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A review of evidence supporting amyloid beta reduction as a surrogate endpoint in Alzheimer’s disease

Chen, Tianle ; Hutchison, R. Matthew ; Rubel, Carrie ; Murphy, Jennifer ; Xie, Jing ; O’Gorman, John ; Dent, Gersham ; Molenberghs, Geert ; Sormani, Maria Pia and Hendrix, Suzanne , et al. (2026) In Journal of Prevention of Alzheimer's Disease 13(2).
Abstract

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient’s clinical status,... (More)

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient’s clinical status, and its use can provide ethical, logistical, and economic advantages. Establishing biomarkers as surrogate endpoints involves evaluating scientific evidence through diverse statistical approaches to demonstrate their predictivity of clinical benefit. This article evaluated evidence supporting amyloid β plaque reduction as a surrogate endpoint in symptomatic AD by exploring regulatory considerations and guidelines for surrogate endpoints, examining the amyloid hypothesis and the current therapeutic landscape in AD, and presenting supporting evidence of surrogate endpoints from a recent clinical development program of AD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Amyloid β, Biomarker, Positron emission tomography, Surrogate endpoint
in
Journal of Prevention of Alzheimer's Disease
volume
13
issue
2
article number
100458
publisher
Elsevier Masson SAS
external identifiers
  • pmid:41478826
  • scopus:105026388633
ISSN
2274-5807
DOI
10.1016/j.tjpad.2025.100458
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s).
id
fe71a78a-638e-488e-b3e0-8b58b6c8f823
date added to LUP
2026-03-23 11:44:02
date last changed
2026-04-06 12:06:32
@article{fe71a78a-638e-488e-b3e0-8b58b6c8f823,
  abstract     = {{<p>Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient’s clinical status, and its use can provide ethical, logistical, and economic advantages. Establishing biomarkers as surrogate endpoints involves evaluating scientific evidence through diverse statistical approaches to demonstrate their predictivity of clinical benefit. This article evaluated evidence supporting amyloid β plaque reduction as a surrogate endpoint in symptomatic AD by exploring regulatory considerations and guidelines for surrogate endpoints, examining the amyloid hypothesis and the current therapeutic landscape in AD, and presenting supporting evidence of surrogate endpoints from a recent clinical development program of AD.</p>}},
  author       = {{Chen, Tianle and Hutchison, R. Matthew and Rubel, Carrie and Murphy, Jennifer and Xie, Jing and O’Gorman, John and Dent, Gersham and Molenberghs, Geert and Sormani, Maria Pia and Hendrix, Suzanne and Hansson, Oskar and Aisen, Paul and Haeberlein, Samantha Budd and Tian, Ying}},
  issn         = {{2274-5807}},
  keywords     = {{Alzheimer’s disease; Amyloid β; Biomarker; Positron emission tomography; Surrogate endpoint}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{Journal of Prevention of Alzheimer's Disease}},
  title        = {{A review of evidence supporting amyloid beta reduction as a surrogate endpoint in Alzheimer’s disease}},
  url          = {{http://dx.doi.org/10.1016/j.tjpad.2025.100458}},
  doi          = {{10.1016/j.tjpad.2025.100458}},
  volume       = {{13}},
  year         = {{2026}},
}