Clinical meaningfulness of biomarker endpoints in Alzheimer’s disease research

Abstract

Advancement in biomarker research has enabled the in vivo detection of Alzheimer’s disease (AD) pathophysiology, including amyloid plaques, neurofibrillary tangles, and neuronal degeneration. AD biomarkers play an important role in characterizing the trajectory of AD and have been incorporated in the research criteria for AD diagnosis. The presence of abnormal biomarkers for AD pathology in cognitively normal individuals has further led to the proposal of a preclinical stage in the AD spectrum. With the emerging conceptual framework that intervention in the early stages of the disease offers the greatest chance of success in preventing or delaying AD progression, recent clinical trials are now focusing on individuals with preclinical AD. While there are clear benefits from the use of biomarkers in research settings such as the enrichment of clinical trial population to confirm the presence of target brain pathology and target engagement by the intervention, the role of biomarkers in the clinical setting is less clear, especially in asymptomatic individuals. Potential ethical issues also arise with the use of biomarkers due to the conflict between the principles of benefits and not doing harm. In fact, a unique set of ethical issues arises in asymptomatic individuals, such as the disclosure of genetic mutation status, and abnormal biomarker results when their diagnostic validity is uncertain. In this chapter, we will discuss the issues and clinical meaningfulness of biomarkers in AD research. Specifically, we will focus on the potential benefits and ethical considerations when genetics and biomarkers for amyloid, tau, and neurodegeneration are used in the early stages of AD.