The Role of Biomarkers in Alzheimer's Disease Drug Development

Abstract

Biomarkers have a key role in Alzheimer's disease (AD) drug development. Biomarkers can assist in diagnosis, demonstrate target engagement, support disease modification, and monitor for safety. The amyloid (A), tau (T), neurodegeneration (N) Research Framework emphasizes brain imaging and CSF measures relevant to disease diagnosis and staging and can be applied to drug development and clinical trials. Demonstration of target engagement in Phase 2 is critical before advancing a treatment candidate to Phase 3. Trials with biomarker outcomes are shorter and smaller than those required to show clinical benefit and are important to understanding the biological impact of an agent and inform go/no-go decisions. Companion diagnostics are required for safe and effective use of treatments and may emerge in AD drug development programs. Complementary biomarkers inform the use of therapies but are not mandatory for use. Biomarkers promise to de-risk AD drug development, attract sponsors to AD research, and accelerate getting new drugs to those with or at risk for AD.

Keywords: Alzheimer’s disease; Amyloid; Biomarker; Clinical trials; Drug development; Neurodegeneration; Positron-emission tomography; Tau.

Fig. 2.1

Normal (left) and abnormal (right) amyloid PET

Fig. 2.2

Low tau (above) and high tau (below) PET aligned with MRI (images courtesy of Dawn Matthews)

Fig. 2.3

Early AD (left) and late AD (right) MRI. The scan on the right shows whole brain atrophy and ventricular enlargement (images courtesy of Karthik Sreenivasan)

Fig. 2.4

Normal (left) and abnormal (right) fluorodeoxyglucose PET scans

Fig. 2.5

Prevalence of amyloid PET positivity by age (data from Jansen et al. [30])

Fig. 2.6

Pharmacodynamic biomarkers. Tau (T) and amyloid (A) biomarkers function as target engagement biomarkers showing that an agent affects the brain protein; N biomarkers support disease modification if a drug-placebo difference is demonstrated

Fig. 2.7

Relationship of ATN (amyloid, tau, neurodegeneration) pathology to circuits that underlie human cognition and emotion is comprised in AD

Fig. 2.8

Area of difference in default mode network (DMN) activation on functional MRI (fMRI) between cognitively normal amyloid-negative older adults and amyloid-positive individuals with mild cognitive impairment (MCI) from the AD Neuroimaging Initiative (ADNI) (figure courtesy of Zhengshi Yang)

Fig. 2.9

The amyloid (A), tau (T), and neurodegeneration (N) framework of AD with consensus and emerging biomarkers (figure courtesy of Mike de la Flor)