The Biomarker Profile of Alzheimer's Disease for Disease-Modifying Treatment Eligibility: Questions and Debates

Abstract

Alzheimer's disease (AD) is the most common cause of cognitive decline; currently, anti-amyloid monoclonal antibodies are available for clinical use as disease-modifying treatments, while many other substances are being tested in clinical trials. Molecular biomarkers for AD have been studied for more than two decades, and various guidelines and diagnostic recommendations have been published. However, there are still questions and controversies about the biomarker profile needed to confirm AD and the eligibility for such established treatments and clinical trials. Is amyloid positivity sufficient for eligibility, or is a biomarker for tau biochemistry/pathology also needed? What is the role of hybrid ratios combining amyloid and tau? Should we rely on plasma biomarkers alone? This review aimed to describe and discuss such questions and controversies.

Keywords: Alzheimer’s disease; amyloid beta; biomarkers; disease modifying treatments; donanemab; lecanemab; phospho-tau protein; tau protein.

Figure 1

Theoretical diagram of biomarker changes during Alzheimer’s disease evolution and progression [41,43,103,144,145,146,147,148]. The changes in biomarkers follow the smooth increase in color intensity throughout the course of AD. The red arrow shows the period that is the target of monoclonal antibodies’ clinical trials. Deviations may occur in some patients based on genetic or other factors, as well as the biomarker tests used. Cerebrospinal fluid (CSF) T₁ refers to τ_P-181, τ_P-217, and τ_P-231. Plasma T₁ refers to τ_P-217, τ_P-181, and τ_P-212. CSF T₂ mainly refers to τ_P-205 and MDBR-τ₂₄₃. For simplicity reasons, neurodegeneration markers are shown together in one bar, although they are not equivalent and may become abnormal at relatively different time points.

Figure 2

Use of biomarkers for the confirmation of AD presence in 5 scenarios, starting from CSF analysis. N: normal; M: marginal. Green “O.K. symbols” indicate confirmation. Yellow “O.K. symbols” indicate the likely presence of AD. Question marks indicate the presence of amyloid pathology, but AD (additional occurrence of tau pathology) cannot be verified. In scenario (a), the typical CSF profile of AD is present (A⁺T⁺ or A⁺T₁⁺). In scenario (b), Aβ₄₂/Aβ₄₀ is normal, raising questions about the presence of amyloid pathology, despite the abnormality of both Aβ₄₂ and τ_P-181. In this case, a PET scan for Aβ or (if not available) the τ_P-181/Aβ₄₂ ratio is required to reach a conclusion. In scenario (c), the A⁺T⁻ profile is present with abnormality only in the Aβ₄₂/Aβ₄₀ ratio (or alternatively the amyloid PET). In this case, the τ_P-181/Aβ₄₂ ratio can be used, but if normal, a T₂ biomarker (if available) may be required. In scenario (d), the A⁻T⁻ (A⁻T₁⁻) profile is inconsistent with AD. In scenario (e), both molecular biomarkers are marginal. In such patients, the τ_P-181/Aβ₄₂ ratio and/or PET scans for Aβ and/or tau may be needed according to availability and cost.