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Introduction: With the advent of disease-modifying therapies, accurate assessment of biomarkers indicating the presence of disease-associated amyloid beta (Aβ) pathology becomes crucial in patients with clinically suspected Alzheimer's disease (AD). We evaluated Aβ levels in cerebrospinal fluid (Aβ CSF) and Aβ levels in positron emission tomography (Aβ PET) biomarkers in a real-world memory-clinic setting to develop an efficient algorithm for clinical use., Methods: Patients were evaluated for AD-related Aβ pathology from two independent cohorts (Ludwig Maximilian University [LMU], n  = 402, and Medical University of Vienna [MUV], n  = 144). Optimal thresholds of CSF biomarkers were deduced from receiver operating characteristic curves and validated against Aβ PET positivity., Results: In both cohorts, a CSF Aβ42/40 ratio ≥ 7.1% was associated with a low risk of a positive Aβ PET scan (negative predictive value: 94.3%). Implementing two cutoffs revealed 14% to 16% of patients with intermediate results (CSF Aβ42/40 ratio: 5.5%-7.1%), which had a strong benefit from Aβ PET imaging (44%-52% Aβ PET positivity)., Discussion: A two-cutoff approach for CSF Aβ42/40 including Aβ PET imaging at intermediate results provides an effective assessment of Aβ pathology in real-world settings., Highlights: We evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid beta (Aβ) biomarkers for Alzheimer's disease in real-world cohorts.A CSF Aβ 42/40 ratio between 5.5% and 7.1% defines patients at borderline levels.Patients at borderline levels strongly benefit from additional Aβ PET imaging.Two-cutoff CSF Aβ 42/40 and PET will allow effective treatment stratification., Competing Interests: A.D. reports research support by Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA, Ariceum Therapeutics as well as speaker honorary/advisory boards by Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital, Lilly; stock by Siemens Healthineers, Lantheus Holding, Structured therapeutics, Lilly; and a patent for 18F‐JK‐PSMA‐ 7 (Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021). E.S. has received grants from Roche, Eisai, FFG/AAL, Horizon2020, and the Austrian Alzheimer Association (all to the institution); consulting fees from Biogen, Eisai, and Lilly; support for attending meetings and/or travel from Roche; and has received payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events by Biogen, Roche, Eisai, and Novartis. E.S. has participated on advisory boards (Biogen, Roche, Eisai, Sanofi) and held leadership or a fiduciary role in scientific societies (Austrian Alzheimer Association, the EAN scientific panel dementia). J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Esteve, Zambon, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is an inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4‐Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH, and is an inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. M.B. is a member of the Neuroimaging Committee of the EANM. M.B. received speaker honoraria from Roche, GE Healthcare, and Life Molecular Imaging and served as an advisor of MIAC and Life Molecular Imaging. N.F. has received speaker honoraria from Eisai, GE Healthcare, Life Molecular Imaging, and Consulting Honoraria from MSD. R.P. has received honoraria for advisory boards and speaker engagements from Roche, EISAI, Eli Lilly, Biogen, Janssen‐Cilag, Astra Zeneca, Schwabe, Grifols, Novo Nordisk, and Tabuk. W.G.K. reports consulting fees from BMS, Boehringer Ingelheim, Need Inc., mintMedical, and FalkFoundation (unrelated to the paper). All other authors declare no competing interests. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)