Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease - 02/07/25

Doi : 10.1016/j.tjpad.2025.100133

David M Cash ^a,^b,^⁎,^{^{1
Joint first authors}} , Katy E Morgan ^c,^{^{1
Joint first authors}}, Antoinette O'Connor ^a, Thomas D Veale ^a, Ian B Malone ^a, Teresa Poole ^c, Tammie LS Benzinger ^d, Brian A Gordon ^d,^e, Laura Ibanez ^f,^g, Yan Li ^f, Jorge J. Llibre-Guerra ^f, Eric McDade ^f, Guoqiao Wang ^f, Jasmeer P Chhatwal ^h, Gregory S Day ⁱ, Edward Huey ^j, Mathias Jucker ^k,^l, Johannes Levin ^m,^n,^o, Yoshiki Niimi ^p, James M Noble ^q, Jee Hoon Roh ^r, Racquel Sánchez-Valle ^s, Peter R Schofield ^t,^u, Randall J Bateman ^e,^f,^v, Chris Frost ^c,^{^{2
Joint senior authors}}, Nick C Fox ^a,^b,^{^{2
Joint senior authors}}
The Dominantly Inherited Alzheimer Network (DIAN)
^a Dementia Research Centre, UCL Queen Square Institute of Neurology, First floor, 8-11 Queen Square, London, WC1N 3AR, UK
^b UK Dementia Research Institute, 6th Floor, Maple House, Tottenham Court Road, London W1T 7NF, UK
^c London School of Hygiene and Tropical Medicine, Keppel Street London, WC1E 7HT, UK
^d Department of Radiology. Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 USA
^e Knight Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park Ave., Suite 200, St. Louis, MO 63108 USA
^f Department of Neurology, Washington University in St Louis, 660 S. Euclid Ave., St. Louis, MO 63110 USA
^g Department of Psychiarty, Washington University in St Louis, 660 S. Euclid Ave., St. Louis, MO 63110 USA
^h Brigham and Women's Hospital, Massachusetts General Hospital; Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
ⁱ Department of Neurology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224, USA
^j Alpert Medical School of Brown University, Department of Psychiatry and Human Behavior, 222 Richmond St., Providence, RI 02903, USA
^k Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Strasse 27, 72076 Tübingen, Germany
^l German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 23, 72076 Tübingen, Germany
^m Department of Neurology, LMU University Hospital, Marchioninistr. 15 D-81377, Munich, Germany
ⁿ German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany
^o Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany
^p Unit for early and exploratory clinical development, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
^q Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, GH Sergievksy Center, Columbia University, 710W 168th St #3, New York, NY 10032, USA
^r Departments of Neurology and Physiology, Korea University Anam Hospital, Korea University College of Medicine, 73 goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic Of Korea
^s Alzheimer's disease and other cognitive disorders group. Hospital Clínic de Barcelona. FRCB-IDIBAPS. University of Barcelona, Carrer de Villarroel, 170, L'Eixample, 08036 Barcelona, Spain
^t Neuroscience Research Australia, Margarete Ainsworth Building Barker Street, Randwick NSW 2031 Australia
^u School of Biomedical Sciences, University of New South Wales, UNSW Sydney, NSW 2052 Australia
^v Hope Center for Neurological Disorders, Washington University in St Louis, 4370 Duncan Ave., St. Louis, MO 63110, USA

^⁎Corresponding author: David M Cash, Box 16, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG United Kingdom.National Hospital for Neurology and Neurosurgery, Queen SquareBox 16LondonWC1N 3BGUnited Kingdom

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Highlights

•	Sample sizes were estimated for trials in presymptomatic autosomal dominant AD.
•	Both point estimates of sample sizes and measures of uncertainty were computed.
•	Detecting a 25 % reduction in amyloid PET after 4 years needs 40–70 carriers per arm.
•	250–900 carriers per arm would be needed to detect 50 % slowing in neurodegeneration.
•	Sample sizes are reduced across outcomes when mildly impaired carriers are included.

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Abstract

Introduction

Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

Methods

Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).

Results

Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).

Discussion

Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.

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Keywords : Alzheimer's disease, Clinical trials, Autosomal dominant, Longitudinal, Sample size, MRI, PET, CSF, ß-amyloid, Linear mixed effects models

Plan

Cerebrospinal fluid analysis

Choosing a target therapeutic effect

Study design and statistical methods

Results

Discussion

Sample sizes to detect a slowing in the rate of neurodegeneration

Sample sizes to detect a reduction of the outcome at the end of the study

Uncertainty in sample size estimates

Conclusion

Declaration of generative AI and AI-assisted technologies in the writing process

CRediT authorship contribution statement

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Vol 12 - N° 6

Article 100133- juin 2025 Retour au numéro

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Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease - 02/07/25

Highlights

Abstract

Introduction

Methods

Results

Discussion

Plan

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