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. 2024 Nov 22;16(4):e70031.
doi: 10.1002/dad2.70031. eCollection 2024 Oct-Dec.

Aβ status assessment in a hypothetical scenario prior to treatment with disease-modifying therapies: Evidence from 10-year real-world experience at university memory clinics

Matthias Brendel  1   2   3 , Tandis Parvizi  1   4   5 , Johannes Gnörich  1 , Christof Elias Topfstedt  6 , Katharina Buerger  2   6 , Daniel Janowitz  6 , Boris-Stephan Rauchmann  7 , Robert Perneczky  2   3   5   8   9 , Carolin Kurz  7 , Dirk Mehrens  10 , Wolfgang G Kunz  10 , Julia Kusche-Palenga  1 , Agnes Bernadette Kling  1 , Antonia Buchal  10 , Elizabet Nestorova  7 , Sara Silvaieh  4   5 , Raphael Wurm  4   5 , Tatjana Traub-Weidinger  11   12 , Sigrid Klotz  5   13 , Günther Regelsberger  5   13 , Axel Rominger  14 , Alexander Drzezga  15   16   17 , Johannes Levin  2   3   18 , Elisabeth Stögmann  4   5 , Nicolai Franzmeier  3   6   19 , Günter U Höglinger  2   3   18
Affiliations

Aβ status assessment in a hypothetical scenario prior to treatment with disease-modifying therapies: Evidence from 10-year real-world experience at university memory clinics

Matthias Brendel et al. Alzheimers Dement (Amst). .

Abstract

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.

Keywords: Alzheimer's disease; biomarkers; cerebrospinal fluid; dementia; positron emission tomography; real world.

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Conflict of interest statement

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.

Figures

FIGURE 1
FIGURE 1
Data‐driven cutoff for the CSF Aβ42/40 ratio regarding Aβ PET positivity and evaluation of a two‐cutoff approach in the German (LMU) and Austrian (MUV) cohort. ROC curves were constructed to determine the optimal cutoff for the CSF Aβ42/40 ratio in predicting Aβ PET positivity in the CSF Aβ42/40 negative cohort (> 5.5%, A) and positive cohort (≤ 5.5%, B). These data‐driven thresholds were further used to implement two cutoffs, which categorized patients as at low, intermediate, and high risk of harboring a positive Aβ PET scan (C). AUC, area under the curve; Aβ, amyloid beta; CSF, cerebrospinal fluid; LMU, Ludwig Maximilian University; MUV, Medical University of Vienna; PET, positron emission tomography; ROC, receiver operating characteristic
FIGURE 2
FIGURE 2
Discrepancies of cerebral Aβ status based on PET and CSF results in both cohorts at different cutoffs as well as proportions of Aβ PET positive and negative findings in the proposed borderline range of CSF Aβ42/40. Findings are displayed in both whole cohorts and subsets of early symptomatic patients. Frequencies of each group are illustrated in each bar (marked with X). Aβ, amyloid beta; CSF, cerebrospinal fluid; LMU, Ludwig Maximilian University; MCI, mild cognitive impairment; mD, mild dementia; MUV, Medical University of Vienna; PET, positron emission tomography
See this image and copyright information in PMC

References

    1. Frisoni GB, Festari C, Massa F, et al. European intersocietal recommendations for the biomarker‐based diagnosis of neurocognitive disorders. Lancet Neurol. 2024;23(3):302‐312. - PubMed
    1. Doecke JD, Ward L, Burnham SC, et al. Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid‐PET imaging. Alzheimers Res Ther. 2020;12(1):36. - PMC - PubMed
    1. Palmqvist S, Zetterberg H, Blennow K, et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β‐Amyloid 42: a cross‐validation study against amyloid positron emission tomography. JAMA Neurol. 2014;71(10):1282‐1289. - PubMed
    1. Palmqvist S, Zetterberg H, Mattsson N, et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. 2015;85(14):1240‐1249. - PMC - PubMed
    1. Mattsson N, Insel PS, Landau S, et al. Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease. Ann Clin Transl Neurol. 2014;1(8):534‐543. - PMC - PubMed

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