Journal Article

DZNE-2025-00781

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease.

Cash, D. M. ; Morgan, K. E. ; O'Connor, A. ; Veale, T. D. ; Malone, I. B. ; Poole, T. ; Benzinger, T. L. ; Gordon, B. A. ; Ibanez, L. ; Li, Y. ; Llibre-Guerra, J. J. ; McDade, E. ; Wang, G. ; Chhatwal, J. P. ; Day, G. S. ; Huey, E. ; Jucker, M.DZNE* ; Levin, J.DZNE* ; Niimi, Y. ; Noble, J. M. ; Roh, J. H. ; Sánchez-Valle, R. ; Schofield, P. R. ; Bateman, R. J. ; Frost, C. ; Fox, N. C. ; Network, D. I. A. (Collaboration Author)

2025
Springer International Publishing Cham

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Please use a persistent id in citations: doi:10.1016/j.tjpad.2025.100133

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

Keyword(s): Humans (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Alzheimer Disease: diagnosis (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Amyloid beta-Peptides: cerebrospinal fluid (MeSH) ; Sample Size (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; Male (MeSH) ; Female (MeSH) ; Clinical Trials as Topic (MeSH) ; Outcome Assessment, Health Care (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Positron-Emission Tomography (MeSH) ; Brain: pathology (MeSH) ; Brain: diagnostic imaging (MeSH) ; Middle Aged (MeSH) ; Alzheimer's disease ; Autosomal dominant ; CSF ; Clinical trials ; Linear mixed effects models ; Longitudinal ; MRI ; PET ; Sample size ; ß-amyloid ; Biomarkers ; Amyloid beta-Peptides ; tau Proteins

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Contributing Institute(s):

1. Cell Biology of Neurological Diseases (AG Jucker)
2. Clinical Research (Munich) (Clinical Research (Munich))
3. Clinical Neurodegeneration (AG Levin)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Springer ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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