Blood-based biomarkers for Alzheimer's disease

Abstract

Neurodegenerative disorders such as Alzheimer's disease (AD) represent a mounting public health challenge. As these diseases are difficult to diagnose clinically, biomarkers of underlying pathophysiology are playing an ever-increasing role in research, clinical trials, and in the clinical work-up of patients. Though cerebrospinal fluid (CSF) and positron emission tomography (PET)-based measures are available, their use is not widespread due to limitations, including high costs and perceived invasiveness. As a result of rapid advances in the development of ultra-sensitive assays, the levels of pathological brain- and AD-related proteins can now be measured in blood, with recent work showing promising results. Plasma P-tau appears to be the best candidate marker during symptomatic AD (i.e., prodromal AD and AD dementia) and preclinical AD when combined with Aβ42/Aβ40. Though not AD-specific, blood NfL appears promising for the detection of neurodegeneration and could potentially be used to detect the effects of disease-modifying therapies. This review provides an overview of the progress achieved thus far using AD blood-based biomarkers, highlighting key areas of application and unmet challenges.

Keywords: Alzheimer; Aβ; P-tau; biomarkers; blood.

Figure 1. A schematic overview of the included P‐tau assays

Schematic illustration of full‐length tau‐441, including N‐terminal, proline‐rich region, microtubuli binding domain, and C‐terminal. Anti‐tau antibodies are indicated for each of the five included P‐tau assays under the respective epitope region. P‐tau181_UGOT is the P‐tau181 assay from the University of Gothenburg, as detailed in Karikari et al (2021). For P‐tau231_ADx, the inverted V symbol represents a biotin‐conjugated N‐terminal anti‐tau mouse monoclonal antibody, as detailed in Ashton et al (2021c).

Figure 2. Most promising plasma‐based biomarkers across the clinical continuum of AD

In this figure, cognitive function is represented on the y‐axis (top to bottom, unimpaired to dementia), with clinical disease stage shown on the x‐axis (preclinical AD, MCI due to AD [prodromal AD], and AD dementia). The dashed line represents the typical clinical trajectory from preclinical AD through prodromal and dementia stages. In each stage, the most promising plasma biomarker or plasma biomarker combination is indicated. For example, in preclinical AD, plasma P‐tau217 in combination with either plasma Aβ42/Aβ40 or GFAP is likely to prove best, while in prodromal AD plasma P‐tau217 in combination with simple to administer cognitive tests is likely best. In the AD dementia stage, plasma P‐tau217 alone is sufficient.