and only partly specific to the disease, raising concerns about reproducibility and interpretation. The reported performance is solid in carefully selected groups, but is likely to be less robust in broader real-world populations with lower disease prevalence, mixed pathologies, and higher comorbidity. If biomarker-based enrollment is shaped by imperfect specificity, misclassification may propagate into trial recruitment, treatment-effect estimates, and downstream validation. This concern is amplified when biomarkers are validated within partially circular frameworks in which plasma assays, positron emission tomography, cerebrospinal fluid markers, and clinical diagnosis reinforce one another without fully independent neuropathological confirmation. Blood-based assays remain promising, but their clinical use should be guided by rigorous analytical scrutiny, broad validation across diverse populations, standardized pre-analytical handling, and transparent data sharing. The aim of biomarker science should be not striking receiver operating characteristic curves in curated cohorts, but biological fidelity across human heterogeneity and validation grounded in mechanism. Until then, the p-tau217\/A\u03b2\n                    <jats:sub>1\u221242<\/jats:sub>\n                    ratio is best regarded as a useful contextual or research tool rather than a standalone diagnostic benchmark, so that precision medicine does not rest on associations whose causal and mechanistic basis remains insufficiently established.\u00a0Its most appropriate use may be in longitudinal monitoring within the same individual, where changes over time may be more informative than a single threshold-based diagnostic result.\n                  <\/jats:p>","DOI":"10.1007\/s00109-026-02676-8","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:49:08Z","timestamp":1778546948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular and statistical weaknesses of the p-tau217\/A\u03b21\u221242 plasma ratio for alzheimer\u2019s diagnosis"],"prefix":"10.1007","volume":"104","author":[{"given":"Christian Gri\u00f1\u00e1n","family":"Ferr\u00e9","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merc\u00e8","family":"Pall\u00e0s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2549-4919","authenticated-orcid":false,"given":"Rafael","family":"Franco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"2676_CR1","doi-asserted-by":"publisher","unstructured":"Bucci M, Almkvist O, Bluma M et al (2025) Profiling Plasma Biomarkers, Particularly pTau217 and pTau217\/A\u03b242, and Their Relation to Cognition in Memory Clinic Patients. 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